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WO2021142237A1 - Procédés d'administration de lucitanib et de combinaisons de ce composé - Google Patents

Procédés d'administration de lucitanib et de combinaisons de ce composé Download PDF

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WO2021142237A1
WO2021142237A1 PCT/US2021/012672 US2021012672W WO2021142237A1 WO 2021142237 A1 WO2021142237 A1 WO 2021142237A1 US 2021012672 W US2021012672 W US 2021012672W WO 2021142237 A1 WO2021142237 A1 WO 2021142237A1
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Prior art keywords
lucitanib
cancer
therapeutic agent
weeks
treatment
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Teresa Cameron
Jin Xiao
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Clovis Oncology Inc
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Clovis Oncology Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present invention relates to methods for administering combination therapeutics and variable dosage regimens thereof for the treatment of cancer. More specifically, the invention relates to methods of treating a cancer patient comprising administering lucitanib according to a variable dosing regimen in combination with a second therapeutic agent administered simultaneously, separately or sequentially.
  • VEGF vascular endothelial growth factor
  • VEGF receptor inhibitors are a promising class for developing new therapeutics.
  • Lucitanib 6-((7-((l-aminocyclopropyl)methoxy)-6-methoxyquinolin-4- yl)oxy)-N-methyl-l-naphthamide, of the following chemical structure: is a powerful angiogenesis inhibitor and a potent inhibitor of the fibroblast growth factor receptors 1-3 (FGFR1-3), vascular endothelial growth factor receptors 1-3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFRa/b).
  • FGFR1-3 fibroblast growth factor receptors 1-3
  • VEGFR1-3 vascular endothelial growth factor receptors 1-3
  • PDGFRa/b platelet-derived growth factor receptors alpha and beta
  • One aspect of the present disclosure pertains to a method for treating a patient with a cancer comprising steps: a) administering to the patient a therapeutically effective amount of lucitanib and a second therapeutic agent, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; and c) if, during the initial treatment period, the patient exhibits i) systolic blood pressure less than or equal to 150 mm Hg; ii) diastolic blood pressure less than or equal to 90 mm Hg; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent; and iv) no treatment-related adverse events greater than Grade 2; then increasing a daily dose of lucitanib by 1 mg to 4 mg in a subsequent treatment period; wherein the lucitanib and the second therapeutic agent treat the cancer in the patient.
  • Another aspect of the present disclosure pertains to a method for treating a patient with a cancer comprising steps: a) administering to the patient a therapeutically effective amount of lucitanib and nivolumab, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; and c) if, during the initial treatment period, the patient exhibits i) systolic blood pressure less than or equal to 150 mm Hg; ii) diastolic blood pressure less than or equal to 90 mm Hg; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent; and iv) no treatment-related adverse events greater than Grade 2; then increasing a daily dose of lucitanib by 1 mg to 4 mg in a subsequent treatment period; wherein the lucitanib and the nivolumab treat
  • Another aspect of the present disclosure pertains to lucitanib and a second therapeutic agent for use in a treatment of a cancer, the use comprising: a) administering to the patient a therapeutically effective amount of lucitanib and a second therapeutic agent, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; and c) if, during the initial treatment period, the patient exhibits i) systolic blood pressure less than or equal to 150 mm Hg; ii) diastolic blood pressure less than or equal to 90 mm Hg; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent; and iv) no treatment-related adverse events greater than Grade 2; then increasing a daily dose of lucitanib by 1 mg to 4 mg in a subsequent treatment period; wherein the lucitanib and
  • Figure 1 depicts the responses to treatment in a Phase lb study as described in
  • Example 1 based on tumor type and number of days on treatment.
  • CR complete response
  • NE not evaluable
  • PD progressive disease
  • PR partial response
  • SD stable disease. *Received continued treatment beyond progression.
  • Figure 2A depicts the plasma concentration-time profile of lucitanib on cycle 1 day 15 at a 6 mg dose.
  • Each solid line represents an individual patient.
  • dashed lines represent simulated median and 90% prediction interval of simulated lucitanib PK at steady state on 500 subjects receiving 6-mg dose using a population PK model developed based on previous monotherapy data.
  • PK pharmacokinetics
  • QD once daily.
  • Figure 2B depicts the plasma concentration-time profile of lucitanib on cycle 1 day 15 at an 8 mg dose. Each solid line represents an individual patient. In the dark gray shaded area, dashed lines represent simulated median and 90% prediction interval of simulated lucitanib PK at steady state on 500 subjects receiving 8-mg dose using a population PK model developed based on previous monotherapy data.
  • Figure 2C depicts the plasma concentration-time profile of lucitanib on cycle 1 day 15 at a 10 mg dose.
  • Each solid line represents an individual patient.
  • dashed lines represent simulated median and 90% prediction interval of simulated lucitanib PK at steady state on 500 subjects receiving 10-mg dose using a population PK model developed based on previous monotherapy data.
  • the dosing regimen is variable such that doses of lucitanib are increased, reduced, administered more frequently, or administered less frequently depending on physiological factors, including, but not limited to, blood pressure.
  • the dose variation may increase patient compliance, increase efficacy, improve therapy, and reduce unwanted and/or adverse effects.
  • administering lucitanib in combination with a second therapeutic agent according to the variable dosage regimens of the disclosure provides an improved overall therapy relative to the administration of each one of lucitanib and a second therapeutic agent by themselves.
  • administrating lucitanib in combination with a second therapeutic agent enhances efficacy of either or both of the agents when used alone to treat cancer.
  • lucitanib and a second therapeutic agent administered as disclosed herein act synergistically to treat cancer.
  • lucitanib is administered in combination with a second therapeutic agent according to a variable dosage regimen such that increasing one or more subsequent doses of lucitanib in subsequent treatment cycles increases the efficacy of lucitanib and/or the second therapeutic agent relative to monotherapy of one or both of the active agents.
  • methods of treatment of cancer including administering lucitanib in combination with a second therapeutic agent according to the variable dosage regimens of the disclosure can provide an improved overall therapy whereby some patients are able to receive a higher dose of lucitanib relative to other patients, while controlling adverse effects, thereby advantageously increasing efficacy.
  • methods of treatment of cancer including administering lucitanib in combination with a second therapeutic agent according to the variable dosage regimens of the disclosure can advantageously aid in the identification of patients who may be eligible to receive a higher dose of lucitanib relative to other patients, while controlling adverse effects.
  • administering lucitanib in combination with a second therapeutic agent according to the variable dosage regimens disclosed herein can make it possible to have fewer and/or less severe side-effects and/or adverse effects than treatment with either or both of the agents alone.
  • administering lucitanib according to the variable dosage regimen as disclosed herein may significantly reduce, or even completely eliminate treatment associated side effects and/or cardiovascular effects which may be associated with lucitanib therapy.
  • lucitanib and the second therapeutic agent such as nivolumab, can have different side effects when administered in monotherapy.
  • Administering one or more therapeutic agent(s) at a different or variable dose in combination, when compared to monotherapy may reduce the individual side effect profile while increasing therapeutic efficacy.
  • the second therapeutic agent is selected based on this profile.
  • doses of existing chemotherapeutic agents can be reduced or administered less frequently in using the combination therapies disclosed herein, thereby increasing patient compliance, improving therapy and reducing unwanted or adverse effects.
  • One embodiment is directed to combination therapies designed to treat or manage cancer in a subject, wherein the combination therapies comprise administering lucitanib in combination with a second therapeutic agent.
  • the combination therapies comprise administering lucitanib in combination with a second therapeutic agent.
  • methods of treating or managing cancer in a subject comprising administering lucitanib in combination with a therapeutically effective amount of a second therapeutic agent administered simultaneously, separately, or sequentially.
  • compositions comprising at least one pharmaceutically-acceptable carrier, in addition to one or more compounds described herein.
  • the compositions can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including without limitation tablets, capsules (solid or liquid filled), powders, granules, syrups and other liquids, elixirs, inhalants, troches, lozenges, and solutions. Injectable compositions or i.v. infusions are also provided in the form of solutions, suspensions, and emulsions.
  • One embodiment as disclosed herein provides a method for treating a patient with a cancer comprising steps: a) administering to the patient a therapeutically effective amount of lucitanib and a second therapeutic agent, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; and c) if, during the initial treatment period, the patient exhibits i) stable clinically acceptable systolic blood pressure; ii) stable clinically acceptable diastolic blood pressure; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent if the patient had preexisting clinically acceptable well-controlled blood pressure prior to the initial treatment period; and iv) only treatment-related adverse events less than or equal to Grade 2; then increasing a daily dose of lucitanib by 1 mg to 4 mg in a subsequent treatment period; wherein the lucitanib and
  • One aspect of the present disclosure pertains to a method for treating a patient with a cancer comprising steps: a) administering to the patient a therapeutically effective amount of lucitanib and a second therapeutic agent, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; and c) if, during the initial treatment period, the patient exhibits i) systolic blood pressure less than or equal to 150 mm Hg; ii) diastolic blood pressure less than or equal to 90 mm Hg; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent; and iv) no treatment-related adverse events greater than Grade 2; then increasing a daily dose of lucitanib by 1 mg to 4 mg in a subsequent treatment period; wherein the lucitanib and the second therapeutic agent treat the cancer in the patient.
  • One embodiment as disclosed herein provides a method for treating a patient with a cancer comprising steps: a) administering to a patient a therapeutically effective amount of lucitanib and a second therapeutic agent, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; and c) if, during the initial treatment period, the patient exhibits i) clinically acceptable systolic blood pressure; ii) clinically acceptable diastolic blood pressure; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent if the patient had preexisting clinically acceptable well-controlled blood pressure prior to the initial treatment period; and iv) no treatment-related adverse events greater than Grade 2; then increasing a daily dose of lucitanib by 1 mg to 4 mg in a subsequent treatment period; or d) if, during the initial treatment period,
  • One embodiment as disclosed herein provides a method for treating a patient with a cancer comprising: a) administering to the patient a therapeutically effective amount of lucitanib and a second therapeutic agent, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; and c) if, during the initial treatment period, the patient exhibits i) stable clinically acceptable systolic blood pressure less than or equal to 150 mmHg; ii) stable clinically acceptable diastolic blood pressure less than or equal to 90 mmHg; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent if the patient had preexisting clinically acceptable well-controlled blood pressure prior to the initial treatment period; and iv) only treatment-related adverse events less than or equal to Grade 2; then increasing a daily dose of lucitanib by 1 mg
  • the method includes the following step: repeating steps a)-c) until the patient fails to exhibit i)-iv) listed in step c) or until the daily dose of the lucitanib reaches 10 mg, or 11 mg, or 12 mg, or 13 mg, or 14 mg, or 15 mg, or 16 mg once daily administration.
  • One embodiment as disclosed herein provides a method for treating a patient with a cancer comprising: a) administering to the patient a therapeutically effective amount of lucitanib and a second therapeutic agent, wherein the lucitanib is administered once daily for an initial treatment period of one to six weeks; b) monitoring the patient’s blood pressure and assessing treatment-related adverse events over the initial treatment period; c) if, during the initial treatment period, the patient exhibits i) stable clinically acceptable systolic blood pressure less than or equal to 150 mmHg; ii) stable clinically acceptable diastolic blood pressure less than or equal to 90 mmHg; iii) no need for an antihypertensive agent or no need for an additional antihypertensive agent if the patient had preexisting clinically acceptable, well-controlled blood pressure prior to the initial treatment period; and iv) no treatment-related adverse events greater than Grade 2; then increasing a daily dose of lucitanib by 1 mg to 4 mg
  • the method includes the following step: repeating steps a)-c) until the patient exhibits the symptoms listed in step d) or until the daily dose of the lucitanib reaches 10 mg, or 11 mg, or 12 mg, or 13 mg, or 14 mg, or 15 mg, or 16 mg once daily administration.
  • stable clinically acceptable systolic blood pressure is less than or equal to 150 mm Hg.
  • stable clinically acceptable systolic blood pressure is less than or equal to 145 mm Hg.
  • stable clinically acceptable systolic blood pressure is less than or equal to 140 mm Hg.
  • stable clinically acceptable diastolic blood pressure is less than or equal to 90 mm Hg.
  • stable clinically acceptable diastolic blood pressure is less than or equal to 85 mm Hg.
  • stable clinically acceptable diastolic blood pressure is less than or equal to 80 mm Hg.
  • not clinically acceptable systolic blood pressure is greater than 150 mm Hg.
  • not clinically acceptable systolic blood pressure is greater than 145 mm Hg.
  • not clinically acceptable systolic blood pressure is greater than 140 mm Hg.
  • not clinically acceptable diastolic blood pressure is greater than 90 mm Hg.
  • not clinically acceptable diastolic blood pressure is greater than 85 mm Hg.
  • not clinically acceptable diastolic blood pressure is greater than 80 mm Hg.
  • the daily dose of lucitanib during the initial treatment period is 4-14mg.
  • the daily dose of lucitanib during the initial treatment period is 4 mg, or 5 mg, or 6 mg, or 7 mg, or 8 mg, or 9 mg, or 10 mg, or 11 mg, or 12 mg, or 13 mg, or 14 mg.
  • the second therapeutic agent is a PD-1/PD-L1 checkpoint inhibitor, a polyADP-ribose polymerase inhibitor, a Selective Effector Cell Activator, a CTLA-4 inhibitor, or a chemotherapeutic agent.
  • the method comprises administering lucitanib and a PD
  • the PD-1/PD-L1 checkpoint inhibitor is nivolumab.
  • the PD-1/PD-L1 checkpoint inhibitor is atezolizumab.
  • the initial treatment period is one week, or two weeks, or three weeks, or four weeks, or five weeks, or six weeks.
  • the daily dose of lucitanib is increased by 1 mg, or 2 mg, or 3 mg, or 4 mg in a subsequent treatment period.
  • the daily dose of lucitanib is reduced by 1 mg, or 2 mg, or
  • the method comprises administering lucitanib and a polyADP-ribose polymerase inhibitor.
  • the polyADP-ribose polymerase inhibitor is rucaparib.
  • the treatment-related side effects comprise one or more of: treatment-related adverse events; proteinuria greater than 1+ or urinary protein > 1.0 g/24 hours; greater than Grade 1 treatment-related diarrhea; or a treatment-related requirement to use one or more antihypertensive agents.
  • the cancer is a solid cancer.
  • the solid cancer is an advanced, recurrent, or metastatic gynecological solid tumor.
  • the method comprises administering lucitanib and a
  • the Selective Effector Cell Activator is ALKS4230.
  • the method comprises administering lucitanib and a
  • the CTLA-4 inhibitor is ipilimumab.
  • the method comprises administering lucitanib and a chemotherapeutic agent.
  • the chemotherapeutic agent is paclitaxel.
  • the solid cancer is cervical cancer.
  • the solid cancer is ovarian cancer. [0065] In one embodiment, the solid cancer is ovarian clear-cell carcinoma.
  • the solid cancer is epithelial ovarian carcinoma.
  • the solid cancer is clear cell cancer.
  • the solid cancer is endometrial cancer.
  • the solid cancer is clear cell endometrial cancer.
  • the solid cancer is non-small cell lung cancer.
  • the solid cancer is triple-negative breast cancer.
  • the solid cancer is gastrointestinal cancer, colorectal cancer, or prostate cancer.
  • the lucitanib is administered orally.
  • the lucitanib is administered by tablet or capsule.
  • the lucitanib is administered by tablet.
  • the second therapeutic agent is administered intravenously.
  • the second therapeutic agent is administered orally.
  • the second therapeutic agent is a PARP inhibitor. In one embodiment, the second therapeutic agent is rucaparib (RUBRACA ® ).
  • the lucitanib and the second therapeutic agent is administered with one or more additional therapeutic agents.
  • treating the cancer is selected from the group consisting of reducing tumor size, increasing overall survival, increasing progression free survival, complete response, partial response, stable disease, decrease in associated symptoms, failure of tumors to reoccur after treatment has stopped and combinations thereof.
  • Any therapeutic agent disclosed herein can be used for the methods, kits, compositions, and/or combination therapy of the disclosure.
  • Lucitanib is suitable for administration as part of a combination therapy with a second therapeutic agent.
  • the lucitanib and second therapeutic agent are initially administered simultaneously.
  • the lucitanib and second therapeutic agent are separate from each other, e.g., each is formulated into separate therapeutic compositions, and the lucitanib and second therapeutic agent are administered simultaneously.
  • the lucitanib and second therapeutic agent are administered at different times or frequencies during the treatment regimen.
  • the lucitanib is administered prior to or concurrently with the administration of the second therapeutic agent, e.g., to treat cancer. In an embodiment, the lucitanib is administered subsequent to the administration of the second therapeutic agent, e.g., to treat cancer. In an embodiment, lucitanib and the second therapeutic agent are administered in an alternating fashion. As described herein, the lucitanib and the second therapeutic agent are each administered in single doses or in multiple doses.
  • the combinations described herein are used for treating cancer or a cell proliferative disorder in a subject in need thereof.
  • the second therapeutic agent is absent.
  • the lucitanib dosing regimen is suitable for lucitanib monotherapy.
  • pharmacokinetic profiles C max , T max , and AUC are defined as follows:
  • AUC extra represents an extrapolated value obtained by C t /lz, where C t is the observed concentration at time t at or above LOQ, and lz is the estimated apparent terminal rate constant; and C min is minimum or “trough” plasma concentration (C mm ) of a drug observed after its administration and just prior to the administration of a subsequent dose.
  • an “adverse event” can be considered as any untoward medical occurrence in a patient or subject who has been administered a therapeutic agent or combination of therapeutic agents and which does not necessarily have a causal relationship with treatment.
  • adverse events are listed in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- CTCAE). In some instances, adverse events take into account a baseline physical exam to be completed either at treatment Day 0 or Day -5 prior to initiating treatment. Baseline measurements involve pre-existing conditions that are ongoing pre-treatment and during treatment which includes but is not limited to diabetes and hypertension and concomitant medications taken prior to treatment.
  • adverse events encompass “adverse reactions” which refers to an adverse event for which there is a reasonable possibility that the treatment caused the adverse event.
  • Reasonable possibility means there is evidence to suggest a causal relationship between the treatment and adverse event.
  • Adverse events are classified, measured and evaluated as serious or non-serious; expected or unexpected; and study -related, possibly study-related, or not study-related and graded generally as follows:
  • lucitanib-specific adverse event may refer to one or more of: hypertension, proteinuria, thrombotic microangiopathy, treatment-related increased lipase, increased blood uric acid, depressed level of consciousness, asthenia hypothyroidism, diarrhea, anorexia, weight loss, thrombocytopenia, nausea, decreases in LVEF, and ECG QTC prolongations.
  • treatment-related requirement to use one or more antihypertensive agents may refer to a need to use an antihypertensive agent after starting lucitanib administration or the need to use an additional antihypertensive agent where an antihypertensive agent was used by a patient prior to lucitanib administration to maintain clinically acceptable blood pressure.
  • Grade 2 includes Grade 2 treatment-related adverse events, Grade 1 treatment-related adverse events, and a lack of treatment-related adverse events.
  • “no treatment-related adverse events greater than Grade 2” includes Grade 2 treatment-related adverse events, Grade 1 treatment-related adverse events, and a lack of treatment-related adverse events.
  • “normotension” is used when both office and out-of-office blood pressure (BP) measurements are normal (or optimal); “hypertension” or “elevated blood pressure”: is used when one or both office and out-of-office blood pressure measurements are higher than normal (or optimal).
  • Masked uncontrolled hypertension MUCH: in which the office BP is controlled but home or ambulatory BP is elevated.
  • White coat uncontrolled hypertension (WUCH) the office BP is elevated but home or ambulatory BP is controlled.
  • Sustained uncontrolled hypertension (SUCH) both office and home or ambulatory BP are uncontrolled.
  • Blood pressure can be generally classified and graded wherein “systolic blood pressure” (SBP) and “diastolic blood pressure” (DBP) are:
  • stable refers to measurements that are reproducible.
  • stable blood pressure does not include momentarily elevated or depressed blood pressure from events such as running or sleeping.
  • stable blood pressure is maintained for one or more hours, one or more days, one or more weeks, or one or more treatment cycles (i.e., treatment periods).
  • stable clinically acceptable blood pressure refers to blood pressure measurements that are reproducible within a range over a period of time, preferably a monitoring period, and does not pose a significant risk to a patient or does not pose the risk of a cardiovascular event.
  • stable clinically acceptable blood pressure refers to a patient exhibiting blood pressure equal to or less than a pre-defmed number.
  • stable clinically acceptable blood pressure includes systolic blood pressure less than or equal to 150 mm Hg.
  • stable clinically acceptable blood pressure includes diastolic blood pressure less than or equal to 90 mm Hg.
  • preexisting refers to an issue or condition that was present before a certain commencement of treatment or before an act is to occur. In some contexts, “preexisting” refers to prior to the initial treatment of lucitanib or prior to one or more treatment cycles of lucitanib.
  • preexisting stable clinically acceptable refers to an issue or condition that was non fluctuating and present before the commencement of treatment or before an act is to occur.
  • preexisting stable clinically acceptable refers to hypertension that is managed to a level that does not pose a significant risk to the patient prior to the initial treatment of lucitanib.
  • proteinuria is a condition characterized by the presence of greater than normal amounts of protein in the urine. It is usually associated with some kind of disease or abnormality but may occasionally be seen in healthy individuals. Screening for protein in the urine may be performed as part of a general health exam or as part of a check up for an individual who is known to have a condition or be undergoing a treatment that may cause proteinuria. Some screening tests include: Urine protein - detects the presence of any type of protein that may be in the urine. It can be performed alone on a random urine sample or as part of a urinalysis. Urinalysis - an evaluation of a urine sample for several different substances that may be in the urine, including protein. Urine albumin (microalbumin) - a sensitive test that is used to monitor people for small amounts of albumin, the main blood protein, in the urine.
  • abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells.
  • Neoplasia as described herein, is an abnormal, unregulated and disorganized proliferation of cells that is distinguished from normal cells by autonomous growth and somatic mutations. As neoplastic cells grow and divide they pass on their genetic mutations and proliferative characteristics to progeny cells. A neoplasm, or tumor, is an accumulation of neoplastic cells. In some embodiments, the neoplasm can be benign or malignant.
  • Metastasis refers to the dissemination of tumor cells via lymphatics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance.
  • angiogenesis is prominent in tumor formation and metastasis. Angiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewing sarcoma, neuroblastoma, and osteosarcoma. A tumor cannot expand without a blood supply to provide nutrients and remove cellular wastes. Tumors in which angiogenesis is important include solid tumors such as renal cell carcinoma, hepatocellular carcinoma, and benign tumors such as acoustic neuroma, and neurofibroma. Angiogenesis has been associated with blood-bom tumors such as leukemias. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia. Prevention of angiogenesis could halt the growth of cancerous tumors and the resultant damage to the subject due to the presence of the tumor.
  • cell proliferative disorder refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous.
  • Exemplary cell proliferative disorders encompass a variety of conditions wherein cell division is deregulated.
  • Exemplary cell proliferative disorder includes, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells.
  • Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/
  • pineoblastoma and supratentorial primitive neuroectodermal tumors pineuitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewing family of sarcoma tumors, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestation
  • the cancer is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CALL), non-Hodgkin lymphoma (NHL), multiple myeloma, mantle cell lymphoma (MCL), diffuse large b-cell lymphoma (DLBCL), primary mediastinal b-cell lymphoma (PFBC), or transformed follicular lymphoma (TFF).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • CALL chronic lymphoblastic leukemia
  • NHL non-Hodgkin lymphoma
  • MCL mantle cell lymphoma
  • DLBCL diffuse large b-cell lymphoma
  • PFBC primary mediastinal b-cell lymphoma
  • TMF transformed follicular lymphoma
  • the cancer is mesothelioma, pancreatic cancer, glioma, neuroblastoma, ovarian cancer, glioblastoma, myelodysplastic syndromes (MDS), breast cancer, prostate cancer, colorectal cancer, skin cancer, oesophageal cancer, esophageal cancer, gastric cancer, astrocytic cancer, endometrial cancer, cervical cancer, bladder cancer, renal cancer, lung cancer, liver cancer, thyroid cancer, or head and neck cancer.
  • MDS myelodysplastic syndromes
  • the cancer is selected from the group consisting of cervical cancer, ovarian cancer, clear cell cancer, endometrial cancer, non-small cell lung cancer, breast cancer, triple-negative breast cancer, gastrointestinal cancer, colorectal cancer, prostate cancer, metastatic castration resistant prostate cancer, head and neck squamous cell cancer.
  • treat is meant to include alleviating or abrogating a disorder, disease, or condition; or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
  • the term “alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased.
  • a sign or symptom can be alleviated without being eliminated.
  • the administration of pharmaceutical compositions disclosed herein leads to the elimination of a sign or symptom, however, elimination is not required.
  • Effective dosages are expected to decrease the severity of a sign or symptom.
  • a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.
  • Treating cancer can include, for example, reduction in tumor size, increase in overall survival (OS), increase in progression free survival (PFS), complete response (CR), partial response (PR), stable disease (SD), decrease in associated symptoms, and/or failure of tumors to reoccur after treatment has stopped.
  • OS overall survival
  • PFS progression free survival
  • CR complete response
  • PR partial response
  • SD stable disease
  • a reduction in size of a tumor may also be referred to as “tumor regression”.
  • tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a combination of this disclosure comprising lucitanib and a second therapeutic agent.
  • a “pharmaceutical composition” or “therapeutic composition” is a formulation containing at least one active ingredient, such as lucitanib and/or another therapeutic agent, including the second therapeutic agent, in a form suitable for administration to a subject.
  • pharmaceutical compositions may be conveniently presented as one or more unit dose forms containing a predetermined amount of an active agent of each ingredient per dose. Alternatively, each active ingredient is formulated separately.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of dosage forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g . , a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is a particular amount and is varied according to the particular treatment involved.
  • One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • active ingredient or “therapeutic agent” as employed herein refers to an ingredient with a pharmacological effect, such as a therapeutic effect, at a relevant dose.
  • an active ingredient can be an anti-cancer agent which has a therapeutic effect in the treatment of cancer at a relevant dose.
  • a pharmaceutical composition may suitably comprise a therapeutically effective amount of the lucitanib and/or the second therapeutic agent.
  • therapeutically effective amount refers to an amount of a therapeutic agent needed to treat, ameliorate or prevent a targeted disease or condition, for example, cancer, or to exhibit a detectable therapeutic, pharmacological or preventative effect.
  • the therapeutically effective amount can be determined using various factors including, for example, measuring blood pressure or other diagnostic tests, including to detect side effects.
  • Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug interaction(s), reaction sensitivities, and tolerance/response to therapy.
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped.
  • the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • a “subject in need thereof’ or “patient” is a subject suffering from a cell proliferative disorder or having an increased risk of developing such disorder relative to the population at large.
  • a subject in need thereof can have a precancerous condition.
  • a “subject” or “patient” includes a mammal.
  • the mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or pig.
  • the mammal is a human.
  • a “proxy measure” is an indirect measure of the desired outcome which is itself strongly correlated to that outcome and is commonly necessary when direct measures of the outcome are unobservable, unavailable, or not readily available. Accordingly, in some embodiments, blood pressure measurements serve as a proxy measure for the lucitanib concentration in circulation. In some embodiments, an increase in blood pressure indicates that the therapeutically effective dosage of lucitanib has been reached. In some embodiments, the change in blood pressure at particular time points is a more accurate proxy measure of lucitanib circulation compared to blood pressure at particular time points. In other embodiments, the blood pressure at particular time points is a more accurate proxy measure of lucitanib circulation than the change in blood pressure at particular time points.
  • compositions or therapies disclosed herein may be administered individually to a patient or may be administered in combination (e.g. simultaneously or sequentially/separately).
  • the term “combination” or “combination therapy” is intended to embrace administration of two or more therapeutic agents disclosed herein in a sequential or simultaneous manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents concurrently, or in a substantially simultaneous manner.
  • Simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed or variable ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • one therapeutic agent of the combination may be administered by intravenous injection while the other therapeutic agent(s) of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered can vary. Therapeutic agents may also be administered in alternation.
  • the lucitanib and the second therapeutic agent are administered in temporal proximity. Accordingly, the present disclosure provides a method of treating or preventing cancer comprising administering lucitanib and the second therapeutic agent in temporal proximity.
  • the lucitanib and the second therapeutic agent can be initially administered simultaneously, followed by subsequent administration in temporal proximity.
  • “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the another therapeutic agent. In some embodiments, the therapeutic effect of the one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent.
  • “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the another therapeutic agent. “Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered.
  • “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within a week, within 2 weeks, within 3 weeks, within 4 weeks, with 6 weeks, or within 8 weeks.
  • multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent.
  • temporal proximity may change during a treatment cycle or within a dosing regimen.
  • the combinations and methods disclosed herein may further include treatments which are supplemented with one or more additional therapeutic agents or therapies, e.g., radiation therapy, surgery, or additional anti cancer agents or chemotherapy.
  • additional therapeutic agents or therapies e.g., radiation therapy, surgery, or additional anti cancer agents or chemotherapy.
  • Example of therapeutic agents that can be used either as the second therapeutic agent or as additional therapeutic agents to supplement the combinations and methods disclosed herein include, but are not limited to, alkylating/DNA-damaging agents (e.g. carboplatin, cisplatin), antimetabolites (e.g. capecitabine, gemcitabine, 5-fluorouracil), mitotic inhibitors (e.g.
  • alkylating/DNA-damaging agents e.g. carboplatin, cisplatin
  • antimetabolites e.g. capecitabine, gemcitabine, 5-fluorouracil
  • mitotic inhibitors e.g.
  • paclitaxel paclitaxel, vincristine
  • IL-2 sipuleucel-T
  • talimogene laherparepvec peginterferon alfa-2a
  • antibody ingredients for example epidermal growth factor receptor family (EGFR, HER-2), vascular endothelial growth factor receptors (VEGFR), platelet derived growth factor receptor (PDGFR) antibodies, such as nivolumab, ipilimumab, atezolizumab, elotuzumab, daratumumab, pembrolizumab, ramucirumab, brentuximab, brentuximab vedotin, ofatumumab, denosumab, and combinations thereof), or non-antibody ingredients, such as imatinib, dasatinib, nilotinib, bosutinib, gefitinib, erlotinib, temsirolimus, vande
  • the second therapeutic agent or additional therapeutic agent includes a polyADP-ribose polymerase (PARP) inhibitor, a PD-1/PD-L1 checkpoint inhibitor, a Selective Effector Cell Activator, a CTLA-4 inhibitor, or a chemotherapeutic agent.
  • chemotherapeutic agent refers to cytotoxic anti-cancer agents, including, but not limited to, alkylating/DNA-damaging agents (e.g. carboplatin, cisplatin), antimetabolites (e.g. capecitabine, gemcitabine, 5-fluorouracil), mitotic inhibitors (e.g. paclitaxel, vincristine), enzymes, topoisomerase inhibitors, retinoids, aziridines, and certain antibiotics. Many therapeutic agents disclosed herein may be classified within more than one of the groups of agents disclosed herein.
  • PARP inhibitors refer to a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).
  • PARP inhibitors include, but are not limited to, Olaparib (AZD-2281, LYNPARZA®), Rucaparib (PF- 01367338, RUBRACA®), Niraparib (MK-4827, ZEJULA® by Tesaro), Talazoparib (BMN- 673), Vebparib (ABT-888), CEP 9722, E7016 (developed by Eisai), BGB-2901, Iniparib (BSI 201), and 3-aminobezamide.
  • PD- 1 Programmed Cell Death- 1
  • the second therapeutic agent is a PD-1/PD-L1 checkpoint inhibitor.
  • PD-1 is a cell surface receptor that is a member of the CD28 family of T-cell regulators, within the immunoglobulin superfamily of receptors.
  • the human PD-1 gene is located at chromosome 2q37, and the full-length PD-1 cDNA encodes a protein with 288 amino acid residues with 60% homology to murine PD-1. It is present on CD4- CD8- (double negative) thymocytes during thymic development and is expressed upon activation in mature hematopoietic cells such as T and B cells, NKT cells and monocytes after prolonged antigen exposure.
  • binding of the ligand PD-L1 to PD-1 downregulates effector anti -tumor T-cell activity and facilitates immune evasion. This is supported by the finding of an association between PD-1/PD-L1 expression and poor prognosis in several tumor types including gastric, ovarian, lung and renal carcinomas. In melanoma, PD-1 has been reported to be predominantly expressed by tumor infiltrating T lymphocytes.
  • targeting PD-1 may act as an effective therapeutic strategy for cancer.
  • the principal method for targeting PD-1 clinically has been through the development of genetically engineered monoclonal antibodies that inhibit either PD-1 or PD-L1 function.
  • PD-L1 has also been shown to bind to B7-1 (CD80), an interaction that also suppresses T-cell proliferation and cytokine production; however, the exact relative contributions of the PD-L1: PD-1 and PD-L1: B7-1 pathways in cancer remain unclear.
  • the PD-1 -targeting agents currently in development inhibit both pathways. However, as the binding sites for PD-1 and B7-1 are adjacent but not overlapping, agents that specifically target one or the other may potentially be developed.
  • Cancer cells drive high expression levels of PD-L1 on their surface, allowing activation of the inhibitory PD-1 receptor on any T cells that infiltrate the tumor microenvironment, effectively switching those cells off.
  • upregulation of PD-L1 expression levels has been demonstrated in many different cancer types (e.g., melanoma [40%- 100%], NSCLC (non-small cell lung cancer) [35%-95%], and multiple myeloma [93%]), and high levels of PD-L1 expression have been linked to poor clinical outcomes.
  • tumor-infiltrating T cells have been shown to express significantly higher levels of PD-1 than T cells that infiltrate normal tissue.
  • the tumor microenvironment may secrete pro-inflammatory cytokines, including interferon-gamma (IFNy) to upregulate the expression of PD-1 on tumor-infiltrating T cells to ensure that they can respond to the high levels of PD- L1 expressed on the tumor.
  • pro-inflammatory cytokines including interferon-gamma (IFNy) to upregulate the expression of PD-1 on tumor-infiltrating T cells to ensure that they can respond to the high levels of PD- L1 expressed on the tumor.
  • IFNy interferon-gamma
  • PD-1 inhibitors and PD-L1 inhibitors refer to a group of checkpoint inhibitors or immune checkpoint inhibitors useful in the treatment of cancer.
  • PD1 and PD-L1 are both proteins present on the surface of cells.
  • PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand (PD-L1) with its receptor, programmed cell death protein 1 (PD-1).
  • Exemplary PD-1 and/or PD-L1 inhibitors include, but are not limited to Nivolumab (OPDIVO®), Pembrolizumab (MK-3475 or lambrolizumab, KEYTRUDA®), Atezolizumab (TECENTRIQ®), Avelumab (BAVENCIO®), Durvalumab (IMFINZI®), pidilizumab, AMP-224, AMP-514, PDR001, cemiplimab, BMS-936559, and CK-301.
  • Nivolumab OPDIVO®
  • Pembrolizumab MK-3475 or lambrolizumab, KEYTRUDA®
  • Atezolizumab TECENTRIQ®
  • Avelumab BAVENCIO®
  • Durvalumab IMFINZI®
  • Nivolumab (OPDIVO®, formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Pat. No. 8,008,449; Wang et ak, 2014 Cancer Immunol. Res. 2(9):846-56).
  • Atezolizumab or “MPDL3280A” refers a fully humanized, engineered monoclonal antibody of IgGl isotype against the protein programmed cell death ligand 1 (PD- Ll). In the customary sense, atezolizumab refers to CAS Registry number 1380723-44-3.
  • Cytotoxic T-lymphocyte-associated antigen 4 is a T cell surface molecule that was originally identified by differential screening of a murine cytolytic T cell cDNA library.
  • CTLA-4 is also a member of the immunoglobulin (Ig) superfamily; CTLA-4 comprises a single extracellular Ig domain.
  • CTLA-4 transcripts have been found in T cell populations having cytotoxic activity, suggesting that CTLA-4 might function in the cytolytic response.
  • Anti-CTLA-4 antibodies demonstrate an ability to increase the magnitude of protective immunity in a subject already immunized to protective antigens from a pathogen, e.g., cancer antigens or antigens from an infectious agent. Antibodies against CTLA-4 have been described for treating cancer.
  • CTLA-4 blocking CTLA-4 using antagonistic antibodies against CTLA such as ipilimumab (FDA approved for melanoma in 2011) and tremelimumab (not FDA approved) as a means of inhibiting immune system tolerance to tumors and thereby providing a potentially useful immunotherapy strategy for patients with cancer.
  • antagonistic antibodies against CTLA such as ipilimumab (FDA approved for melanoma in 2011) and tremelimumab (not FDA approved)
  • Ipilimumab (YERVOY®) is a fully human, IgGl monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligands, thereby stimulating T cell activation and improving overall survival (OS) in patients with advanced melanoma (Hodi et al. (2010) N. Engl. J. Med. 363:711-23).
  • the present disclosure provides a variable treatment regimen for lucitanib in combination with a second therapeutic agent.
  • the dose of lucitanib is varied according to blood pressure.
  • the dose of lucitanib is increased if elevated blood pressure is not present during a particular treatment period.
  • the dose of lucitanib is decreased if elevated blood pressure is present during a particular treatment period.
  • the dose of lucitanib is held constant if elevated blood pressure is not present during a particular treatment period.
  • the dose of lucitanib is held constant if elevated blood pressure is not present during a particular treatment period and lucitanib is administered at a subsequent time at an increased dose.
  • the dose of lucitanib is held constant if elevated blood pressure is present during a particular treatment period and lucitanib is administered at a subsequent time at a reduced dose.
  • the dose of lucitanib is increased if stable clinically acceptable blood pressure is present during a particular treatment period.
  • the dose of lucitanib is reduced if stable clinically acceptable blood pressure is not present during a particular treatment period.
  • the dose of lucitanib is held constant if stable clinically acceptable blood pressure is not present during a particular treatment period.
  • the dose of lucitanib is held constant if stable clinically acceptable blood pressure is present during a particular treatment period and lucitanib is administered at a subsequent time at an increased dose. In some embodiments, the dose of lucitanib is held constant if stable clinically acceptable blood pressure is not present during a particular treatment period and lucitanib is administered at a subsequent time at a reduced dose. In some embodiments, the dose of lucitanib is varied according to treatment related adverse events. In some embodiments, the dose of lucitanib is held constant according to treatment related adverse events. In some embodiments, the dose of lucitanib is held constant according to treatment related adverse events and lucitanib is administered at a subsequent time at an increased dose.
  • the dose of lucitanib is held constant according to treatment related adverse events and lucitanib is administered at a subsequent time at a reduced dose. In some embodiments, the dose of lucitanib is increased in a treatment period and lucitanib is administered at a subsequent time at a reduced dose. In some embodiments, the dose of lucitanib is reduced in a treatment period and lucitanib is administered at a subsequent time at an increased dose.
  • lucitanib is administered daily during a treatment cycle (i.e., treatment period). In some embodiments, lucitanib is administered on day 1 of the treatment cycle. In some embodiments, lucitanib is administered orally. In some embodiments, lucitanib is administered twice a day. In some embodiments, lucitanib is administered at a daily dose of 1 mg to 14 mg. In some embodiments, lucitanib is administered at a daily dose of 1 mg. In some embodiments, lucitanib is administered at a daily dose of 2 mg. In some embodiments, lucitanib is administered at a daily dose of 3 mg. In some embodiments, lucitanib is administered at a daily dose of 4 mg.
  • lucitanib is administered at a daily dose of 5 mg. In some embodiments, lucitanib is administered at a daily dose of 6 mg. In some embodiments, lucitanib is administered at a daily dose of 7 mg. In some embodiments, lucitanib is administered at a daily dose of 8 mg. In some embodiments, lucitanib is administered at a daily dose of 9 mg. In some embodiments, lucitanib is administered at a daily dose of 10 mg. In some embodiments, lucitanib is administered at a daily dose of 11 mg. In some embodiments, lucitanib is administered at a daily dose of 12 mg. In some embodiments, lucitanib is administered at a daily dose of 13 mg. In some embodiments, lucitanib is administered at a daily dose of 14 mg.
  • lucitanib is administered at a first starting dose during an initial treatment period. In some embodiments, lucitanib is administered at a second daily dose for a subsequent treatment period. In some embodiments, the daily dosage strength of lucitanib is held constant. In some embodiments, the daily dosage strength of lucitanib is held constant across treatment cycles (i.e., treatment periods). In some embodiments, the daily dosage strength of lucitanib is neither increased nor decreased. In some embodiments, the daily dosage strength of lucitanib is neither increased nor decreased after the initial treatment period. In some embodiments, the daily dosage strength of lucitanib is neither increased nor decreased after one or more treatment periods.
  • a treatment period is every 1 - 365 days. In some embodiments, the treatment period is every day, every other day, every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, every 16 weeks, every 17 weeks, every 18 weeks, every 19 weeks, or every 20 weeks, every month, every other month, every 3 months, every 6 months or about every year. As used herein, a “week” means seven consecutive days.
  • lucitanib is administered at a first starting dose during an initial treatment period. In some embodiments, lucitanib is administered at a first daily dose for less than one week. In some embodiments, lucitanib is administered at a first daily dose for one week. In some embodiments, lucitanib is administered at a first daily dose for two weeks. In some embodiments, lucitanib is administered at a first daily dose for three weeks. In some embodiments, lucitanib is administered at a first daily dose for four weeks. In some embodiments, lucitanib is administered at a first daily dose for five weeks. In some embodiments, lucitanib is administered at a first daily dose for six weeks.
  • lucitanib is administered at a first daily dose for 2-6 weeks. In some embodiments, lucitanib is administered at a first daily dose for 3-6 weeks. In some embodiments, lucitanib is administered at a first daily dose for 4-6 weeks. In some embodiments, lucitanib is administered at a first daily dose for 5-6 weeks.
  • lucitanib is administered daily as a first dosage strength during an initial treatment cycle (i.e., initial treatment period). In some embodiments, lucitanib is administered daily as a second dosage strength during a subsequent treatment cycle (i.e., subsequent treatment period). In some embodiments, the second dosage strength is greater than the first dosage strength. In other embodiments, the second dosage strength is less than the first dosage strength.
  • the lucitanib dosage after the initial treatment period is increased or decreased in one or more stepwise increments.
  • the increment is 1 mg to 4 mg. In some embodiments, the increment is 1 mg to 3 mg. In some embodiments, the increment is 1 mg to 2 mg. In some embodiments, the increment is 1 mg, or 2 mg, or 3 mg, or 4 mg. In some embodiments, the increment is 1 mg. In some embodiments, the increment is 2 mg. In some embodiments, the increment is 4 mg. In some embodiments, the dose is increased or decreased while monitoring blood pressure, treatment related side effects and/or adverse effects.
  • the lucitanib dosage is increased or decreased to a subsequent daily dose during a subsequent treatment period.
  • lucitanib is administered at a subsequent daily dose for less than one week.
  • lucitanib is administered at a subsequent daily dose for one week.
  • lucitanib is administered at a subsequent daily dose for two weeks.
  • lucitanib is administered at a subsequent daily dose for three weeks.
  • lucitanib is administered at a subsequent daily dose for four weeks.
  • lucitanib is administered at a subsequent daily dose for five weeks.
  • lucitanib is administered at a subsequent daily dose for six weeks.
  • lucitanib is administered at a subsequent daily dose for 2-6 weeks. In some embodiments, lucitanib is administered at a subsequent daily dose for 3-6 weeks. In some embodiments, lucitanib is administered at a subsequent daily dose for 4-6 weeks. In some embodiments, lucitanib is administered at a subsequent daily dose for 5-6 weeks.
  • the subsequent daily dose of lucitanib is 1 mg to 16 mg per day. In some embodiments, the subsequent daily dose of lucitanib is selected from the group consisting of 1 mg per day, 2 mg per day, 3 mg per day, 4 mg per day, 5 mg per day, 6 mg per day, 7 mg per day, 8 mg per day, 9 mg per day, 10 mg per day, 11 mg per day, 12 mg per day, 13 mg per day, 14 mg per day, 15 mg per day, 16 mg per day, or any amount therebetween.
  • the therapeutically effective amount of lucitanib is 1 mg to 16 mg per day. In some embodiments, the therapeutically effective amount of lucitanib is selected from the group consisting of 1 mg per day, 2 mg per day, 3 mg per day, 4 mg per day, 5 mg per day, 6 mg per day, 7 mg per day, 8 mg per day, 9 mg per day, 10 mg per day, 11 mg per day, 12 mg per day, 13 mg per day, 14 mg per day, 15 mg per day, 16 mg per day, or any amount therebetween.
  • the maximum dose of lucitanib is 10 mg to 16 mg per day. In some embodiments, the maximum dose of lucitanib is selected from the group consisting of 10 mg per day, 11 mg per day, 12 mg per day, 13 mg per day, 14 mg per day, 15 mg per day, 16 mg per day, or any amount therebetween. In preferred embodiments, the maximum dose of lucitanib is 14 mg per day. In one embodiment, the maximum dose of lucitanib is 15 mg per day. In a further embodiment, the maximum dose of lucitanib is 16 mg per day.
  • lucitanib is administered prior to the administration of the second therapeutic agent. In some embodiments, lucitanib is administered after the administration of the second therapeutic agent. In some embodiments, lucitanib is administered simultaneously with the administration of the second therapeutic agent. In some embodiments, lucitanib is initially administered simultaneously with the second therapeutic agent and then subsequent doses of the lucitanib and second therapeutic agent are administered at different frequencies.
  • the second therapeutic agent is administered at least every other day, every week, every 2 weeks, every 3 weeks, every 4 weeks or every month. In certain embodiments, the second therapeutic agent dose is administered every week or every 2 weeks. In certain embodiments, lucitanib and the second therapeutic agent are administered at the same frequency, either simultaneously or sequentially.
  • lucitanib and the second therapeutic agent are administered at the same frequency, but not simultaneously, e.g., every 1 or 2 weeks but the administration of each therapy is separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or at least 14 days.
  • the lucitanib and the second therapeutic agent are administered at different frequencies and each independently is administered every day, every other day, every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, every 16 weeks, every 17 weeks, every 18 weeks, every 19 weeks, or every 20 weeks, or every month.
  • the dosage of the PARP inhibitor is 300 mg to 1200 mg. In certain embodiments, the dosage of the PARP inhibitor is selected from the group consisting of 300 mg per day, 350 mg per day, 400 mg per day, 550 mg per day, 600 mg per day, 650 mg per day, 700 mg per day, 750 mg per day, 800 mg per day, 850 mg per day, 900 mg per day, 950 mg per day, 1000 mg per day, 1050 mg per day, 1100 mg per day, 1150 mg per day, 1200 mg, or any amount therebetween per day. In some preferred embodiments, the PARP inhibitor is rucaparib (RUBRACA ® ).
  • the unit dosage of the PARP inhibitor is 100 mg to 500 mg. In certain embodiments, the unit dosage of the PARP inhibitor is selected from the group consisting of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or any amount therebetween. In some preferred embodiments, the PARP inhibitor is rucaparib (RUBRACA®).
  • the dose of an anti -PD- 1 antibody is a fixed dose in a pharmaceutical composition.
  • the methods of the present disclosure can be used with a flat dose (a dose given to a patient irrespective of the body weight of the patient).
  • the flat dose of the anti -PD- 1 antibody or antigen binding portion thereof is at least 100 mg to 600 mg.
  • the flat dose of the anti -PD- 1 antibody or antigen binding portion thereof is at least 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 360 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 600 mg, or any amount therebetween.
  • a flat dose of anivolumab can be 240 mg.
  • a flat dose of a nivolumab can be 360 mg.
  • a flat dose of a nivolumab can be 480 mg.
  • a flat dose of pembrolizumab can be 200 mg.
  • the anti- PD-1 antibody or antigen-binding portion thereof is administered at a dose of 240 mg. In some embodiments, the anti -PD- 1 antibody or antigen-binding portion thereof is administered at a dose of 360 mg. In some embodiments, the anti -PD- 1 antibody or antigen-binding portion thereof is administered at a dose of 480 mg. In some embodiments, the flat dose of the anti- PD-1 antibody or antigen binding portion thereof is administered once every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks. In one embodiment, 360 mg of the anti -PD- 1 antibody or antigen binding fragment is administered once every 3 weeks. In a preferred embodiment, 480 mg of the anti-PD-1 antibody or antigen binding fragment is administered once every 4 weeks.
  • lucitanib is administered for less than one week, for one week, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks, with no adverse reactions, then the daily lucitanib dose may be increased.
  • lucitanib is administered for less than one week, for one week, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks, with no treatment related adverse-events greater than Grade 2, then the daily lucitanib dose may be increased.
  • lucitanib is administered for less than one week, for one week, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks and the patient is normotensive then the daily lucitanib dose may be increased.
  • the daily lucitanib dose may be increased if the patient’s systolic blood pressure is less than 140 mmHg then the daily lucitanib dose may be increased. In some embodiments, if the patient’s systolic blood pressure is less than 145 mmHg then the daily lucitanib dose may be increased. In some embodiments, if the patient’s systolic blood pressure is less than 150 mmHg then the daily lucitanib dose may be increased.
  • the daily lucitanib dose may be increased. In some embodiments, if the patient’s systolic blood pressure is greater than 150 mmHg then the daily lucitanib dose may be decreased.
  • the daily lucitanib dose may be increased if the patient’s diastolic blood pressure is less than 90 mmHg then the daily lucitanib dose may be increased. In some embodiments, if the patient’s diastolic blood pressure is less than 85 mmHg then the daily lucitanib dose may be increased. In some embodiments, if the patient’s systolic blood pressure is less than 80 mmHg then the daily lucitanib dose may be increased.
  • the daily lucitanib dose may be increased. In some embodiments, if the patient’s diastolic blood pressure is greater than 90 mmHg then the daily lucitanib dose may be decreased.
  • systolic blood pressure includes, for example, clinically acceptable systolic blood pressure and stable clinically acceptable systolic blood pressure.
  • diastolic blood pressure includes, for example, clinically acceptable diastolic blood pressure and stable clinically acceptable diastolic blood pressure.
  • the term “systolic blood pressure less than or equal to” a given number does not include momentarily elevated or depressed systolic blood pressure from events such as, for example, running or sleeping. In some embodiments, the term “diastolic blood pressure less than or equal to” a given number does not include momentarily elevated or depressed diastolic blood pressure from events such as, for example, running or sleeping. [00170] In some embodiments, if lucitanib is administered for less than one week, for one week, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks and the subject is normotensive, without receiving anti -hypertension medication, then the daily lucitanib dose may be increased.
  • a subject having preexisting hypertension that is controlled with an antihypertension medication is treated with lucitanib.
  • a subject has preexisting hypertension before beginning lucitanib treatment.
  • a subject has preexisting hypertension which is managed by one or more hypertensive agents before administration of lucitanib. If lucitanib is administered for less than one week, for one week, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks and the subject does not require any additional antihypertension medication to maintain control of the preexisting hypertension, then the daily lucitanib dose may be increased.
  • stable clinically acceptable systolic blood pressure is less than or equal to 150 mm Hg, less than or equal to 145 mm Hg, or less than or equal to 140 mmHg.
  • stable clinically acceptable diastolic blood pressure is less than or equal to less than or equal to 90 mm Hg, less than or equal to 85 mm Hg, or less than or equal to 80 mm Hg.
  • not stable clinically acceptable systolic blood pressure is greater than 150 mm Hg, greater than 145 mm Hg, greater than 140 mm Hg, greater than 135 mm Hg, greater than 130 mm Hg, or greater than 125 mm Hg.
  • not stable clinically acceptable diastolic blood pressure is greater than 90 mm Hg, greater than 85 mm Hg, or greater than 80 mm Hg.
  • stable clinically acceptable blood pressure has a variance of ⁇ l mmHg, ⁇ 2 mmHg, ⁇ 3 mmHg, ⁇ 4 mmHg, ⁇ 5 mmHg, ⁇ 6 mmHg, ⁇ 7 mmHg, ⁇ 8 mmHg, ⁇ 9 mmHg, ⁇ 10 mmHg, ⁇ 11 mmHg, ⁇ 12 mmHg, ⁇ 13 mmHg, ⁇ 14 mmHg, ⁇ 15 mm Hg, ⁇ 16 mmHg, ⁇ 17 mm Hg, ⁇ 18 mmHg, ⁇ 19 mmHg, or ⁇ 20 mmHg.
  • not stable clinically acceptable blood pressure has a variance of ⁇ 10 mmHg, ⁇ 11 mmHg, ⁇ 12 mmHg, ⁇ 13 mmHg, ⁇ 14 mmHg, ⁇ 15 mmHg, ⁇ 16 mmHg, ⁇ 17 mmHg, ⁇ 18 mmHg, ⁇ 19 mmHg, ⁇ 20 mmHg, ⁇ 21 mmHg, ⁇ 22 mmHg, ⁇ 23 mm Hg, ⁇ 24 mm Hg, ⁇ 25 mm Hg, ⁇ 26 mm Hg, ⁇ 27 mm Hg, ⁇ 28 mm Hg, ⁇ 29 mm Hg, ⁇ 30 mm Hg, ⁇ 31 mm Hg, ⁇ 32 mm Hg, ⁇ 33 mm Hg, ⁇ 34 mm Hg, ⁇ 35 mm Hg, ⁇ 36 mm Hg, ⁇ 37 mm Hg, ⁇ 38 mm Hg, ⁇
  • blood pressure is measured during a monitoring period.
  • a monitoring period is every 1-365 days.
  • a monitoring period is every 1-20 weeks.
  • the monitoring period is every day, every other day, every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, every 16 weeks, every 17 weeks, every 18 weeks, every 19 weeks, or every 20 weeks, every month, every other month, every 3 months, every 6 months or every year.
  • a patient exhibits systolic and diastolic blood pressure equal to or less than a given value during a monitoring period.
  • the patient exhibits stable clinically acceptable blood pressure during a monitoring period.
  • the daily lucitanib dose may be increased if the clinically acceptable blood pressure is stable. In some embodiments, if the clinically acceptable blood pressure is stable for one week, two weeks, three weeks, four weeks, one month, or one treatment cycle, then the daily lucitanib dose may be increased. In some embodiments, if the clinically acceptable blood pressure is stable for one week, then the daily lucitanib dose may be increased.
  • the daily lucitanib dose may be increased if the systolic blood pressure and/or stable clinically acceptable systolic blood pressure is less than or equal to 150 mm Hg for one week, two weeks, three weeks, four weeks, one month, or one treatment cycle. In some embodiments, if the systolic blood pressure and/or stable clinically acceptable systolic blood pressure is less than or equal to 150 mm Hg for one week, then the daily lucitanib dose may be increased if the systolic blood pressure and/or stable clinically acceptable systolic blood pressure is less than or equal to 150 mm Hg for one week, then the daily lucitanib dose may be increased.
  • the daily lucitanib dose may be increased if the diastolic blood pressure and/or stable clinically acceptable diastolic blood pressure is less than or equal to 90 mm Hg for one week, two weeks, three weeks, four weeks, one month, or one treatment cycle. In some embodiments, if the diastolic blood pressure and/or stable clinically acceptable diastolic blood pressure is less than or equal to 90 mm Hg for one week, then the daily lucitanib dose may be increased.
  • elevated systolic blood pressure is greater than 150 mm Hg, greater than 145 mm Hg, greater than 140 mm Hg, greater than 135 mm Hg, greater than 130 mm Hg, or greater than 125 mm Hg.
  • elevated diastolic blood pressure is greater than 90 mm Hg, greater than 85 mm Hg, greater than 80 mm Hg.
  • blood pressure is monitored during treatment.
  • blood pressure is monitored every week, every two weeks, every three weeks, every four weeks, every month, every two months, every three months, every four months, every five months, or every six months during lucitanib treatment.
  • blood pressure is monitored daily, twice per week, or three times per week.
  • blood pressure is measured by the patient.
  • blood pressure is monitored by a healthcare professional, such as a nurse or physician.
  • kits comprising lucitanib and a second therapeutic agent and methods of using such kits for therapeutic uses.
  • Kits typically include a label indicating the intended use of the contents of the kit and instructions for use.
  • the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • this disclosure provides a kit for treating a subject afflicted with a cancer, the kit comprising: lucitanib, a second therapeutic agent, and instructions for using the combination thereof in any method disclosed herein.
  • the kit contains the lucitanib and second therapeutic agent as separate compositions for use in any method disclosed herein.
  • the kit comprises a lucitanib dosage form and instructions for administration with a second therapeutic agent according to any methods disclosed herein.
  • Example 1 Treatment with Lucitanib According to Variable Dosage Strategy in Combination with Nivolumab
  • PK Pharmacokinetic
  • Phase lb is a dose-escalation to determine the RP2D of lucitanib in combination with nivolumab in patients with an advanced refractory or progressive solid tumor with no satisfactory treatment options.
  • Phase 2 evaluates the safety and efficacy of the RP2D combination of lucitanib and nivolumab in patients with an advanced gynecological solid tumor. The effect of food on oral lucitanib PK is investigated in an additional cohort of patients with an advanced, metastatic solid tumor.
  • Treatment cycles are 28 days in length. For both Phase lb and Phase 2, patients come into the study site for a visit on Day 1, Day 4, and Day 15 of Cycle 1; on Day 1 and Day 15 of Cycle 2; and on Day 1 of every cycle thereafter beginning with Cycle 3. All patients are monitored for safety throughout the treatment phase. In addition, patients are assessed for disease status by the investigator using RECIST vl.l every 8 weeks of treatment ( ⁇ 7 days) for the first 52 weeks following initiation of combination study treatment (Cycle 1, Day 1), then every 12 weeks ( ⁇ 7 days) until radiological disease progression as assessed by the investigator, death, loss to follow up, withdrawal from study, study termination, or initiation of subsequent anticancer treatments.
  • This phase is based on a 4+3 dose-escalation design, which is a modified version of a 3+3 dose-escalation design.
  • the dose-limiting toxicity (DLT) evaluation period is the first 28 days of treatment (i.e., Cycle 1).
  • dose-limiting toxicities that occur after Cycle 1 are collected and evaluated on an ongoing basis and considered in determination of the RP2D.
  • the initial combination dose consists of oral lucitanib 6 mg QD, administered continuously, and intravenous (IV) nivolumab 480 mg administered on Day 1 of every 28 day cycle.
  • the dose of lucitanib is escalated in 2 mg increments up to a maximum of 10 mg QD.
  • Doses of lucitanib less than 6 mg QD are evaluated based on unacceptable toxicities observed at Dose Level 1.
  • additional intermediate lucitanib dose levels based on 1 mg increments, and/or alternative schedules of lucitanib, are also evaluated.
  • a DLT is defined as any of the following events that occur during Cycle 1 that is assessed by the investigator as possibly related to lucitanib and/or nivolumab and unrelated to disease progression. Where applicable, events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 or later:
  • Grade 4 anemia i.e., life-threatening consequences; urgent intervention indicated
  • Hypertension defined as systolic blood pressure (SBP) > 160 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg, that does not resolve to ⁇ Grade 2 within 14 days despite optimized antihypertensive therapy, or any Grade 4 hypertension (hypertension with life-threatening consequences);
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • UPN normal
  • ALP alkaline phosphatase
  • the RP2D for evaluation in Phase 2 is selected based on overall safety and tolerability, PK, and preliminary efficacy.
  • the RP2D may or may not be the same as the MTD (maximum tolerated dose) identified in the dose-escalation portion. For example, if the MTD is not reached or if subsequent cycles of treatment provide additional insight on the safety profile of the combination, then the RP2D may be a different, though not higher, dose than the MTD.
  • the expansion phase follows a Simon 2- stage study approach to evaluate the safety and efficacy of the combination of lucitanib and nivolumab in patients with cytologically or histologically, radiologically confirmed advanced, recurrent, or metastatic tumors.
  • Selected gynecological tumor cohorts include endometrial cancer (EC), clear cell endometrial and ovarian cancer (OECCC), ovarian cancer (OV), and cervical cancer (CC). Clear cell histology are excluded from the OV cohort. All patients receive at least 1 prior regimen of standard-of-care chemotherapy.
  • Lucitanib tablets are administered QD and swallowed with water (240 mL or 8 oz) taken at approximately the same time each day, on an empty stomach, at least 2 hours before and 1 hour after a meal (fasting window is a total of 3 hours). Patients are advised to attend the Cycle 1, Day 1 visit with an empty stomach or have eaten their last meal at least 1 hour prior to attending clinic. For subsequent clinic visits, patients are advised not to take their dose of lucitanib for that day until after the necessary blood samples have been collected. [00231] Nivolumab is administered as a 30 minute IV infusion on Day 1 of every 28 days (4 weeks), starting with Cycle 1, Day 1.
  • the starting dose in the Phase lb study part is lucitanib 6 mg QD and nivolumab 480 mg Day 1 of each cycle.
  • the starting dose in the Phase 2 expansion portion of the study is the 6 mg QD RP2D of lucitanib determined in the phase lb portion in combination with nivolumab 480 mg IV every 4 weeks.
  • Cycle 1 (4 weeks) of treatment with lucitanib + nivolumab has been completed, patients who meet all of the following criteria will increase their dose of lucitanib by 2 mg:
  • Lucitanib dose can be interrupted and/or reduced in 2 mg decrements to a minimum of 2 mg in the event of toxicity.
  • nivolumab Treatment with nivolumab is given for up to 24 months in the absence of disease progression, unacceptable toxicity, or withdrawal of patient consent, whichever occurs sooner.
  • Lucitanib is given until disease progression by RECIST vl.1 as assessed by the investigator, unacceptable toxicity, or other reason for discontinuation, whichever occurs first. Treatment interruption or dose reduction of lucitanib are permitted in the event of unacceptable toxicity. Doses of nivolumab may be interrupted or delayed but may not be reduced.
  • patients will take the RP2D of lucitanib both in a fasting state and with a high-fat meal according to the randomization. If the results from food- effect PK evaluation show no clinically meaningful food effect, the meal restriction is lifted in the rest of this study.
  • Efficacy measures include tumor assessments consisting of clinical examination and appropriate imaging techniques (including computed tomography (CT) scans of the chest, abdomen, and pelvis with appropriate slice thickness per RECIST v 1.1 ; as well as, for example, magnetic resonance imaging (MRI), X-ray, positron emission tomography (PET), and ultrasound, if required).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • ultrasound if required
  • Tumor response is interpreted using RECIST vl.l, as assessed by the investigator. Disease progression will primarily be determined by RECIST. Tumor assessment measurements are performed at screening, at the end of every 8 weeks of treatment ( ⁇ 7 days) for the first 52 weeks relative to Cycle 1, Day 1, and then every 12 weeks ( ⁇ 7 days) until objective radiological disease progression, or discontinuation of treatment, and as clinically indicated. Pseudoprogression is excluded through confirmation of radiological progression. [00241] Patients who discontinue treatment for a reason other than disease progression or death should continue to have tumor scans performed every 12 weeks until radiological disease progression as assessed by the investigator, death, loss to follow up, withdrawal from study, study termination, or initiation of subsequent anti cancer treatments.
  • ECGs 12-lead electrocardiograms
  • PK samples of nivolumab are collected prior to dosing on Day 1 of Cycles 1, 2, 5 and every 4 cycles after Cycle 5. End-of-infusion PK samples are collected in Phase lb and Phase 2 on Day 1 of Cycle 1. In addition, nivolumab PK samples are collected at the End-of- treatment Visit and the Safety Follow-up Visits.
  • Blood and tissue samples are collected throughout the studies and are tested for DNA, RNA and protein biomarkers to identify associations with response or resistance to treatment.
  • Trough-level plasma PK samples are collected and used for developing lucitanib population PK and exposure-response analysis in combination with nivolumab. Blood samples are collected for the assessment of nivolumab PK and anti -nivolumab antibodies in patient serum.
  • Examples of potential biomarker assessments include, but are not limited to, TMB; MSI; dMMR; PD-L1; CD8/immune phenotype; RNA expression; Soluble analytes (e.g., growth factors, cytokines, etc.); Germline/somatic gene alterations; tumor genomics and circulating tumor DNA (ctDNA); immune composition/frequency of immune subsets and expression of genes or proteins.
  • Soluble analytes e.g., growth factors, cytokines, etc.
  • Germline/somatic gene alterations e.g., tumor genomics and circulating tumor DNA (ctDNA); immune composition/frequency of immune subsets and expression of genes or proteins.
  • Adverse events/IMAEs are summarized overall and with separate summaries for serious adverse events (SAEs), AEs leading to discontinuation, AEs leading to death, and NCI-CTCAE v5.0 Grade 3 or higher AEs.
  • Body weight and vital signs are summarized descriptively (N, mean, standard deviation, median, minimum, and maximum).
  • ECOG is summarized categorically and descriptively.
  • the primary efficacy endpoint for Phase 2 is analyzed by calculating the RECIST vl.l overall response rate (ORR).
  • ORR is defined as the proportion of patients with a documented and confirmed best overall response of CR or PR per RECIST vl.l as assessed by the investigator.
  • a confirmed complete response (CR) or partial response (PR) is a response that is maintained and documented on a subsequent tumor assessment no less than 28 days after initial response.
  • Lucitanib Phase lb Dose Escalation and Food Effect cohorts steady-state minimum concentration (Cmin , ss), area under the plasma concentration-time curve at steady state (AUCss), steady-state maximal concentrations (C max, ss), Time to Cmax at steady-state (T ma . ss). and apparent total clearance of drug after oral administration (CL/F), if data allow.
  • PK parameters are calculated if data allow.
  • the PK data and selected safety and efficacy endpoints may be included in exploratory population PK and exposure- response analyses, with the results to be reported separately.
  • the study is a 4+3 dose-escalation design, which is a modified version of a 3+3 dose-escalation design and the overall sample size depends on the occurrence of DLTs observed at the different dose levels.
  • Each cohort are evaluated in a Simon 2 stage design with the option to stop enrollment in the cohort after the first stage if the prespecified confirmed responses are not observed.
  • sample size estimates for each cohort are as follows:
  • phase lb dose-escalation study described in Example 1 used a 4+3 dose- escalation design and enrolled patients with an advanced refractory or progressive solid tumor and no satisfactory treatment options.
  • Lucitanib was evaluated at a once-daily dose of 6, 8, and 10 mg.
  • DLTs Dose-limiting toxicities
  • TMB tumor mutation burden
  • PD-L1 expression PD-L1 expression
  • tumor types included adenoid cystic carcinoma of the parotid gland, anal cancer, head and neck cancer, pancreatic cancer, and liposarcoma.
  • DLT grade 3 proteinuria
  • Treatment-emergent hypertension was otherwise grade 1 or 2 (4 patients), and readily managed with close monitoring and early antihypertensive therapy.
  • Treatment-emergent adverse events were consistent with those expected for lucitanib and nivolumab, and there were no apparent differences in TEAE frequencies between doses.
  • Table 1 depicts treatment-emergent adverse events (TEAEs) occurring in >2 patients receiving Lucitanib 3 + Nivolumab combination at various doses of lucitanib. Data sorted by decreasing any-grade incidence across groups. Only 1 patient discontinued lucitanib due to a TEAE (grade 3 proteinuria). Grade 3 hypokalaemia was reported in 1 patient. a Across all doses. b Asthenia and fatigue. C lncreased blood pressure and hypertension increased blood thyroid-stimulating hormone and hypothyroidism. ALT, alanine aminotransferase; AST, aspartate aminotransferase; TEAE, treatment-emergent adverse event.
  • TEAE treatment-emergent adverse event.
  • Lucitanib PK profiles in this study show that nivolumab may have no impact on lucitanib PK.
  • lucitanib was selected as 6 mg once daily, to be given in combination with fixed-dose IV nivolumab (480 mg once every 28 days).
  • Table 2 depicts a summary of PK parameters on Cycle 1 Day 15 by lucitanib Dose. Data are mean ⁇ SD, except for T max , which is median (min, max). AUC24, Area under the concentration-time curve at 24 h; C max , maximum concentration; C min , minimum concentration; CL SS /F, apparent total body clearance after oral administration (at steady state); PK, pharmacokinetic; SD, standard deviation; T max , time taken to reach C max .
  • Table 3 depicts biomarker data. a Recent: tumor sample collected ⁇ 6 months before starting treatment with lucitanib and nivolumab (no intervening anticancer treatment); archival: tumor sample collected >6 months prior to starting treatment with lucitanib and nivolumab (other anti cancer treatments may have been given in the interim).
  • CPS [(# of all PD-L1 stained tumor cells, lymphocytes and macrophages/total # viable tumor cells) x 100]
  • c Immune phenotype IHC assay to detect amount/location of infiltrating CD8+ T cells which characterizes immune phenotype; desert, no-to-very low infiltration; excluded-intratumoral, CD8+ T cells excluded from the intraepithelial compartment of the tumor but abundant in the intrastromal compartment; inflamed, abundant CD8+ T cells within the intraepithelial compartment of the tumor.
  • TMB score # somatic mutations at VAF >5%/total DNA region (Mb) covered at 50x sequencing depth.
  • e Microsatellite status [(# unstable microsatellite sites/# useable sites) x 100] where MSS, ⁇ 20% unstable sites; MSI-High, >20% unstable sites.
  • CPS combined positive score
  • CR complete response
  • IHC immunohistochemistry
  • MSI microsatellite instability
  • MSS microsatellite stable
  • NA not available
  • NE not evaluable
  • PD progressive disease
  • PD-L1 programmed cell death ligand 1
  • PR partial response
  • SD stable disease
  • TMB tumor mutation burden
  • VAF variant allele frequency
  • Example 3 Status of Phase 2 Study for Treatment with Lucitanib According to Variable Dosage Strategy in Combination with Nivolumab

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Abstract

La présente invention concerne des procédés d'administration de produits thérapeutiques combinés et de dosages variables de ceux-ci pour le traitement du cancer. Plus spécifiquement, l'invention concerne des méthodes de traitement du cancer consistant à administrer du lucitanib à un régime variable en combinaison avec un agent pharmaceutique actif secondaire administré simultanément, séparément ou séquentiellement.
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