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WO2025061057A1 - Utilisation d'un inhibiteur de parp dans une thérapie d'entretien du cancer de l'ovaire - Google Patents

Utilisation d'un inhibiteur de parp dans une thérapie d'entretien du cancer de l'ovaire Download PDF

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Publication number
WO2025061057A1
WO2025061057A1 PCT/CN2024/119509 CN2024119509W WO2025061057A1 WO 2025061057 A1 WO2025061057 A1 WO 2025061057A1 CN 2024119509 W CN2024119509 W CN 2024119509W WO 2025061057 A1 WO2025061057 A1 WO 2025061057A1
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administration
patient
dose
daily dose
grade
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Chih-Yi Hsieh
Sui Xiong Cai
Cong XU
Huan XIA
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Impact Therapeutics Shanghai Inc
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Impact Therapeutics Shanghai Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Definitions

  • the present invention relates to use of a PARP inhibitor in maintenance therapy of ovarian cancer.
  • Ovarian cancer begins to form lumps called tumors when healthy cells in the ovaries change and grow uncontrollably.
  • Tumors can be malignant or benign.
  • a malignant tumor means it can grow and spread to other parts of the body.
  • a benign tumor means the tumor can grow but not spread.
  • the benign ovarian tumor can be treated by removing the ovary or the tumorous portion of the ovary.
  • Types of ovarian cancer include: epithelial cancer, germ cell tumor, or stromal tumor.
  • the epithelial cancer constitutes 85%to 90%of ovarian cancer.
  • Ovarian cancer is often used to describe a cancer that originate from the ovary, fallopian tube, and primary peritoneal cancer.
  • Ovarian cancer is the most common fatal malignant tumor of the female reproductive tract. According to statistics, the annual number of new cases of ovarian cancer worldwide reaches 310,000, and the number of deaths reaches 210,000 (Sung H et al., CA Cancer J Clin. 2021; 71 (3) : 209-49) . Due to the insidious and non-specific early symptoms of ovarian cancer, about 80%of patients are diagnosed at an advanced stage, and the 5-year survival rate is only 40% (Morgan RJ Jr et al., J Natl Compr Canc Netw. 2016; 14: 1134-63) .
  • ovarian cancer can be alleviated following initial platinum-based chemotherapy, most patients will inevitably suffer recurrence (Jayson GC et al., Lancet. 2014; 384 (9951) : 1376-88) .
  • Characteristics of ovarian tumors include deficiencies in DNA repair, such as BRCA mutations.
  • BRCA1 and BRCA2 are originally identified as tumor suppressor genes associated with an increased incidence of certain malignancies including ovarian cancer.
  • BRCA deficiencies are present in 28%of ovarian cancer in the Chinese population due to a combination of germline and sporadic mutations and hypermethylation of a promoter (Yang Jiaxin et al., Chinese Journal of Obstetrics and Gynecology 2017, Issue 1) .
  • PARP Poly (ADP-ribose) polymerase
  • PARP is a protease family consisting of 17 family members.
  • PARP1 and PARP2 are key molecules in the DNA damage repair pathway and are part of the base excision repair (BER) complex.
  • BER base excision repair
  • PARP1 and PARP2 attach poly (ADP-ribose) (PAR) to histones or their own proteins, a reaction called PARylation. This process is crucial to maintaining the integrity and stability of DNA and chromosomes, and is an important guarantee for the survival of mammalian cells.
  • WO 2012130166 discloses 1- (arylmethyl) quinazoline-2, 4 (1H, 3H) -dione as a PARP inhibitor and an application thereof, including 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione (also referred to herein as “senaparib” ) , which has the following chemical structure:
  • Senaparib is currently subject to phase II/III clinical studies for indications such as ovarian cancer and small cell lung cancer globally, including in China.
  • PARP inhibitors are changing the treatment patterns of ovarian cancer, and the maintenance therapy of ovarian cancer can prolong the response duration after the first-line platinum-containing chemotherapy, and delay the recurrence (Khalique S et al., Curr Opin Oncol. 2014; 26 (5) : 521-8) .
  • WO 2018005818 discloses a method for treating ovarian cancer with niraparib, in which in order to improve the condition of poor tolerance, the dose of niraparib can be reduced from approximately 300 mg QD to 200 mg QD, or from 200 mg QD to 100 mg QD for any patients, the dose can be reduced for up to 2 times, and the dose cannot be reduced to lower than 100 mg QD.
  • the present invention relates to the use of PARP inhibitor 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof or a medicament containing the pharmaceutical composition for maintenance therapy of patients or cancers with or without BRCA1 and/or BRCA2 mutations, in particular of patients or cancers without BRCA1 and/or BRCA2 mutations.
  • the present invention finds that using the maintenance therapy and dose adjustment regimen of the present invention can effectively reduce the incidence and severity of hematological and non-hematological toxicities in patients, which has good tolerance, reduces the proportion of permanent discontinuation, while maintaining good drug efficacy;
  • the maintenance therapy of the present invention can significantly improve PFS and reduce the patient's risk of disease progression or death.
  • the present invention provides a maintenance therapy for a patient with ovarian cancer, which includes administering an effective amount for the maintenance therapy of 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H) -dione, the hydrate or the pharmaceutically acceptable salt thereof or a medicament containing the pharmaceutical composition to a patient with ovarian cancer who has received a first-line platinum-containing therapeutic regimen and achieved complete response or partial response.
  • the present invention provides a maintenance therapy for a patient with ovarian cancer.
  • the initial dose of senaparib for maintenance therapy is 100 mg once daily.
  • the maintenance therapy further includes steps for toxic response evaluation, drug dose adjustment, and/or suspension of administration on the patient, wherein the dose of the drug is adjusted in a magnitude of 20 mg, such as reducing the daily dose from 100 mg to 80 mg; reducing the daily dose from 80 mg to 60 mg; reducing the daily dose from 60 mg to 40 mg; and if the daily dose is reduced to 40 mg and the patient remains intolerant, then the therapy is terminated.
  • the dose adjustment regimen of the present invention can reduce the incidence and severity of hematological and non-hematological toxicities in patients, improve tolerance, and reduce the proportion of permanent discontinuation. At the same time, it maintains good efficacy, significantly improves PFS, and reduces the disease progression of patients.
  • the present invention further provides a kit comprising a pharmaceutical composition containing 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H) -dione, a hydrate or a pharmaceutically acceptable salt thereof or a medicament containing the pharmaceutical composition for use in a maintenance therapy of a patient with ovarian cancer.
  • the present invention further provides the use of 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione, a hydrate or a pharmaceutically acceptable salt thereof in the preparation of a drug for maintenance therapy of a patient with ovarian cancer.
  • FIG. 1 depicts a graphical representation of BICR-evaluated progression free survival in 404 patients when treated with senaparib or placebo.
  • the y-axis shows the estimated probability of progression free survival, and the x-axis shows the duration of progression free survival (in months) following randomization.
  • the hazard ratio for disease progression is shown on the graph as HR (95%CI) 0.43 (0.32, 0.58) .
  • FIG. 2 depicts a graphical representation of BICR-evaluated progression free survival in 138 BRCA positive patients when treated with senaparib or placebo.
  • the y-axis shows the estimated probability of progression free survival, and the x-axis shows the duration of progression free survival (in months) following randomization.
  • the hazard ratio for disease progression is shown on the graph as HR (95%CI) 0.43 (0.24, 0.76) .
  • FIG. 3 depicts a graphical representation of BICR-evaluated progression free survival in 266 BRCA negative patients when treated with senaparib or placebo.
  • the y-axis shows the estimated probability of progression free survival, and the x-axis shows the duration of progression free survival (in months) following randomization.
  • the hazard ratio for disease progression is shown on the graph as HR (95%CI) 0.43 (0.30, 0.61) .
  • FIG. 4 depicts hazard rate results for the subgroup analysis of PFS in 404 BICR-evaluated patients when treated with senaparib or placebo.
  • a clinically significant reduction in the risk of PD or death in the senaparib group was observed in all prespecified subgroups (HR 0.26 to HR 0.76) .
  • FIG. 5 depicts a graphical representation of investigator-evaluated progression free survival in 404 patients when treated with senaparib or placebo.
  • the y-axis shows the estimated probability of progression free survival, and the x-axis shows the duration of progression free survival (in months) following randomization.
  • the hazard ratio for disease progression is shown on the graph as HR (95%CI) 0.43 (0.32, 0.57) .
  • FIG. 6 depicts a graphical representation of BICR-evaluated progression free survival in 161 patients with positive HRD data when treated with senaparib or placebo.
  • the y-axis shows the estimated probability of progression free survival, and the x-axis shows the duration of progression free survival (in months) following randomization.
  • the hazard ratio for disease progression is shown on the graph as HR (95%CI) 0.36 (0.22, 0.61) .
  • FIG. 7 depicts a graphical representation of the comparison of progression free survival of patients in the senaparib group treated with adjusted different doses.
  • the y-axis shows the estimated probability of progression free survival, and the x-axis shows the duration of progression free survival (in months) following randomization.
  • administering refers to administration of an active ingredient or a composition thereof to a subject or system.
  • dose refers to administration of an active ingredient or a composition thereof to a subject or system.
  • routes may be used to administer the active ingredients or compositions thereof to a subject or system.
  • the active ingredients or compositions thereof may be administered ocularly, orally, parenterally, topically, or the like.
  • the composition can be administered via bronchus (e.g., via bronchial instillation) , buccal, skin (including topical administration such as dermal, intradermal, interdermal, transdermal administration, etc.
  • enteral intraarterial, intradermal, intragastrical, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intrahepatic, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., via intratracheal instillation) , vaginal, vitreous body route, etc.
  • timing and mode of administration including intermittent administration and continuous administration.
  • the former means that the active ingredient or the composition thereof can be administered irregularly or regularly, and the latter means that the active ingredient or the composition thereof can be administered continuously to the patient for a certain period of time.
  • continuous administration include infusion. Of course, the infusion itself can also be performed regularly or irregularly.
  • the term “dosage form” or “unit dosage form” refers to a physically discrete unit containing an amount of active ingredient for administration to a subject for the treatment and/or prevention of diseases. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, such amounts are unit doses (or entire portions thereof) suitable for administration according to a regimen that has been established to be associated with the desired or beneficial outcomes when administered to the population of interest (i.e., when using a therapeutic regimen) .
  • a regimen that has been established to be associated with the desired or beneficial outcomes when administered to the population of interest (i.e., when using a therapeutic regimen) .
  • the total amount of a therapeutic composition or an agent to be administered to a particular subject is determined by the attending physician or physicians and may involve the administration of multiple dosage forms.
  • a given therapeutic agent is administered according to a regimen, which may involve one or more doses.
  • a regimen includes multiple doses, each dose being separated in time from the other doses.
  • individual doses are separated from each other by a period of the same length of time.
  • a regimen includes multiple doses, where the doses are separated by a period of varying lengths of time.
  • the regimen includes doses of the same amount.
  • the regimen includes doses of varying amounts.
  • a regimen includes at least one dose, where the dose contains one unit dose of therapeutic agent. In some embodiments, a regimen includes at least one dose, where the dose contains two or more unit doses of therapeutic agent. For example, a 250 mg dose may be administered as a single 250 mg unit dose or as two 125 mg unit doses. In some embodiments, a regimen is associated with or results in desired or beneficial outcomes when administered (i.e., the regimen is a therapeutic regimen) in a relevant population.
  • the term “patient” , “subject” , “individual, ” or “test subject” refers to any organism to whom a compound described herein, or a hydrate and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered according to the present invention. Such an administration includes various purposes including experimental, diagnostic, prophylactic and/or therapeutic purposes.
  • Subjects are generally animals, including: mammals, such as non-human primates and humans. In a preferred embodiment, the subject is human. In some embodiments, the subject may suffer from and/or be susceptible to a disease, disorder, and/or condition (e.g., a cancer, such as ovarian, fallopian tube, peritoneal, and breast cancers) .
  • a disease, disorder, and/or condition e.g., a cancer, such as ovarian, fallopian tube, peritoneal, and breast cancers.
  • the patient is a human with one or more female reproductive organs.
  • the patient is a human female (i.e., a female) who has been diagnosed with gynecological cancers, such as ovarian, fallopian tube, peritoneal, and breast cancers.
  • a “patient population” or “subject population” refers to a plurality of patients or subjects.
  • the patients are an intention-to-treat analysis (ITT) population: all randomized subjects are included. Analyzes are performed according to randomized treatment group, regardless of the treatment subjects actually receive. Baseline characteristics, efficacy, and health-related quality of life are analyzed based on the ITT population.
  • ITT intention-to-treat analysis
  • the term “treatment” refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays the onset of, reduces the severity of, a particular disease, disorder, and/or condition, and/or decreases the incidence, characteristics, and/or causes of one or more symptoms of a particular disease, disorder, and/or condition.
  • a treatment may be directed to a subject manifesting no signs of the relevant disease, disorder, and/or condition, and/or a subject only manifesting early signs of the disease, disorder, and/or condition.
  • such a treatment may be a treatment that a subject manifesting one or more established signs of the relevant disease, disorder and/or condition has.
  • the treatment may be a treatment that a subject diagnosed with the relevant disease, disorder, and/or condition has. In some embodiments, the treatment may be a treatment that a subject known to have one or more susceptibility factors has, the susceptibility factors are statistically associated with an increased risk of development of the relevant disease, disorder, and/or condition.
  • the term “maintenance therapy” or “maintenance treatment” refers to a treatment used to prevent disease recurrence and/or control disease progression.
  • the maintenance therapy can prevent the recurrence of a cancer after the cancer has been significantly reduced or eliminated after initial therapy.
  • Maintenance therapy may be a continuous therapy in which multiple doses are administered at intervals, such as daily, every other day, weekly, every 2 weeks, every 3 weeks, every 4 weeks, or every 6 weeks.
  • the maintenance therapy can be continued for a predetermined length of time.
  • the maintenance therapy may be continued until unacceptable toxicity occurs and/or disease progression occurs. If adverse events occur during the maintenance therapy, the therapy can be interrupted when toxicity occurs. If toxicity resolves appropriately to baseline or to grade 1 or less within 28 days, the patient may resume maintenance therapy, which may include reduced dose level.
  • a “therapeutically effective amount” refers to an amount of a therapeutic agent that produces a desired therapeutic effect of administration. In some embodiments, the term refers to an amount sufficient to treat a disease, disorder, and/or condition when administered to a population suffering from or susceptible to the disease, disorder, and/or condition according to a regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and/or severity of, and/or delays the onset of, one or more symptoms of a disease, disorder, and/or condition. One of ordinary skill in the art will appreciate that the term “therapeutically effective amount” is not actually required to achieve successful treatment in a particular individual.
  • a therapeutically effective amount may be an amount that, when administered to a patient in need of such a treatment, provides specific desired pharmacological responses in a large number of subjects.
  • reference to a therapeutically effective amount may refer to, a mount as measured in one or more specific tissues (e.g., tissue affected by a disease, disorder, or condition) or fluid (e.g., blood, saliva, serum, sweat, tears, urine, etc. ) .
  • tissue e.g., tissue affected by a disease, disorder, or condition
  • fluid e.g., blood, saliva, serum, sweat, tears, urine, etc.
  • a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose.
  • an effective therapeutic agent may be formulated and/or administered in multiple doses, for example, as part of a regimen.
  • an “effective amount for maintenance therapy” refers to an amount of an active ingredient that is effective in preventing the occurrence, progression and/or recurrence of a disease.
  • an “effective amount for maintenance therapy” refers to a dose administered during “maintenance therapy” or “maintenance treatment” as described herein.
  • chemotherapeutic agent refers to a chemical agent that inhibits the proliferation, growth, longevity, and/or metastatic activity of cancer cells.
  • the chemotherapeutic agent is a platinum-based agent.
  • the platinum-based agent includes, but is not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, triplatinum tetranitrate, phenanthriplatin, picoplatin, or satraplatin; preferably, cisplatin and carboplatin.
  • homologous recombination refers to a process in which nucleotide sequences between different DNA strands are exchanged. Homologous recombination is involved in many different biological processes, for example, homologous recombination occurs as part of the DNA repair process (e.g., double-strand break repair pathway) , and during the meiotic/gametogenic processes in eukaryotes.
  • homologous recombination deficiency refers to a reduction or impairment of the homologous recombination process.
  • chromosomal aberration or “CA” refers to a detectable variation in the chromosomal DNA of a sample.
  • a CA may fall within at least one of three overlapping categories: loss of heterozygosity (LOH) , allelic imbalance (e.g., telomeric allelic imbalance (TAI) ) , or large-scale transition (LST) .
  • LHO loss of heterozygosity
  • allelic imbalance e.g., telomeric allelic imbalance (TAI)
  • LST large-scale transition
  • “HRD status” is determined by CA detection in a sample obtained from the patient (e.g., a tumor sample) .
  • a positive HRD status or HRD positive refers to a sample obtained from a patient having a CA at or higher than a CA threshold number or level at a specified number of chromosome indicator regions;
  • a negative HRD status or HRD negative refers to a sample obtained from a patient having a CA lower than a CA threshold number or level at a specified number of chromosome indicator regions.
  • the HRD status is determined with commercially available diagnostic reagents to detect the chromosomal aberrations in a sample (e.g., a tumor sample) and/or to evaluate whether a sample is unable to repair the double-strand DNA breaks.
  • diagnostic reagents for evaluating HRD status include the HRD TM diagnostic kit.
  • the term “gene involved in DNA repair” refers to any gene involved in DNA repair in a cell. These include genes involved in homologous recombination, which is a genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA molecules. Homologous recombination is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, called double-strand breaks.
  • BRCAl, BRCA2, ATM, BARD1, BRIP1, CHEK2, DMC1, EME1 (MMS4L) , EME2, GEN1, GIYD2 (SLX1B) , MRE11A, MUS81, NBN, PALB2, RAD50, RAD51, RAD5IB, RD51C, RAD5ID, RAD52, RAD54B, RAD54L, RBBP8, SHFMl (DSSl) , XRCC2, and XRCC3 are genes known to be involved in homologous recombination.
  • DNA repair status refers to the presence or absence of mutations in one or more genes involved in DNA repair.
  • the present invention relates to the use of PARP inhibitors to treat cancer patients regardless of DNA repair status.
  • progression Free Survival means the time between the initiation of treatment and the observation of disease progression or death from any causes in a patient with neoplastic diseases. Progression free survival can be evaluated as the time period in which there is no progression of tumor growth and/or in which the patient's disease status is not determined to be progressive disease. In some embodiments, the progression free survival of subjects having cancers is evaluated by evaluating tumor (lesion) size, tumor (lesion) number, and/or metastasis.
  • progression of tumor growth or “progressive disease (PD) ” indicates an increase in the sum of diameters of target lesions (tumors) .
  • progression of tumor growth refers to an increase of at least 20%in the sum of diameters of target lesions, with reference to the minimum sum in the study (including the sum of baseline, if it is the minimum in the study) .
  • the sum of the diameters of the target lesions must demonstrate an absolute increase of at least 5 mm in addition to a 20%relative increase. The appearance of one or more new lesions may also be considered in determining the progression of tumor growth.
  • Progression for purposes of determining progression free survival may also be determined if at least one of the following criteria is met: 1) tumor evaluation by CT/MRI clearly shows progressive disease according to RECIST 1.1 criteria; or 2) an additional diagnostic test (e.g., histology/cytology, ultrasonography, endoscopy, positron emission tomography) identifies new lesions.
  • an additional diagnostic test e.g., histology/cytology, ultrasonography, endoscopy, positron emission tomography
  • partial response refers to a reduction in tumor progression in a subject, as indicated by a reduction in the sum of diameters of target lesions, with the sum of baseline diameters as a reference.
  • PR refers to at least a 30%reduction in the sum of diameters of the target lesions, with the sum of baseline diameters as a reference.
  • RECIST guideline is used for identifying an exemplary method for evaluating partial response (Eisenhauer et al., 2009 Eur. J. of Cancer, 45: 228-247) .
  • stable disease or “SD” in tumor growth means neither shrinking enough to qualify for PR nor increasing enough to qualify for PR.
  • stable disease refers to a change (increase or decrease) of less than 30%, 25%, 20%, 15%, 10%, or 5%in the sum of diameters of target lesions, with the sum of baseline diameters as a reference.
  • Exemplary methods for evaluating stabilization of tumor growth or a stable disease are identified by the RECIST guideline (Eisenhauer et al., 2009 Eur. J. of Cancer, 45: 228-247) .
  • CR complete response
  • CR refers to an 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%or 100% (i.e., disappearance of lesions) reduction in the sum of diameters of target lesions, with the sum of baseline diameters as a reference.
  • CR indicates retention of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of total lesion diameter after treatment.
  • Exemplary methods for evaluating complete response are identified by the RECIST guideline (Eisenhauer et al., 2009 Eur. J. of Cancer, 45: 228-247) .
  • a “hazard ratio” (or “HR” in the context of the calculation of treatment effect for senaparib, e.g. HR 0.43) is the risk or chance of an event occurring in the treatment group as a ratio to the event occurring in the control group.
  • the hazard ratio can be determined by a Cox model, which is a regression method for survival data that provides an estimate of the hazard ratio and its confidence interval.
  • the hazard ratio is an estimate of the ratio of the hazard rate in the treatment group relative to that in the control group.
  • the hazard rate is the probability that the event in question will occur within the next time interval if it has not yet occurred, divided by the length of that interval.
  • the assumption of proportional hazards regression is that the hazard ratio is constant over time.
  • the present invention relates to the comparison of results achieved for two or more agents, entities, situations, sets of conditions, and populations, etc.
  • agents, entities, situations, sets of conditions, populations, etc. may be considered “comparable” to each other when they are not identical, but are similar enough to permit the comparison therebetween, and thus conclusions can be reasonably obtained based on the observed differences or similarities.
  • comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical characteristics and one or a small number of varying characteristics. In this context, one of ordinary skill in the art will understand what degree of identity is required for two or more of such agents, entities, situations, sets of conditions in any given instance to be considered comparable.
  • references refers to a standard or control against which a comparison is performed.
  • agents, animals, individuals, populations, samples, sequences, or values of interest are compared with reference or control agents, animals, individuals, populations, samples, sequences, or values.
  • a reference or control is tested and/or determined substantially concurrently with the test or determination of interest.
  • a reference or control is a historical reference or control, optionally embodied in a tangible medium.
  • a reference or control is determined or characterized under conditions or circumstances comparable to those under evaluation. Those skilled in the art will know when there is sufficient similarity to demonstrate the reliance on and/or comparison with specific possible references or controls.
  • senaparib means 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione, which is a potent inhibitor on poly (ADP-ribose) polymerase PARP1 and PARP2.
  • the preparation methods of senaparib can be found in WO 2012130166, WO 2022099442 and WO 2022100577, the entire contents of which are incorporated herein by reference.
  • hydrate refers to a crystalline form having a stoichiometric or non-stoichiometric amount of water incorporated into the crystal structure.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and lower animals without inappropriate toxicities, irritations, allergic reactions, etc., and have reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts include inorganic and organic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, mandelates and oxalates; as well as inorganic and organic base salts formed with bases such as sodium hydroxide, tris (hydroxymethyl) aminomethane (TRIS, tromethamine) and N-methylglucamine.
  • the term “pharmaceutical composition” or “medicament” refers to a composition containing an active agent and one or more pharmaceutically acceptable carriers.
  • Pharmaceutical compositions typically contain a therapeutically effective amount of active agents, the therapeutically effective amount is typically a unit dose as defined herein, which may be administered in a therapeutic regimen.
  • the pharmaceutical composition can be formulated into a suitable dosage form according to the mode of administration, such as a solid dosage form or a liquid dosage form.
  • dosage forms suitable for oral administration include solutions (aqueous or non-aqueous solutions or suspensions) , tablets (e.g., those targeting at buccal, sublingual, and systemic absorption) , bolus, powders, granules, pastes for application to the tongue, etc.
  • the active agent is one or more of senaparib, and a hydrate and a pharmaceutically acceptable salt thereof described herein.
  • the dose or administration dose of a drug described herein refers to the dose of the active agent, namely senaparib, and a hydrate and a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable carrier refers to various types of carriers well known in the art, including but not limited to one or more of any solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, lubricants, etc. Appropriate pharmaceutically acceptable carriers can be selected according to different dosage forms.
  • Examples of pharmaceutically acceptable carriers include, but are not limited to: sugars, such as lactose, glucose, and sucrose; starch, such as corn starch and potato starch; cellulose and a derivative thereof, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talcum powder; cocoa butter; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; buffers; pyrogen-free water; isotonic saline; Ringer's solution; lubricants, such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coating materials; sweeteners; flavorings and spices, preservatives, antioxidants, etc.
  • sugars such as lactose,
  • tumor response can be measured, for example, according to RECIST V 1.1 guideline (Eisenhauer et al., 2009 Eur. J. of Cancer, 45: 228-247) .
  • This guideline first requires an estimate of overall tumor burden at baseline, which is used as a comparator for subsequent measurements.
  • Tumors can be measured by using any imaging system known in the art, such as by CT scan or X-ray.
  • Measurable diseases were defined by the presence of at least one measurable lesion.
  • the regimen In studies in which the primary endpoint is tumor progression (time to progression or proportion of progression at a fixed date) , the regimen must specify whether entry is limited to patients with measurable diseases, or whether patients with only unmeasurable diseases are also eligible.
  • all lesions representing up to a total of five lesions in all involved organs (and a maximum of two lesions per organ) should be identified as target lesions and will be recorded and measured at baseline (which means that in cases where the patient has only one or two organ sites involved, a maximum of two and four lesions will be recorded respectively) .
  • Target lesions should be selected based on their sizes (lesions with the longest diameter) , representative of all organs involved, but additionally should be those that enable reproducible repeated measurements.
  • Lymph nodes deserve special mention because they are normal anatomic structures that can be seen on imaging even when not involved by the tumor.
  • the pathological nodules must meet the short axis criterion of 15 mm by CT scan. Only the short axis of these nodules constitutes the baseline sum.
  • the short axis of a nodule is the diameter commonly used by radiologists to determine whether a nodule is involved by a solid tumor. Nodule size is usually reported as two dimensions in the plane in which the image is acquired (for CT scans, this is almost always the axial plane; for MRI, the acquisition plane can be axial, sagittal, or coronal) . The smaller one of these measurements is the short axis.
  • an abdominal nodule reported as 20 mm ⁇ 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable nodule.
  • 20 mm should be recorded as the nodule measurement.
  • All other pathological nodules should be considered non-target lesions.
  • Lymph nodes ⁇ 10 mm in the short axis are considered nonpathological and should not be recorded or tracked.
  • the sum of diameters of all target lesions is calculated (where the longest diameter of the target lesion is used to calculate the sum of diameters for non-nodular lesions and the short axis of the target lesion is used to calculate the sum of diameters for nodular lesions) , and reported as the sum of baseline diameters. If lymph nodes are to be included in the sum, then only the short axis is added to the sum as described above.
  • the sum of baseline diameters will be used as a reference to further characterize any objective tumor regression in measurable dimensions of a disease.
  • All other lesions (or sites of diseases) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required, and these lesions should be tracked as “present, ” “absent, ” or in rare cases, “definite progression” . Additionally, it is possible to record multiple non-target lesions involving the same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’ ) .
  • drugs containing an active agent described herein i.e., the PARP inhibitor senaparib, a hydrate or a pharmaceutically acceptable salt thereof
  • an active agent described herein i.e., the PARP inhibitor senaparib, a hydrate or a pharmaceutically acceptable salt thereof
  • Using the method of the present application can achieve: i) prolonged progression free survival compared with a control; ii) reduced hazard ratio for disease progression or death compared with a control; and/or iii) prolonged overall survival compared with a control.
  • the cancer is ovarian cancer.
  • BRCA1 and BRCA2 are two genes that inhibit the occurrence of malignant tumors and are called tumor suppressor genes. They play an important role in damage repair (including homologous recombination) and normal cell growth. If the structure of the BRCA1/2 gene is mutated, its function of inhibiting tumorigenesis will be affected. Tumor cells with BRCA deficiency/homologous recombination deficiency (HRD) are particularly sensitive to DNA damage.
  • HRD BRCA deficiency/homologous recombination deficiency
  • BRCA mutation means changes or differences in the sequences of at least one copy of either or both of BRCA1 or BRCA2 genes relative to reference sequences (e.g., BRCA negative, wild-type BRCA1 and BRCA2, and/or BRCA1 and BRCA2 present in non-cancer cells of a subject) .
  • Mutations in BRCA1/2 genes can result in BRCA1/2 deficiencies, which can include, for example, loss or reduction in expression or function of the BRCA genes and/or encoded proteins. Such mutations may also be referred to as “deleterious mutations” or may be suspected of being deleterious.
  • a BRCA mutation can be a “germline BRCA mutation, ” which indicates that it is inherited from one or both parents. Germline mutations affect every cell in an organism and are passed on to future generations. BRCA mutations may also be acquired during a person's lifespan, i.e., arise sporadically (i.e., non-genetically) in any cells of the body at any time during the patient's lifespan, which is interchangeably referred to herein as “sporadic BRCA mutations” or “somatic BRCA mutations” .
  • a subject can be tested for the presence of a BRCA mutation using methods well known in the art.
  • BRCA1/2 variants can be detected and classified using the kit.
  • Polymerase chain reaction (PCR) and nucleotide sequencing can be used to identify single nucleotide variants and small insertions and deletions, and multiplex PCR can be used to detect large deletions and duplications in BRCA1 and BRCA2.
  • PCR Polymerase chain reaction
  • nucleotide sequencing can be used to identify single nucleotide variants and small insertions and deletions
  • multiplex PCR can be used to detect large deletions and duplications in BRCA1 and BRCA2.
  • BRCA status it can be described by whether there is a mutation in at least one copy of BRCA1 and BRCA2, as well as the mRNA expression level, methylation level or other epigenetic modification of either or both of BRCA1 and BRCA2.
  • a patient who is “BRCA positive” refers to a patient whose sample has been determined to contain a BRCA1 mutation and/or a BRCA2 mutation.
  • BRCA positivity refers to the presence of a germline BRCA mutation (gBRCAmut) or a somatic BRCA mutation (sBRCAmut) .
  • determining BRCA status with respect to a germline BRCA mutation is performed on a blood sample of the subject.
  • BRCA status is determined with respect to a somatic BRCA mutation (sBRCAmut) or total BRCA mutations (tBRCAmut, which includes both somatic and BRCA germline mutations) .
  • the methods described herein are not only applicable to the maintenance therapy of cancers with BRCA1 and/or BRCA2 ( “BRCA gene” ) mutations, but also to the maintenance therapy of cancers without BRCA1 and/or BRCA2 mutations.
  • cancers with or without BRCA1 and/or BRCA2 ( “BRCA genes” ) mutations are gynecological cancers, that is, cancers of the female reproductive system.
  • the cancers of the female reproductive system include, but not limited to, ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer.
  • the gynecological cancers are associated with homologous recombination repair deficiency (HRD) and/or BRCA1/2 mutations.
  • the cancer is ovarian cancer.
  • the ovarian cancer includes epithelial cancer, germ cell tumor or stromal tumor.
  • ovarian cancer refers to epithelial cancer that originates from the ovaries, fallopian tubes, and the lining of the abdominal cavity called the peritoneum.
  • the ovarian cancer is FIGO stages III-IV high-grade serous ovarian cancer, high-grade endometrioid ovarian cancer, or other histological types of ovarian cancer with breast cancer susceptibility gene mutations that originates from the ovary, fallopian tube, or primary peritoneum.
  • Senaparib, a hydrate or a pharmaceutically acceptable salt thereof for use in the maintenance therapy described herein may be administered in the form of a suitable pharmaceutical composition or medicament.
  • suitable dosage forms of senaparib include amorphous solid dispersions of senaparib disclosed in WO 2016155655 and oral capsules disclosed in WO 2022199697, the entire contents of which are incorporated herein by reference.
  • the pharmaceutical composition of senaparib suitable for use herein may contain a solid dispersion powder of 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione, and a filler, a disintegrant, a glidant and a lubricant.
  • the solid dispersion powder contains the active ingredient 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione and the polymer hydroxypropyl methylcellulose phthalate.
  • hydroxypropyl methylcellulose phthalate accounts for 65-77%, more preferably 73-77%of the total weight of the solid dispersion powder; the active ingredient accounts for 25-33%of the total weight of the solid dispersion powder.
  • the solid dispersion powder contains the active ingredient 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione and hydroxypropyl methylcellulose phthalate at a weight ratio of 1 : 2 to 1 : 3.
  • the solid dispersion powder consists of the active ingredient 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione and hydroxypropyl methylcellulose phthalate at a weight ratio of 1 : 2 to 1 : 3, preferably consists of the active ingredient 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione and hydroxypropyl methylcellulose phthalate at a weight ratio of 1 : 2 or 1 : 3.
  • the solid dispersion powder further contains a surfactant.
  • the surfactant is a poloxamer.
  • the content of the surfactant is 2%to 5%based on the total weight of the solid dispersion powder.
  • the solid dispersion powder consists of 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione, hydroxypropyl methylcellulose phthalate and poloxamer, and the weight ratio of the three is 1 : 2.8 : 0.2.
  • the filler in the pharmaceutical composition may be selected from one or more of starch, sucrose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, lactose, pregelatinized starch, glucose, maltose, cyclodextrin, cellulose and silicified microcrystalline cellulose. Based on the total weight of the pharmaceutical composition, the content of the filler may be in a range of 60%to 85%, preferably in a range of 70%to 82%, and more preferably in a range of 75%to 82%.
  • the filler includes microcrystalline cellulose.
  • the microcrystalline cellulose has a D90 of 170 ⁇ m to 480 ⁇ m.
  • the microcrystalline cellulose has a D90 of 170 ⁇ m to 283 ⁇ m.
  • the microcrystalline cellulose has a D90 of 275 ⁇ m to 480 ⁇ m.
  • the D90 is measured using a Malvern Mastersizer 2000 laser particle size analyzer, according to the particle size and particle size distribution determination method (Chinese Pharmacopoeia, 2015 Edition, Volume IV, General Rule 0982, Method 3: Dry Method Determination. ) , with the refractive index of the test sample being 1.45.
  • the particle size distribution was measured by a dry method using a laser particle size analyzer (Beckman Coulter LS 200 or LS 230) ; where the vibration sample feeding speed is 15%to 30%, the Auger Speed is 30%to 45%, and the obscuration range is 4%to 12%.
  • a laser particle size analyzer Beckman Coulter LS 200 or LS 230
  • the content of the mannitol is 25%to 70%based on the total weight of the pharmaceutical composition.
  • the content of the mannitol is 50%to 70%, preferably 50%to 65%, based on the total weight of the pharmaceutical composition.
  • the content of the mannitol is 50%to 55%based on the total weight of the pharmaceutical composition; In some other embodiments, the content of the mannitol is 58%to 63%.
  • the content of the mannitol is 25%to 45%based on the total weight of the pharmaceutical composition.
  • the content of the microcrystalline cellulose is 10%to 28%, preferably 15%to 28%, 24%to 28%, or 12%to 18%, based on the total weight of the pharmaceutical composition; the content of the mannitol is 50%to 65%, 50%to 55%or 58%to 63%. In some other embodiments, based on the total weight of the pharmaceutical composition, the content of the microcrystalline cellulose is 35%to 55%, preferably 38%to 55%, and the content of the mannitol is 25%to 43%.
  • the disintegrant in the pharmaceutical composition may be selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof.
  • the disintegrant is crospovidone or croscarmellose or croscarmellose sodium.
  • the content of the disintegrant in the pharmaceutical composition can be 0.1%to 10%, preferably 0.5%to 3%, based on the total weight of the pharmaceutical composition.
  • the disintegrant is crospovidone and/or croscarmellose sodium, and the content of crospovidone and/or croscarmellose sodium is 0.5%to 3%, based on the total weight of the pharmaceutical composition.
  • the range of the particle size of crospovidone is controlled to D90: 270 ⁇ m to 385 ⁇ m.
  • the lubricant may be selected from zinc stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearyl fumarate, and any combination thereof.
  • the lubricant is magnesium stearate.
  • the content of the lubricant can be 0.1%to 3%, preferably 0.3%to 1%, such as 0.5% ⁇ 0.1%, based on the total weight of the pharmaceutical composition.
  • a binder and/or a solubilizer may also be included in the pharmaceutical compositions herein.
  • the solid dispersion powder consists of the active ingredient 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione and hydroxypropyl methylcellulose phthalate at a weight ratio of 1 : 3, and less than 5%by weight, more preferably less than 1%by weight of 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione is in a crystalline form;
  • a particle size distribution of particles with a size of > 75 ⁇ m is not less than 70%, preferably not less than 90%in the mannitol;
  • the medicament used herein is a capsule, containing the pharmaceutical composition as described in any embodiment herein and a capsule shell.
  • the capsule shell is selected from plant a capsule shell and a gelatin capsule shell, more preferably a gelatin capsule shell.
  • the specification of the capsule is 10 mg or 20 mg.
  • the capsule is a capsule with a specification of 10 mg/capsule
  • the pharmaceutical composition in the capsule contains:
  • the solid dispersion powder consists of the active ingredient 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione and hydroxypropyl methylcellulose phthalate at a weight ratio of 1 : 3, and less than 5%by weight, more preferably less than 1%by weight of 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione is in a crystalline form;
  • a D90 of the microcrystalline cellulose is in a range of 170 ⁇ m to 480 ⁇ m, preferably 275 ⁇ m to 480 ⁇ m;
  • a particle size distribution of particles with a size of > 75 ⁇ m is not less than 70%, preferably not less than 80%, more preferably not less than 90%in the mannitol;
  • the capsule is a capsule with a specification of 20 mg/capsule
  • the pharmaceutical composition in the capsule contains:
  • the solid dispersion powder consists of the active ingredient 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione and hydroxypropyl methylcellulose phthalate at a weight ratio of 1 : 3, and less than 5%by weight, more preferably less than 1%by weight of 5-fluoro-1- (4-fluoro-3- (4- (pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H) -dione is in a crystalline form;
  • a D90 of the microcrystalline cellulose is in a range of 170 ⁇ m to 480 ⁇ m, preferably 275 ⁇ m to 480 ⁇ m;
  • a particle size distribution of particles with a size of > 75 ⁇ m is not less than 70%, more preferably not less than 90%in the mannitol;
  • Intravenous infusion chemotherapeutics usually involves the administration of a taxane (paclitaxel or docetaxel) and a platinum-based chemotherapy drugs (such as cisplatin or carboplatin) .
  • methods of maintenance therapy of cancers with or without BRCA1 and/or BRCA2 include administering an effective amount for the maintenance therapy of senaparib, the hydrate or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof or a medicament containing the pharmaceutical composition to patients having the cancers.
  • the maintenance therapy described herein is independent of the patient's BRCA status or independent of the patient's HRD status. Accordingly, in some embodiments, the maintenance therapy method described herein is initiated prior to determining the patient's BRCA status or HRD status. In other embodiments, the maintenance therapy method described herein is initiated without determining the BRCA status or HRD status of the patient.
  • the patient has any one, any two, or all three of the following characteristics (1) to (3) :
  • the patient has a BRCA1 mutation and/or a BRCA2 mutation. In some embodiments, the patient does not have a BRCA1 mutation and/or a BRCA2 mutation.
  • the patient is a patient with negative HRD status. In some embodiments, the patient is a patient with positive HRD status. In some embodiments, the patient does not have a BRCA1 mutation and/or a BRCA2 mutation and has a positive HRD status. In some embodiments, the patient does not have a germline mutation in BRCA1 and/or BRCA2 and has a positive HRD status. In some embodiments, the patient does not have a BRCA1 mutation and/or a BRCA2 mutation and has a negative HRD status.
  • the patient has or does not have a germline mutation (gBRCAmut) in BRCA1 and/or BRCA2. In some embodiments, the patient has or does not have a somatic mutation or a sporadic mutation in BRCA1 and/or BRCA2.
  • gBRCAmut germline mutation
  • somatic mutation or a sporadic mutation in BRCA1 and/or BRCA2.
  • the patient has at least: i) a germline mutation in BRCA1 and/or BRCA2, or ii) a somatic or sporadic mutation in BRCA1 and/or BRCA2.
  • the patient has high-grade serous ovarian cancer or high-grade serous-predominant ovarian cancer.
  • the patient does not have a germline mutation in BRCA1 and/or BRCA2.
  • the patient does not have a somatic mutation or a sporadic mutation in BRCA1 and/or BRCA2.
  • the administration scheme of senaparib, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof or a medicament containing the pharmaceutical composition is as follows: 100 mg/day, the administration frequency is once daily, the cycle is 28 days, until the progression of diseases or occurrence of unacceptable toxicities, or the subjects begin to receive other antitumor therapies.
  • the above-mentioned procedure may be repeated, and the daily dose of senaparib, a hydrate or a pharmaceutically acceptable salt thereof is reduced from 80 mg to 60 mg and the maintenance therapy is continued; if anemia still occurs and the hematological toxicity is grade 3 or 4 after the administration of a daily dose of 60 mg, the above-mentioned procedure may be repeated, and the daily dose of senaparib, a hydrate or a pharmaceutically acceptable salt thereof is reduced from 60 mg to 40 mg and the maintenance therapy is continued; if the patient does not tolerate the daily dose of 40 mg, then the therapy is terminated.
  • the administration is suspended; and if the hematological toxicity returns to ⁇ grade 1 or a baseline level within 28 days after the administration is suspended, and continuation of administration can benefit the patient, then the previous dose level is either maintained to continue the therapy, or reduced (e.g., from 100 mg down to 80 mg, or from 80 mg down to 60 mg) to continue the maintenance therapy.
  • the patient develops neutropenia and leukopenia and the hematological toxicity is grade 3 or 4 after the administration of a daily dose of 100 mg of senaparib, a hydrate or a pharmaceutically acceptable salt thereof, then the administration is suspended; and if the hematological toxicity returns to ⁇ grade 1 or a baseline level within 28 days after the administration is suspended, and continuation of administration can benefit the patient, the daily dose of senaparib, the hydrate or the pharmaceutically acceptable salt thereof is reduced to 80 mg and the maintenance therapy is continued at the daily dose of 80 mg.
  • the progression free survival of a patient is prolonged by at least 6 months using the maintenance therapy as described herein. In some embodiments, the prolonged progression free survival is at least 9 months. In some embodiments, the progression free survival is at least 12 months. In some embodiments, the progression free survival is at least 15 months. In some embodiments, the progression free survival is at least 18 months. In some embodiments, the progression free survival is at least 21 months. In some embodiments, the progression free survival is at least 24 months. In some embodiments, the progression free survival is at least 27 months. In some embodiments, the progression free survival is at least 30 months. In some embodiments, the progression free survival is at least 33 months. In some embodiments, the progression free survival is at least 36 months. In some embodiments, the progression free survival is at least 48 months. In some embodiments, the progression free survival is at least 51 months.
  • the patients with BRCA1 and/or BRCA2 mutations will have a prolonged progression free survival of at least 6 months after receiving the maintenance therapy described herein.
  • the prolonged progression free survival is at least 9 months.
  • the prolonged progression free survival is at least 12 months.
  • the prolonged progression free survival is at least 15 months.
  • the prolonged progression free survival is at least 18 months.
  • the prolonged progression free survival is at least 21 months.
  • the prolonged progression free survival is at least 24 months.
  • the prolonged progression free survival is at least 27 months.
  • the prolonged progression free survival is at least 30 months.
  • the prolonged progression free survival is at least 33 months.
  • the prolonged progression free survival is at least 36 months.
  • the progression free survival is at least 48 months.
  • the progression free survival is at least 51 months.
  • the patient does not have a BRCA1 and/or BRCA2 mutation.
  • the prolonged progression free survival is at least 6 months using the therapy described herein. In some embodiments, the prolonged progression free survival is at least 9 months. In some embodiments, the prolonged progression free survival is at least 12 months. In some embodiments, the prolonged progression free survival is at least 15 months. In some embodiments, the prolonged progression free survival is at least 18 months. In some embodiments, the prolonged progression free survival is at least 21 months. In some embodiments, the prolonged progression free survival is at least 24 months. In some embodiments, the prolonged progression free survival is at least 27 months. In some embodiments, the prolonged progression free survival is at least 30 months. In some embodiments, the prolonged progression free survival is at least 33 months. In some embodiments, the prolonged progression free survival is at least 36 months. In some embodiments, the progression free survival is at least 48 months. In some embodiments, the progression free survival is at least 51 months.
  • the patient does not have a BRCA1 and/or BRCA2 mutation, and the HRD status of the patient is positive, and the prolonged progression free survival is at least 6 months using the maintenance therapy described herein.
  • the prolonged progression free survival is at least 9 months.
  • the prolonged progression free survival is at least 12 months.
  • the prolonged progression free survival is at least 15 months.
  • the prolonged progression free survival is at least 18 months.
  • the prolonged progression free survival is at least 21 months.
  • the prolonged progression free survival is at least 24 months.
  • the prolonged progression free survival is at least 27 months.
  • the prolonged progression free survival is at least 30 months.
  • the prolonged progression free survival is at least 33 months.
  • the prolonged progression free survival is at least 36 months.
  • the progression free survival is at least 48 months.
  • the progression free survival is at least 51 months.
  • the hazard ratio for disease progression or death is reduced using therapy described herein.
  • the hazard ratio for disease progression is about 0.4.
  • the hazard ratio for disease progression is about 0.45.
  • the hazard ratio for disease progression is about 0.5.
  • the hazard ratio for disease progression is less than about 0.5.
  • the hazard ratio for disease progression is less than about 0.45.
  • the hazard ratio for disease progression is less than about 0.4.
  • the hazard ratio for disease progression is less than about 0.35. In some embodiments, the hazard ratio for disease progression is less than about 0.3.
  • the patient has a BRCA1 and/or BRCA2 mutation.
  • the hazard ratio for disease progression is about 0.3. In some embodiments, the hazard ratio for disease progression is about 0.4. In some embodiments, the hazard ratio for disease progression is about 0.45. In some embodiments, the hazard ratio for disease progression is about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.45. In some embodiments, the hazard ratio for disease progression is less than about 0.4. In some embodiments, the hazard ratio for disease progression is less than about 0.35. In some embodiments, the hazard ratio for disease progression is less than about 0.3.
  • the patient does not have a BRCA1 and/or BRCA2 mutation and the HRD status is negative.
  • the hazard ratio for disease progression is about 0.3. In some embodiments, the hazard ratio for disease progression is about 0.4. In some embodiments, the hazard ratio for disease progression is about 0.45. In some embodiments, the hazard ratio for disease progression is about 0.5. In some embodiments, the hazard ratio for disease progression is about 0.75. In some embodiments, the hazard ratio for disease progression is less than about 0.75. In some embodiments, the hazard ratio for disease progression is less than about 0.5. In some embodiments, the hazard ratio for disease progression is less than about 0.45. In some embodiments, the hazard ratio for disease progression is less than about 0.4. In some embodiments, the hazard ratio for disease progression is less than about 0.35. In some embodiments, the hazard ratio for disease progression is less than about 0.3.
  • kits including senaparib, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a medicament containing the pharmaceutical composition.
  • the kit of the present invention is used for maintenance therapy, that is, it is used to prevent cancer recurrence and/or control cancer progression after the first-line chemotherapy has achieved complete response or partial response.
  • the quantity of senaparib, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof or a medicament containing the pharmaceutical composition contained in the kit is preferably at least sufficient for 14 days of administration, and further preferably at least sufficient for 1 cycle of administration (28 days) .
  • the administration includes 100 mg once daily.
  • the kit further includes instructions, wherein the instructions include the content of taking the drug according to the maintenance therapy described in any one of the embodiments herein.
  • the specification of a pharmaceutical composition or a medicament of senaparib, a hydrate or a pharmaceutically acceptable salt thereof includes 10 mg or 20 mg of senaparib, the hydrate or the pharmaceutically acceptable salt thereof per unit or per capsule, to be suitable for patients to take a daily dose of 100 mg, 80 mg, 60 mg, or 40 mg of senaparib, the hydrate or the pharmaceutically acceptable salt thereof.
  • the maintenance therapy is as described in any embodiment herein.
  • senaparib also provided herein is senaparib, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a medicament containing the pharmaceutical composition, for use in the maintenance therapy described herein to prevent cancer recurrence and/or control cancer progression in a patient with or without a BRCA1 and/or BRCA2 mutation.
  • the maintenance therapy and senaparib, a hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or a medicament thereof is as described in any one of the embodiments herein, respectively.
  • Example 1 FIGO stage III-IV ovarian cancer treatment
  • HGS high grade serous
  • HGE high grade endometrioid
  • BRCA breast cancer susceptibility gene
  • the patients were randomly stratified according to the following criteria within 8 weeks after the last chemotherapy administration (that is, the day of the last infusion) : response to first-line platinum-containing chemotherapy (CR/PR) and baseline BRCA status (BRCA mutant type [BRCAmut] /BRCA wild type [BRCAwt] ) .
  • AEs adverse events
  • Tumor evaluations based on Response Evaluation Criteria in Solid Tumors (RECISTs) v1.1 were performed at baseline, and performed every 12 weeks ( ⁇ 1 week) from the date of randomization until week 120, then performed every 24 weeks ( ⁇ 1 week) until objective imaging progressive disease (PD) occurred. All computed tomography (CT) /magnetic resonance imaging (MRI) scan data was subjected to a blinded independent central review (BICR) . No BICR review was performed after the primary efficacy analysis.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • Dose interruption and/or reduction can be carried out at any time for any level of toxicity deemed intolerable by patients.
  • ⁇ It is allowed to adjust the dose levels according to the following table in sequence, with one dose level adjusted at a time, and the range of adjustment is as follows: 40 mg QD-100 mg QD.
  • the dose level can be increased by one level until the maximum administration dose or the highest dose level that the patients can tolerate is reached.
  • the subject if a subject develops grade 2 or higher anemia-related hematological toxicity during the therapy, the subject would be treated according to the following table. If it returns to ⁇ grade 1 or baseline level within 28 days after the administration is suspended, and the investigator determines that continued therapy can bring benefits to the patients, then the investigator is allowed to adjust the dose levels with reference to the table below. At the same time, it is also recommended that investigators conduct routine blood monitoring once a week during this period.
  • the subject if a subject develops grade 2 or higher thrombocytopenia -related hematological toxicity during the therapy, the subject would be treated according to the following table. If it returns to ⁇ grade 1 or baseline level within 28 days after the administration is suspended, and the investigator determines that continued therapy can bring benefits to the patients, then the investigator is allowed to adjust the dose levels with reference to the table below. At the same time, it is also recommended that investigators conduct routine blood monitoring once a week during this period.
  • the subject if a subject develops grade 2 or higher neutropenia and leukopenia-related hematological toxicity during the therapy, the subject would be treated according to the following table. If it returns to ⁇ grade 1 or baseline level within 28 days after the administration is suspended, and the investigator determines that continued therapy can bring benefits to the patients, then the investigator is allowed to adjust the dose levels with reference to the table below. At the same time, it is also recommended that investigators conduct routine blood monitoring once a week during this period.
  • the results of BICR evaluation based on RECIST v1.1 showed: among the 404 patients included in the ITT population, the PFS results of the senaparib group showed a statistically significant benefit compared with the placebo group: using the stratified results at randomization, the stratified Cox proportional hazard model estimated the hazard ratio (HR) to be 0.43 (95%CI: 0.32, 0.58) , and the stratified Log-rank test P value was ⁇ 0.0001.
  • the median PFS of the senaparib group has not yet been reached, and continuous observation is required in following studies; the median PFS in the placebo group was 13.634 months (95%CI: 10.875, 16.624) .
  • the PFS KM curves of the two groups began to separate early, with the curve of the senaparib group consistently higher than that of the placebo group, remaining separated throughout the subsequent observation period.
  • the progression free survival rates of the senaparib group and the placebo group were 72.15%and 53.69%at 12 months, and 63.01%and 31.31%at 24 months, respectively.
  • the KM curves remain consistently separated and shows no significant changes, indicating that PFS benefits can be sustained after the therapy was completed.
  • senaparib can significantly reduce PD in patients compared with placebo.
  • Table 1 Survival analysis -progression free survival (months) -BICR evaluation (ITT population)
  • the HRs for the subgroups with positive and negative BRCA status at baseline were 0.43 (95%CI: 0.24, 0.76) and 0.43 (95%CI: 0.30, 0.61) respectively, and the P values were 0.0026 and ⁇ 0.0001 respectively, that is, the risks were both reduced by 57%, showing superior efficacy regardless of BRCA status.
  • Table 2 and Table 3 below, and FIG. 2 and FIG. 3.
  • the senaparib group could prolong the PFS of patients in all subgroups compared with placebo.
  • the HRs of the CR and PR subgroups in response to the first-line platinum-containing chemotherapy were 0.41 (95%CI: 0.30, 0.58) and 0.45 (95%CI: 0.19, 1.05) respectively, and the P values were ⁇ 0.0001 and 0.0575, respectively, indicating that regardless of whether the response to the first-line platinum-containing chemotherapy is CR or PR, the patients can benefit or the risk of PD or death of the patients can be reduced, as shown in FIG. 4.
  • the results of investigator evaluation based on RECIST v1.1 showed: among the 404 patients included in the ITT population, the PFS results of the senaparib group showed a significant benefit compared with the placebo group: using the stratified results at randomization, the stratified Cox proportional hazard model estimated the HR to be 0.43 (95%CI: 0.32, 0.57) , and the stratified Log-rank test P value was ⁇ 0.0001.
  • the median PFS of the senaparib group has not yet been reached, and continuous observation is required in following studies; the median PFS in the placebo group was 11.105 months (95%CI: 9.396, 15.474) .
  • the PFS KM curves of the two groups began to separate early, with the curve of the senaparib group consistently higher than that of the placebo group, remaining separated throughout the subsequent observation period.
  • the progression free survival rates of the senaparib group and the placebo group were 72.69%and 49.15%at 12 months, and 58.45%and 31.00%at 24 months, respectively; at 30 months and 33 months, the progression free survival rate in the senaparib group was 54.67%, and the progression free survival rate in the placebo group was 19.64%.
  • senaparib can significantly reduce PD in patients compared with placebo.
  • the PFS results evaluated by the investigator were consistent with those evaluated by BICR.
  • the median CFI of the senaparib group has not yet been reached.
  • the currently available data show that the CFI results of the senaparib group show a benefit compared with the placebo group (median CFI: 16.690 months [95%CI: 13.897, 23.589] ) : the stratified Cox proportional hazard model estimated the HR to be 0.41 (95%CI: 0.30, 0.55) , and the stratified Log-rank test P value was ⁇ 0.0001. This demonstrates that senaparib can significantly prolong the CFI of patients compared with placebo.
  • the median TFST of the senaparib group has not yet been reached.
  • the currently available data show that the TFST results of the senaparib group show a benefit compared with the placebo group (median TFST: 14.390 months [95%CI] : 11.269, 17.117) : the stratified Cox proportional hazard model estimated the HR to be 0.44 (95%CI: 0.33, 0.59) , and the stratified Log-rank test P value was ⁇ 0.0001. This demonstrates that senaparib can significantly prolong the TFST of patients compared with placebo.
  • Time to discontinuation of study treatment or death (TDT):
  • HRD genomic instability score
  • Comparison of the baseline characteristics of senaparib group with those of the placebo group for the 222 patients suggests that the two are balanced.
  • a comparison of the baseline characteristics of the 222 patients with those of the general ITT population shows that the baseline characteristics of the two are basically similar, suggesting that the HRD data of these 222 patients are representative in the HRD data of the general ITT population.
  • the median time i.e., the time required for half of the patients to experience adjustment of dose reduction was 2.79 (ranging from 0.62 to 22.60) months and 2.37 (ranging from 0.69 to 20.53) months, respectively.
  • Treatment Emergent Adverse Event occurred in 269/270 (99.6%) patients and 130/133 (97.7%) patients in the senaparib group and the placebo group, respectively, and 267 patients (98.9%) and 107 patients (80.5%) patients experienced TEAEs related to the study drugs, respectively.
  • TEAEs Treatment Emergent Adverse Events
  • the incidence of serious TEAEs related to the study drugs, TEAEs of CTCAE ⁇ grade 3 related to the study drugs, TEAEs causing dose reduction, etc. gradually decreased with the decrease in dose, and there were no TEAEs causing deaths in each dose group.
  • the incidence of different hematological toxicities e.g., ⁇ grade 3 anemia, neutropenia, and thrombocytopenia
  • the PARP inhibitor niraparib has been approved globally for first-line maintenance therapy of the overall population of advanced ovarian cancer.
  • a total of 2 phase III confirmatory clinical studies of niraparib have been conducted for the indications of first-line maintenance therapy of the overall ovarian cancer population, i.e., the PRIMA (conducted globally) and the PRIME study (conducted in China) , which enrolled 733 and 384 patients, respectively.
  • the initial dose of niraparib for patients was 300 mg QD.
  • the dose of niraparib can be reduced from approximately 300 mg QD to 200 mg QD, or from 200 mg QD to 100 mg QD for any patients, the dose can be reduced for up to 2 times, and the dose cannot be reduced to lower than 100 mg QD.
  • the primary endpoints of FLAMES study of senaparib and PRIMA and PRIME studies of niraparib are PFS evaluated by BICR.
  • senaparib had a lower median PFS hazard ratio in the FLAMES study (HR 0.43 vs. 0.45 and 0.62) .
  • the median PFS in the senaparib group has not yet been reached, and is estimated to be 40 months, which is 26.4 months longer than placebo.
  • the absolute benefit of PFS is better than the results of the niraparib PRIMA and PRIME studies (26.4 months vs. 5.6 months and 16.5 months) . See Table 6 and Table 7 for data details.
  • niraparib was used at an individualized initial dose (ISD) in the PRIME study, that is, the initial dose for patients with body weight ⁇ 77 kg or baseline blood platelet count ⁇ 150 ⁇ 10 9 /L was reduced to 200 mg QD.
  • ISD individualized initial dose
  • the median PFS hazard ratio of senaparib in the FLAMES study was lower, and the absolute PFS benefit was greater; senaparib had a generally low incidence and severity of non-hematological toxicities, a generally low incidence of adverse events leading to permanent discontinuation of administration, a wider therapeutic window, and good tolerance.
  • the results of the FLAMES study showed that senaparib had a significant benefit/risk ratio for first-line maintenance therapy in patients with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
  • the FLAMES study has completed its interim analysis, and the data as of March 16, 2023 show:
  • the median PFS based on BICR evaluation was either not reached or 13.6 months in the senaparib group and the placebo group, respectively, HR 0.43, p ⁇ 0.0001, and the primary endpoint was achieved.
  • Senaparib can significantly reduce the risk of disease progression or death of patients regardless of BRCA mutation status.
  • Senaparib has a lower PFS hazard ratio compared with the results of studies on comparable drugs.
  • the median PFS in the senaparib group is estimated to be about 40 months, which is prolonged by 26.4 months compared with placebo.
  • the absolute benefit of PFS is better than the results of the niraparib PRIMA and PRIME studies (prolonged by 5.6 months and 16.5 months, respectively) .
  • niraparib a comparable drug
  • the dose of niraparib, a comparable drug could only be reduced once for most patients (200 mg ⁇ 100 mg)
  • senaparib had a wider therapeutic window and the dose could be reduced 3 times (100 mg ⁇ 80 mg ⁇ 60 mg ⁇ 40 mg) .
  • the incidence and severity of adverse reactions could be significantly reduced while maintaining efficacy, the incidence of adverse events leading to permanent discontinuation of administration was only 4.4%, and senaparib had better tolerance and greater efficacy benefits.
  • using the maintenance therapy and dose adjustment regimen can effectively reduce the incidence and severity of hematological and non-hematological toxicities in patients, which has good tolerance, reduces the proportion of permanent discontinuation, while maintaining good drug efficacy.
  • the maintenance therapy of the present invention can significantly improve PFS and reduce the patient's risk of disease progression or death.
  • the interim analysis data of this phase III clinical study reached the preset superiority standard, providing solid evidence for senaparib in the maintenance therapy of adult patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer after achieving CR or PR with the first-line platinum-containing chemotherapy.

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Abstract

L'invention concerne l'utilisation d'un inhibiteur de PARP dans le traitement d'un cancer, et en particulier l'utilisation d'un inhibiteur de PARP dans la thérapie d'entretien du cancer de l'ovaire. Plus spécifiquement, l'invention concerne une thérapie d'entretien pour une patiente atteinte d'un cancer de l'ovaire, qui comprend l'administration d'une quantité efficace de 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)pipérazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione, d'un hydrate ou d'un sel pharmaceutiquement acceptable de celle-ci, ou d'une composition pharmaceutique contenant de la 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)pipérazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione, de l'hydrate ou du sel pharmaceutiquement acceptable de celle-ci ou d'un médicament contenant la composition pharmaceutique à une patiente atteinte d'un cancer de l'ovaire ayant reçu un régime thérapeutique de première intention contenant du platine et ayant obtenu une réponse complète ou une réponse partielle.
PCT/CN2024/119509 2023-09-19 2024-09-18 Utilisation d'un inhibiteur de parp dans une thérapie d'entretien du cancer de l'ovaire Pending WO2025061057A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025217307A1 (fr) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Procédés de prédiction de la réponse à un inhibiteur de ras(on) et polythérapies
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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