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WO2018141921A1 - Traitement du cancer - Google Patents

Traitement du cancer Download PDF

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Publication number
WO2018141921A1
WO2018141921A1 PCT/EP2018/052694 EP2018052694W WO2018141921A1 WO 2018141921 A1 WO2018141921 A1 WO 2018141921A1 EP 2018052694 W EP2018052694 W EP 2018052694W WO 2018141921 A1 WO2018141921 A1 WO 2018141921A1
Authority
WO
WIPO (PCT)
Prior art keywords
erdafitinib
treatment
serum phosphate
cancer
daily
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2018/052694
Other languages
English (en)
Inventor
Kim STUYCKENS
Juan Jose PEREZ RUIXO
Peter Marie Z. DE PORRE
Anjali Narayan AVADHANI
Yohann LORIOT
Arlene O. SIEFKER-RADTKE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to UAA201909567A priority Critical patent/UA126336C2/uk
Priority to AU2018216969A priority patent/AU2018216969B2/en
Priority to HRP20230697TT priority patent/HRP20230697T1/hr
Priority to DK18702299.1T priority patent/DK3576740T3/da
Priority to EP23178682.3A priority patent/EP4286005A3/fr
Priority to MX2019009304A priority patent/MX2019009304A/es
Priority to EP18702299.1A priority patent/EP3576740B1/fr
Priority to ES18702299T priority patent/ES2953005T3/es
Priority to MA47408A priority patent/MA47408B1/fr
Priority to SI201830961T priority patent/SI3576740T1/sl
Priority to SM20230233T priority patent/SMT202300233T1/it
Priority to JP2019541398A priority patent/JP2020505425A/ja
Priority to EA201991818A priority patent/EA201991818A1/ru
Priority to LTEPPCT/EP2018/052694T priority patent/LT3576740T/lt
Priority to KR1020257014703A priority patent/KR20250069693A/ko
Priority to CA3049737A priority patent/CA3049737A1/fr
Priority to FIEP18702299.1T priority patent/FI3576740T3/fi
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to BR112019016043-4A priority patent/BR112019016043A2/pt
Priority to RS20230615A priority patent/RS64778B1/sr
Priority to CN201880008126.XA priority patent/CN110198716A/zh
Priority to US16/483,579 priority patent/US11077106B2/en
Priority to PL18702299.1T priority patent/PL3576740T3/pl
Priority to SG11201907199QA priority patent/SG11201907199QA/en
Priority to KR1020197024552A priority patent/KR20190110581A/ko
Publication of WO2018141921A1 publication Critical patent/WO2018141921A1/fr
Priority to IL268463A priority patent/IL268463A/en
Priority to PH12019501885A priority patent/PH12019501885A1/en
Anticipated expiration legal-status Critical
Priority to US17/360,618 priority patent/US20220110935A1/en
Priority to JP2022189239A priority patent/JP7668777B2/ja
Priority to AU2024201871A priority patent/AU2024201871A1/en
Priority to JP2024196985A priority patent/JP2025024064A/ja
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention provides for the treatment of cancer with erdafitinib with a high potential for response while limiting potential toxicities such as for example nail toxicities.
  • the present invention provides for treatment of cancer with erdafitinib that maximizes erdafitinib exposure while limiting potential toxicities.
  • the present invention provides for treatment of cancer with erdafitinib with a high objective response rate, in particular with an objective response rate of at least 40%, in particular with an objective response rate of at least 40 % in chemo-nai ' ve cancer patients, with an objective response rate of at least 40 % in cancer patients who had disease progression after one prior line of chemotherapy, with an objective response rate of at least 40 % in cancer patients who had disease progression after two or more prior lines of chemotherapy.
  • the present invention provides for treatment of cancer with erdafitinib with a short time to response, in particular with a median time to response less than 2 months.
  • Figure 1 represents the study scheme for the Phase 2, multicenter, open-label study to evaluate the efficacy and safety of erdafitinib in subjects with metastatic or surgically unresectable urothelial cancer harboring selected FGFR (fibroblast growth factor receptor) genetic alterations (FGFR translocations or mutations).
  • FGFR fibroblast growth factor receptor
  • Figure 2 represents a Waterfall plot of maximum percentage reduction from baseline in sum of target lesion diameters among patients treated with the regimen of 8 mg continuous erdafitinib (Regimen 3 of the phase 2 study (Fig. 1)).
  • the present invention provides for the treatment of cancer with erdafitinib that maximizes erdafitinib exposure already within the first cycle of treatment (set at, for example, the first 28 days of treatment or the first 21 days of treatment, in particular with daily continuous dosing) as well as during further treatment cycles (set at, for example, 28 days/cycle or 21 days/cycle, in particular with daily continuous dosing) while limiting potential toxicities.
  • the present invention provides for treatment of cancer with erdafitinib that maximizes erdafitinib exposure and brings the subject in need of erdafitinib quickly at the target serum phosphate range, in particular ranging from and including 5.5 mg/dL to ⁇ 7 mg/dL or ranging from and including 5.5 mg/dL to ⁇ 9 mg/dL, to keep phosphate based toxicities under control.
  • Erdafitinib or N-(3 ,5 -dimethoxyphenyl)-N'-( 1 -methylethyl)-N- [3 -( 1 -methyl- 1 H-pyrazol- 4-yl)quinoxalin-6-yl]ethane-l,2-diamine is a pan- fibroblast growth factor receptor (FGFR 1,2,3,4) tyrosine kinase inhibitor.
  • Serum phosphate levels may represent an on-target pharmacodynamic marker pointing towards FGFR target engagement by erdafitinib. Levels of serum phosphate are likely to increase with target engagement. But the serum phosphate levels need to be monitored to minimize or avoid or control acute and prolonged hyperphosphatemia.
  • the proportion of patients showing objective response rate is, depending on the cancer type, at least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, 50%, 55%, 60%, 65% or above 65%.
  • the exposure to erdafitinib is such that it provides for an objective response rate, depending on the cancer type, of at least 15%, or 20%>, or 25%, or 30%>, or 35%, or 40%, or 45%, 50 %, 55%, 60%, 65% or above 65%.
  • the serum phosphate levels of the cancer patient is > 5.5 mg/dL, in particular ranging from and including 5.5 mg/dL to ⁇ 7 mg/dL or ranging from and including 5.5 mg/dL to ⁇ 9 mg/dL, upon exposure to erdafitinib providing for an objective response rate, depending on the cancer type, of at least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, 50 %, 55%, 60%, 65% or above 65%.
  • the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein provide for an objective response rate of at least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, 50 %, 55%, 60%, 65% or above 65%.
  • the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein, wherein the cancer is urothelial cancer, metastatic or surgically unresectable urothelial cancer, in particular urothelial cancer, metastatic or surgically unresectable urothelial cancer with selected FGFR genetic alterations provide for an objective response rate of at least 40 %, in particular is about 40%>, is about 41%, is about 42%, is about 43%, is about 44%, is about 45%), is about 46%, is about 47%, is about 48%, is about 49%, is about 50%.
  • the objective response rate ranges from 40% to 50%, or ranges from 40% to 45%, or ranges from 42% to 45%,
  • the objective response rate upon exposure to erdafitinib according to the dosing regimens as disclosed herein is at least 40%), in particular is about 40%, is about 41%, is about 42%, is about 43%, is about 44%, is about 45%, is about 46%, is about 47%, is about 48%, is about 49%, is about 50%.
  • the objective response rate ranges from 40% to 50%, or ranges from 40% to 45%, or ranges from 42% to 45%,
  • the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein provide for a median duration of response of at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months.
  • the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein, wherein the cancer is urothelial cancer, metastatic or surgically unresectable urothelial cancer, in particular urothelial cancer, metastatic or surgically unresectable urothelial cancer with selected FGFR genetic alterations provide for a median duration of response of at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or is about 4 months, or about 5 months or about 6 months or about 7 months. In particular, the median duration of response ranges between 4 months and 7 months.
  • the median duration of response upon exposure to erdafitinib according to the dosing regimens as disclosed herein is at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or is about 4 months, or about 5 months or about 6 months or about 7 months.
  • the median duration of response ranges between 4 months and 7 months.
  • the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein provide for a median progression free survival of at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months.
  • the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein, wherein the cancer is urothelial cancer, metastatic or surgically unresectable urothelial cancer, in particular urothelial cancer, metastatic or surgically unresectable urothelial cancer with selected FGFR genetic alterations provide for a median progression free survival of at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or is about 4 months, or about 5 months or about 6 months or about 7 months.
  • the median progression free survival ranges between 4 months and 7 months.
  • the median progression free survival upon exposure to erdafitinib according to the dosing regimens as disclosed herein is at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or is about 4 months, or about 5 months or about 6 months or about 7 months.
  • the median progression free survival ranges between 4 months and 7 months.
  • the median time to response to the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein is very short.
  • the median time to response is less than 2 months, in particular less than 1.5 months, in particular is around 1.4 months.
  • the methods of treatment of cancer as described herein or the uses for the manufacture of a medicament for the treatment of cancer as described herein or erdafitinib for use in the treatment of cancer as described herein, wherein the cancer is urothelial cancer, metastatic or surgically unresectable urothelial cancer, in particular urothelial cancer, metastatic or surgically unresectable urothelial cancer with selected FGFR genetic alterations provide for a median time to response of less than 2 months, in particular less than 1.5 months, in particular is around 1.4 months.
  • the median time to response upon exposure to erdafitinib according to the dosing regimens as disclosed herein is less than 2 months, in particular less than 1.5 months, in particular is around 1.4 months.
  • the response to the treatments of cancer as described herein is independent of the number of prior lines treatment received by the patient, e.g. a chemo-na ' ive patient, in particular a chemo-nai ' ve patient ineligible for cisplatin, a patient who had disease progression after one prior line of chemotherapy or a patient who had disease progression after two or more prior lines of chemotherapy.
  • the response to the treatment is similar for patients with different numbers of prior lines of treatment received, e.g. a chemo-na ' ive patient, in particular a chemo-na ' ive patient ineligible for cisplatin, a patient who had disease progression after one prior line of chemotherapy or a patient who had disease progression after two or more prior lines of chemotherapy.
  • the response to the treatments of cancer by patients with prior line chemotherapy e.g. a patient who had disease progression after one prior line of chemotherapy or a patient who had disease progression after two or more prior lines of chemotherapy, is not worse than for chemo- na ' ive patients.
  • serum phosphate levels of >7 mg/dL, in particular >9 mg/dL may warrant temporary erdafitinib treatment interruption or erdafitinib dose adjustment (dose decrease).
  • temporary erdafitinib interruption represents interruption of erdafitinib administration until serum phosphate levels are again ⁇ 5.5 mg/dL.
  • temporary erdafitinib interruption represents interruption of erdafitinib administration until serum phosphate levels are again ⁇ 7 mg/dL.
  • an efficacious and safe treatment with erdafitinib is administering erdafitinib in a therapeutically effective dose such that the serum phosphate levels range from and including 5.5 mg/dL to ⁇ 7 mg/dL or range from and including 5.5 mg/dL to ⁇ 9 mg/dL.
  • Serum phosphate levels can be measured with commercially available kits such as for example ab65622 Phosphate Assay Kit (Colorimetric) (Abeam). It has been found that with a dose of 8 mg of erdafitinib daily, preferably once daily, on a continuous basis (every day, no treatment interruption, no intermittent administration unless the contexts indicates differently) the potential for the subject in need of erdafitinib administration, in particular the cancer patient, to reach or cross the 5.5 mg/dL serum phosphate levels increases, while minimizing the need for treatment interruption or dose reduction for potential drug related adverse events.
  • kits such as for example ab65622 Phosphate Assay Kit (Colorimetric) (Abeam). It has been found that with a dose of 8 mg of erdafitinib daily, preferably once daily, on a continuous basis (every day, no treatment interruption, no intermittent administration unless the contexts indicates differently) the potential for the subject in need of erdafitinib administration, in
  • the 5.5 mg/dL serum phosphate levels may be reached in the first cycle (set at, for example, the first 28 days or the first 21 days) of erdafitinib treatment. It has been found that with a dose of 8 mg of erdafitinib daily, preferably once daily, on a continuous basis the potential for the subject in need of erdafitinib administration, in particular the cancer patient, to reach or cross the 5.5 mg/dL serum phosphate levels early enough during the first cycle (e.g. at day 14 ⁇ 2 days of the treatment) of erdafitinib treatment increases to maximize efficacious treatment while minimizing the need for treatment interruption or dose reduction for potential drug related adverse events.
  • the serum phosphate levels of the subject in need of erdafitinib treatment, in particular the cancer patient are monitored.
  • the serum phosphate levels of the subject in need of erdafitinib treatment, in particular the cancer patient are monitored and early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically shown by the subject, in need of erdafitinib treatment, in particular the cancer patient, are monitored.
  • early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically comprise grade 3 or higher xerostomia or stomatitis/mucositis, dry skin, dry eye, nail toxicity (or grade 2 if lasting more than 1 week) or grade 2 or higher eye toxicity (keratitis, central serious retinopathy/retinal pigment epithelial detachments).
  • Early onset toxicity may warrant treatment interruption or dose reduction. It is up to the discretion of the physician and it may depend on the disease state of the patient.
  • early onset toxicity or early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically as described herein means clinically significant toxicity considered related to FGFR inhibitors in general or to erdafitinib specifically, usually considered to be grade 3 or higher, consisting of one or more of the following : stomatitis/mucositis, dry skin, dry eye, nail toxicity or specific eye toxicity (keratitis, or retinopathy also described as central serous retinopathy, retinal detachment, retinal edema, retinal pigment epithelial detachment, chorioretinopathy) or pertaining to other significant toxicity considered related to FGFR inhibitors in general or to erdafitinib specifically.
  • Early onset toxicity may warrant treatment interruption or dose reduction. It is up to the discretion of the physician and it may depend on the disease state of the patient.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, an amount of erdafitinib so that the levels of serum phosphate range from and including 5.5 mg/dL to ⁇ 7 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, an amount of erdafitinib so that the levels of serum phosphate attain, within the first cycle of erdafitinib administration (a treatment cycle duration set at, for example, the first 28 days of administration or the first 21 days of administration and the serum phosphate level assessed at or around the 28 th day, or at or around the 21 st day or at or around the 14 th day of administration) the range from and including 5.5 mg/dL to ⁇ 7 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, an amount of erdafitinib so that the levels of serum phosphate range from and including 5.5 mg/dL to ⁇ 9 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, an amount of erdafitinib so that the levels of serum phosphate attain, within the first cycle of erdafitinib administration (a treatment cycle duration set at, for example, the first 28 days of administration or the first 21 days of administration and the serum phosphate level assessed at or around the 28 th day, or at or around the 21 st day or at or around the 14 th day of administration) the range from and including 5.5 mg/dL to ⁇ 9 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer, in an amount so that the levels of serum phosphate range from and including 5.5 mg/dL to ⁇ 7 mg/dL.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer, in an amount so that the levels of serum phosphate attain, within the first cycle of erdafitinib
  • administration (a treatment cycle duration set at, for example, the first 28 days of administration or the first 21 days of administration and the serum phosphate level assessed at or around the 28 th day, or at or around the 21 st day or at or around the 14 th day of administration) the range from and including 5.5 mg/dL to ⁇ 7 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer, in an amount so that the levels of serum phosphate range from and including 5.5 mg/dL to ⁇ 9 mg/dL.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer, in an amount so that the levels of serum phosphate attain, within the first cycle of erdafitinib
  • administration (a treatment cycle duration set at, for example, the first 28 days of administration or the first 21 days of administration and the serum phosphate level assessed at or around the 28 th day, or at or around the 21 st day or at or around the 14 th day of administration) the range from and including 5.5 mg/dL to ⁇ 9 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns erdafitinib for use in the treatment of cancer, wherein erdafitinib is administered in an amount so that the levels of serum phosphate range from and including 5.5 mg/dL to ⁇ 7 mg/dL.
  • the present invention concerns erdafitinib for use in the treatment of cancer, wherein erdafitinib is administered in an amount so that the levels of serum phosphate attain, within the first cycle of erdafitinib administration (a treatment cycle duration set at, for example, the first 28 days of administration or the first 21 days of administration and the serum phosphate level assessed at or around the 28 th day, or at or around the 21 st day or at or around the 14 th day of administration) the range from and including 5.5 mg/dL to ⁇ 7 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns erdafitinib for use in the treatment of cancer, wherein erdafitinib is administered in an amount so that the levels of serum phosphate range from and including 5.5 mg/dL to ⁇ 9 mg/dL.
  • the present invention concerns erdafitinib for use in the treatment of cancer, wherein erdafitinib is administered in an amount so that the levels of serum phosphate attain, within the first cycle of erdafitinib administration (a treatment cycle duration set at, for example, the first 28 days of administration or the first 21 days of administration and the serum phosphate level assessed at or around the 28 th day, or at or around the 21 st day or at or around the 14 th day of administration) the range from and including 5.5 mg/dL to ⁇ 9 mg/dL.
  • the amount of erdafitinib is 8 mg, in particular 8 mg daily administered on a continuous basis.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 8 mg of erdafitinib daily, in particular once daily, on a continuous basis. Dose adjustment may be done based on serum phosphate level and observed or absence of toxicity.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer, wherein the medicament comprises erdafitinib in an amount of 8 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis. Dose adjustment may be done based on serum phosphate level and observed or absence of toxicity.
  • the present invention concerns erdafitinib for use in the treatment of cancer, wherein erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis. Dose adjustment may be done based on serum phosphate level and observed or absence of toxicity.
  • serum phosphate levels can be monitored. If the levels of serum phosphate are ⁇ 5.5 mg/dL, then the dose of erdafitinib can be increased, can be up-titrated to 9 mg daily, preferably once daily, on a continuous basis. In an embodiment, the levels of serum phosphate for determining whether or not to up-titrate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day
  • serum phosphate levels can be monitored. If the levels of serum phosphate are ⁇ 7 mg/dL or range from and include 7 mg/dL to ⁇ 9 mg/dL or are ⁇ 9 mg/dL, then the dose of erdafitinib can be increased, can be up-titrated to 9 mg daily, preferably once daily, on a continuous basis.
  • the levels of serum phosphate for determining whether or not to up-titrate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 8 mg of erdafitinib daily, in particular once daily, on a continuous basis which method comprises monitoring of serum phosphate levels of the subject.
  • the levels of serum phosphate for determining whether or not to up-titrate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 8 mg, wherein the medicament is for daily, in particular once daily, administration on a continuous basis and wherein serum phosphate levels of the cancer patient are monitored.
  • the levels of serum phosphate for determining whether or not to up-titrate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis and wherein the serum phosphate levels of the cancer patient are monitored.
  • the levels of serum phosphate for determining whether or not to up-titrate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 8 mg of erdafitinib daily, in particular once daily, on a continuous basis, which method comprises monitoring of serum phosphate levels of the subject and when the serum phosphate levels are ⁇ 5.5 mg/dL, the daily amount, preferably the once daily amount, of erdafitinib administered on a continuous basis, is increased to 9 mg.
  • the serum phosphate levels range from and including 5.5 mg/dL to ⁇ 7 mg/dL, the subject remains on the 8 mg daily continuous treatment.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, or the daily continuous dose is adjusted to ⁇ 8 mg, in particular the treatment is interrupted temporarily, in particular until serum phosphate levels are ⁇ 5.5 mg/dL.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 5.5 mg/dL and then erdafitinib treatment is re-started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 8 mg of erdafitinib daily, in particular once daily, on a continuous basis, which method comprises monitoring of serum phosphate levels of the subject and when the serum phosphate levels are ⁇ 7 mg/dL, the daily amount, preferably the once daily amount, of erdafitinib administered on a continuous basis, is increased to 9 mg.
  • the daily amount preferably the once daily amount, of erdafitinib administered on a continuous basis, is increased to 9 mg, while concurrently treatment with a phosphate binder, such as for example sevelamer, is optionally initiated.
  • concurrent treatment with a phosphate binder such as for example sevelamer, is initiated.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, and, upon serum phosphate being below 7 mg/dL, the daily continuous dose is adjusted to the same or a lower daily dose.
  • the treatment is interrupted permanently, in particular erdafitinib treatment is interrupted permanently.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 8 mg of erdafitinib daily, in particular once daily, on a continuous basis, which method comprises monitoring of serum phosphate levels of the subject and monitoring of early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically shown by the subject, and when the serum phosphate levels are ⁇ 5.5 mg/dL and no early onset toxicity is shown, the daily amount, preferably the once daily amount, of erdafitinib administered on a continuous basis, is increased to 9 mg.
  • the subject When the serum phosphate levels range from and including 5.5 mg/dL to ⁇ 7 mg/dL and no early onset toxicity is shown, the subject remains on the 8 mg daily continuous treatment.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, or the daily continuous dose is adjusted to ⁇ 8 mg, in particular the treatment is interrupted temporarily, in particular until serum phosphate levels are ⁇ 5.5 mg/dL.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 5.5 mg/dL and then erdafitinib treatment is re-started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 8 mg of erdafitinib daily, in particular once daily, on a continuous basis, which method comprises monitoring of serum phosphate levels of the subject and monitoring of early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically shown by the subject, and when the serum phosphate levels are ⁇ 7 mg/dL and no early onset toxicity is shown, the daily amount, preferably the once daily amount, of erdafitinib administered on a continuous basis, is increased to 9 mg.
  • the daily amount preferably the once daily amount, of erdafitinib administered on a continuous basis, is increased to 9 mg, while concurrently treatment with a phosphate binder, such as for example sevelamer, is optionally initiated.
  • concurrent treatment with a phosphate binder such as for example sevelamer, is initiated.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, and, upon serum phosphate being below 7 mg/dL, the daily continuous dose is adjusted to the same or a lower daily dose.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitimb treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitimb administration.
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 7 mg/dL and then erdafitinib treatment is re- started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 9 mg of erdafitinib daily, in particular once daily, on a continuous basis, which method comprises monitoring of serum phosphate levels of the subject and wherein the 9 mg is administered to the subject when the serum phosphate levels of said subject are ⁇ 5.5 mg/dL while being on a treatment with erdafitinib 8 mg daily, in particular once daily, on a continuous basis.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 9 mg of erdafitinib daily, in particular once daily, on a continuous basis, wherein the 9 mg is administered to the subject when the serum phosphate levels of said subject are ⁇ 7 mg/dL or when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, while being on a treatment with erdafitinib 8 mg daily, in particular once daily, on a continuous basis.
  • a phosphate binder such as for example sevelamer
  • concurrent treatment with a phosphate binder such as for example sevelamer, is initiated.
  • the levels of serum phosphate are measured on day 14 ⁇ 2 days, in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 9 mg of erdafitinib daily, in particular once daily, on a continuous basis, wherein the 9 mg is administered to the subject when the serum phosphate levels of said subject are
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns a method for the treatment of cancer, which method comprises administering to a subject in need thereof, in particular a cancer patient, 9 mg of erdafitinib daily, in particular once daily, on a continuous basis, wherein the 9 mg is administered to the cancer patient when the serum phosphate levels of said patient are
  • ⁇ 9 mg/dL and no early onset toxicity is shown while being on a treatment with erdafitinib 8 mg daily, in particular once daily, on a continuous basis.
  • concurrent treatment with a phosphate binder such as for example sevelamer
  • concurrent treatment with a phosphate binder is initiated.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 8 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein serum phosphate levels of the cancer patient are monitored and when the serum phosphate levels are ⁇ 5.5 mg/dL, the amount of erdafitinib in the medicament for daily, in particular once daily, administration on a continuous basis is increased to 9 mg.
  • serum phosphate levels range from and including 5.5 mg/dL to ⁇ 7 mg/dL, the patient remains on the 8 mg daily continuous treatment.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, or the daily continuous dose is adjusted to ⁇ 8 mg, in particular the treatment is interrupted temporarily, in particular until serum phosphate levels are
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 5.5 mg/dL and then erdafitinib treatment is re-started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 8 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein serum phosphate levels of the cancer patient are monitored and when the serum phosphate levels are ⁇ 7 mg/dL, the amount of erdafitinib in the medicament for daily, in particular once daily, administration on a continuous basis, is increased to 9 mg.
  • the amount of erdafitinib for daily, in particular once daily, administration on a continuous basis is increased to 9 mg, while concurrently treatment with a phosphate binder, such as for example sevelamer, is optionally initiated.
  • concurrent treatment with a phosphate binder, such as for example sevelamer is initiated.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, and, upon serum phosphate being below 7 mg/dL, the daily continuous dose is adjusted to the same or a lower daily dose.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 7 mg/dL and then erdafitinib treatment is re-started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 8 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein serum phosphate levels of the cancer patient are monitored and early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically shown by the cancer patient is monitored, and when the serum phosphate levels are ⁇ 5.5 mg/dL and no early onset toxicity is shown, the amount of erdafitinib in the medicament for daily, in particular once daily, administration on a continuous basis is increased to 9 mg.
  • the patient remains on the 8 mg daily continuous treatment.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, or the daily continuous dose is adjusted to ⁇ 8 mg, in particular the treatment is interrupted temporarily, in particular until serum phosphate levels are ⁇ 5.5 mg/dL.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 5.5 mg/dL and then erdafitinib treatment is re-started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 8 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein serum phosphate levels of the cancer patient are monitored and early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically shown by the cancer patient is monitored, and when the serum phosphate levels are ⁇ 7 mg/dL and no early onset toxicity is shown, the amount of erdafitinib in the medicament for daily, in particular once daily, administration on a continuous basis, is increased to 9 mg.
  • the amount of erdafitinib for daily, in particular once daily, administration on a continuous basis is increased to 9 mg, while concurrently treatment with a phosphate binder, such as for example sevelamer, is optionally initiated.
  • concurrent treatment with a phosphate binder, such as for example sevelamer is initiated.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, and, upon serum phosphate being below 7 mg/dL, the daily continuous dose is adjusted to the same or a lower daily dose.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 7 mg/dL and then erdafitinib treatment is restarted with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 9 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein the medicament is administered to the cancer patient when the serum phosphate levels of said patient are ⁇ 5.5 mg/dL while being on a treatment with erdafitinib 8 mg daily, in particular once daily, on a continuous basis.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 9 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein the medicament is administered to the cancer patient when the serum phosphate levels of said patient are ⁇ 7 mg/dL or when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, while being on a treatment with erdafitinib 8 mg daily, in particular once daily, on a continuous basis.
  • the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL
  • concurrent treatment with a phosphate binder such as for example sevelamer
  • concurrent treatment with a phosphate binder is initiated.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 9 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein the medicament is administered to the cancer patient when the serum phosphate levels of said patient are ⁇ 5.5 mg/dL and no early onset toxicity is shown while being on a treatment with erdafitinib 8 mg daily, in particular once daily, on a continuous basis.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein the medicament comprises erdafitinib in an amount of 9 mg and wherein the medicament is for daily, in particular once daily, administration on a continuous basis, wherein the medicament is administered to the cancer patient when the serum phosphate levels of said patient are ⁇ 7 mg/dL or when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, and no early onset toxicity is shown while being on a treatment with erdafitinib 8 mg daily, in particular once daily, on a continuous basis.
  • concurrent treatment with a phosphate binder such as for example sevelamer
  • concurrent treatment with a phosphate binder is initiated.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis, wherein the serum phosphate levels in the cancer patient are monitored and when the serum phosphate levels are ⁇ 5.5 mg/dL, the amount of erdafitinib administered daily, preferably once daily, on a continuous basis, is increased to 9 mg.
  • the serum phosphate levels range from and including 5.5 mg/dL to ⁇ 7 mg/dL, the patient remains on the 8 mg daily continuous treatment.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, or the daily continuous dose is adjusted to ⁇ 8 mg, in particular the treatment is interrupted temporarily, in particular until serum phosphate levels are ⁇ 5.5 mg/dL.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis, wherein the serum phosphate levels in the cancer patient are monitored and when the serum phosphate levels are ⁇ 7 mg/dL or when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, the amount of erdafitinib administered daily, preferably once daily, on a continuous basis, is increased to 9 mg.
  • a phosphate binder such as for example sevelamer
  • concurrent treatment with a phosphate binder is initiated.
  • a phosphate binder such as for example sevelamer
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, and, upon serum phosphate being below 7 mg/dL, the daily continuous dose is adjusted to the same or a lower daily dose.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • the treatment is interrupted temporarily until serum phosphate levels are ⁇ 7 mg/dL and then erdafitinib treatment is re-started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis, wherein the serum phosphate levels in the cancer patient are monitored and early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically shown by the cancer patient is monitored, and when the serum phosphate levels are ⁇ 5.5 mg/dL and no early onset toxicity is shown, the amount of erdafitinib administered daily, preferably once daily, on a continuous basis, is increased to 9 mg.
  • the patient remains on the 8 mg daily continuous treatment.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, or the daily continuous dose is adjusted to ⁇ 8 mg, in particular the treatment is interrupted temporarily, in particular until serum phosphate levels are
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day
  • serum phosphate levels during further erdafitimb administration may be managed according to Table 3.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis, wherein the serum phosphate levels in the cancer patient are monitored and early onset toxicity linked to FGFR inhibitors in general or to erdafitinib specifically shown by the cancer patient is monitored, and when the serum phosphate levels are ⁇ 7 mg/dL or when the serum phosphate levels range from and including
  • the amount of erdafitinib administered daily, preferably once daily, on a continuous basis, is increased to 9 mg.
  • concurrent treatment with a phosphate binder such as for example sevelamer
  • concurrent treatment with a phosphate binder such as for example sevelamer, is initiated.
  • the treatment is interrupted temporarily, in particular erdafitinib treatment is interrupted until serum phosphate levels are again ⁇ 7 mg/dL, and, upon serum phosphate being below 7 mg/dL, the daily continuous dose is adjusted to the same or a lower daily dose.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis, when the serum phosphate levels of said patient are
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis, when the serum phosphate levels of said patient are ⁇ 7 mg/dL or when the serum phosphate levels range from and including 7 mg/dL to
  • serum phosphate levels range from and including
  • concurrent treatment with a phosphate binder such as for example sevelamer
  • a phosphate binder such as for example sevelamer
  • concurrent treatment with a phosphate binder is initiated.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis, when the serum phosphate levels of said patient are
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis, when the serum phosphate levels of said patient are
  • the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL and no early onset toxicity is shown, concurrent treatment with a phosphate binder, such as for example sevelamer, may be initiated.
  • concurrent treatment with a phosphate binder, such as for example sevelamer is initiated.
  • the levels of serum phosphate are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the serum phosphate levels (to determine whether the amount of erdafitinib can be increased from 8 mg daily to 9 mg daily) are assessed when steady state levels of erdafitinib plasma concentration and serum phosphate are reached.
  • the serum phosphate levels to determine whether the amount of erdafitinib can be increased from 8 mg daily to 9 mg daily are assessed at a treatment day during the first cycle of erdafitinib treatment, in particular at approximately day 14 ⁇ 2 days of erdafitinib treatment, in particular at day 14 of erdafitinib treatment (day 14 of cycle 1 of erdafitinib treatment).
  • a cycle is 21 days. In an embodiment a cycle is 28 days.
  • the daily amount of erdafitinib as mentioned herein can be administered via one pharmaceutical composition or via more than one pharmaceutical composition.
  • the medicament as mentioned herein can comprise one pharmaceutical composition or more than one pharmaceutical composition.
  • the 8 mg dose of erdafitinib can be administered as 2 formulations, in particular 2 tablets, each comprising 4 mg of erdafitinib.
  • the 9 mg dose of erdafitinib can be administered as 3 formulations, in particular 3 tablets, each comprising 3 mg of erdafitinib.
  • the present invention concerns a method for the treatment of cancer, which method comprises
  • erdafitinib when the serum phosphate levels are ⁇ 5.5 mg/dL, erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis;
  • erdafitinib is further administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns a method for the treatment of cancer, which method comprises
  • c-1) when the serum phosphate levels are ⁇ 7 mg/dL or when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis; and when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, concurrent treatment with a phosphate binder, such as for example sevelamer, is optionally initiated;
  • a phosphate binder such as for example sevelamer
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns a method for the treatment of cancer, which method comprises
  • erdafitinib when the serum phosphate levels are ⁇ 5.5 mg/dL and no early onset toxicity is shown, erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis;
  • erdafitinib is further administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns a method for the treatment of cancer, which method comprises
  • erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis; and when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, concurrent treatment with a phosphate binder, such as for example sevelamer, is optionally initiated;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein
  • the medicament comprises erdafitinib in an amount of 8 mg and wherein the
  • medicament is for daily, in particular once daily, administration on a continuous basis
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration;
  • the patient remains on the 8 mg daily, in particular once daily, continuous treatment;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein
  • the medicament comprises erdafitinib in an amount of 8 mg and wherein the
  • medicament is for daily, in particular once daily, administration on a continuous basis
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein
  • the medicament comprises erdafitinib in an amount of 8 mg and wherein the
  • medicament is for daily, in particular once daily, administration on a continuous basis
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration;
  • c-1) when the serum phosphate levels are ⁇ 5.5 mg/dL and no early onset toxicity is shown, the amount of erdafitinib in the medicament for daily, in particular once daily, administration on a continuous basis is increased to 9 mg; c-2) when the serum phosphate levels range from and including 5.5 mg/dL to
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns the use of erdafitinib for the manufacture of a medicament for the treatment of cancer in a cancer patient, wherein
  • the medicament comprises erdafitinib in an amount of 8 mg and wherein the
  • medicament is for daily, in particular once daily, administration on a continuous basis
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration;
  • the amount of erdafitinib in the medicament for daily, in particular once daily, administration on a continuous basis is increased to 9 mg; and when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, concurrent treatment with a phosphate binder, such as for example sevelamer, is optionally initiated;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein
  • erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration; when the serum phosphate levels are ⁇ 5.5 mg/dL, erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis;
  • erdafitinib is further administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • the erdafitinib treatment is interrupted temporarily until serum phosphate levels are ⁇ 5.5 mg/dL and then erdafitinib treatment is re-started with 8 mg daily, in particular once daily, on a continuous basis.
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein
  • erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration;
  • c-1) when the serum phosphate levels are ⁇ 7 mg/dL or when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis; and when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, concurrent treatment with a phosphate binder, such as for example sevelamer, is optionally initiated;
  • a phosphate binder such as for example sevelamer
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein
  • erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration; c-1) when the serum phosphate levels are ⁇ 5.5 mg/dL and no early onset toxicity is shown, erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis;
  • erdafitinib is further administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 3.
  • the present invention concerns erdafitinib for use in the treatment of cancer in a cancer patient, wherein
  • erdafitinib is administered in an amount of 8 mg daily, in particular once daily, on a continuous basis;
  • the serum phosphate levels of the patient are measured on a treatment day during the first cycle of erdafitinib treatment, in particular on day 14 ⁇ 2 days, more in particular on day 14, of erdafitinib administration;
  • erdafitinib is administered in an amount of 9 mg daily, in particular once daily, on a continuous basis; and when the serum phosphate levels range from and including 7 mg/dL to ⁇ 9 mg/dL, concurrent treatment with a phosphate binder, such as for example sevelamer, is optionally initiated;
  • serum phosphate levels during further erdafitinib administration may be managed according to Table 4.
  • treatment and uses as described herein are based on phosphate levels as a pharmacodynamic marker, but they can be modified or terminated based on toxicity.
  • treatment or uses are modified or terminated as described in Table 1.
  • Table 1 Erdafitinib dose modifications based on toxicity.
  • erdafitinib is interrupted, in particular interrupted consecutively for 1 week or longer due to drug-related toxicity, it may be reintroduced at either the same dose level or the first reduced dose level following recovery from the toxicity.
  • erdafitinib dose reductions levels are as described in Table 2.
  • a second dose reduction may be implemented following a second occurrence of drug-related toxicity, in particular as described in Table 2.
  • the dose may be re-escalated to the next higher level if the patient was deriving benefit from treatment, and the physician can demonstrate that dose re-escalation of erdafitinib is in the best interest of the patient.
  • serum phosphate levels are monitored until they return to the indicated levels, the assessment of serum phosphate is done at least weekly.
  • the interruption is about 7 days, in particular is 7 days.
  • phosphate levels may be further monitored during erdafitinib treatment.
  • clinical management of serum phosphate levels is done as represented in Table 3.
  • a dose reduction may be implemented if clinically indicated
  • Re-start treatment at lower dose e.g. first reduced dose level or second reduced dose level
  • clinical management of serum phosphate levels is done as represented in Table 4.
  • the present invention also concerns a package containing an erdafitinib formulation and written information, e.g. a patient leaflet, on the dosing regimens as described herein.
  • the cancers mentioned herein are cancers mediated by a FGFR kinase.
  • the cancer is bladder cancer.
  • the cancer is hepatocellular cancer.
  • the cancer is squamous cell carcinoma.
  • the cancer is squamous NSCLC (non-small cell lung cancer), in particular squamous NSCLC (non-small cell lung carcinoma) harboring select FGFR genetic alterations, in particular the treatment of cancer in a patient with squamous NSCLC (non-small cell lung carcinoma) harboring select FGFR genetic alterations after relapse of standard of care therapy.
  • squamous NSCLC non-small cell lung cancer
  • squamous NSCLC non-small cell lung carcinoma
  • select FGFR genetic alterations in particular the treatment of cancer in a patient with squamous NSCLC (non-small cell lung carcinoma) harboring select FGFR genetic alterations after relapse of standard of care therapy.
  • the cancer is hepatocellular cancer harboring FGF19 amplification or overexpression.
  • the cancer is cholangiocarcinoma, in particular advanced or metastatic cho langiocarcinoma. In an embodiment, the cancer is urothelial cancer.
  • the cancer is metastatic or surgically unresectable urothelial cancer.
  • the cancer is advanced urothelial cancer with selected FGFR gene alterations, in particular the treatment of cancer in a patient with advanced urothelial cancer with selected FGFR gene alterations who has progressed on or after one prior treatment.
  • the cancer is lung cancer, in particular non small cell lung cancer.
  • the cancer is selected from adenoid cystic carcinoma, mucoepidermoid carcinoma, follicular thyroid carcinoma, breast carcinoma, Ewing sarcoma, small round cell bone tumors, synovial sarcoma, glioblastoma multiforme, pilocytic astrocytoma, lung cancer, clear cell renal cell carcinoma, bladder cancer, prostate cancer, ovarian cancer, colorectal cancer.
  • the cancer is multiple myeloma, in particular t(4; 14) translocation positive multiple myeloma.
  • the cancer is non-muscle-invasive bladder cancer, in particular non- muscle-invasive bladder cancer with FGFR genomic alterations (e.g. translocations, fusions and/or mutations).
  • FGFR genomic alterations e.g. translocations, fusions and/or mutations.
  • the cancer is esophageal cancer or head and neck cancer.
  • the cancer is gastric cancer.
  • the cancers mentioned herein are cancers harboring FGFR genomic alterations (e.g. translocations, fusions and/or mutations), in particular cancers harboring FGFR genomic alterations (e.g. translocations, fusions and/or mutations) sensitive to erdafitinib, e.g. bladder cancer with FGFR genomic alterations (e.g. translocations, fusions and/or mutations), or urothelial cancer with FGFR genomic alterations (e.g. translocations, fusions and/or mutations) or metastatic or surgically unresectable urothelial cancer with FGFR genomic alterations (e.g. translocations, fusions and/or mutations) or
  • cholangiocarcinoma with FGFR genomic alterations e.g. translocations, fusions and/or mutations
  • advanced or metastatic cholangiocarcinoma with FGFR genomic alterations e.g. translocations, fusions and/or mutations
  • cancers mentioned herein are cancers harboring alterations selected from the following fusions FGFR3:TACC3 vl; FGFR3:TACC3 v3; FGFR3:TACC3 Intron; FGFR3 :B AIAP2L 1 ; FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7;
  • the cancers mentioned herein are cancers with a FGFR3-TACC3 fusion or translocation, e.g. bladder cancer with FGFR3-TACC3 translocation, or urothelial cancer with FGFR3-TACC3 translocation, or metastatic or surgically unresectable urothelial cancer with FGFR3-TACC3 translocation.
  • a FGFR3-TACC3 fusion or translocation e.g. bladder cancer with FGFR3-TACC3 translocation, or urothelial cancer with FGFR3-TACC3 translocation, or metastatic or surgically unresectable urothelial cancer with FGFR3-TACC3 translocation.
  • the cancers mentioned herein are cancers harboring alterations selected from the following FGFR3 gene mutations : FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C.
  • the cancers mentioned herein are bladder cancer or urothelial cancer or metastatic or surgically unresectable urothelial cancer harboring at least one of the following FGFR3 gene mutations : FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C.
  • the uses for or the methods of treatment of cancer in a subject in need thereof, in particular a cancer patient is the use for or the treatment of a patient with metastatic or surgically unresectable urothelial carcinoma whose tumors harbor select FGFR genomic alterations, who has failed during or following at least one line of prior systemic chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy, or chemo-na ' ive but ineligible for cisplatin.
  • the uses for or the methods of treatment of cancer in a subject in need thereof, in particular a cancer patient, as mentioned herein, is the use for or the treatment of a patient with luminal cluster I subtype urothelial cancer.
  • erdafitinib is administered as a pharmaceutically acceptable salt.
  • erdafitinib (base) is administered.
  • erdafitinib is administered as a pharmaceutically acceptable salt in an amount corresponding to 8 mg base equivalent or corresponding to 9 mg base equivalent.
  • the salts can be prepared by for instance reacting erdafitinib with an appropriate acid in an appropriate solvent.
  • Acid addition salts may be formed with acids, both inorganic and organic.
  • acid addition salts include salts formed with an acid selected from the group consisting of acetic, hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic
  • erdafitinib is administered in the form of a solvate.
  • solvate means a physical association of erdafitinib with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • solvate is intended to encompass both solution- phase and isolatable solvates.
  • Non-limiting examples of solvents that may form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.
  • Solvates are well known in pharmaceutical chemistry. They can be important to the processes for the preparation of a substance (e.g. in relation to their purification, the storage of the substance (e.g. its stability) and the ease of handling of the substance and are often formed as part of the isolation or purification stages of a chemical synthesis.
  • a person skilled in the art can determine by means of standard and long used techniques whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g.
  • inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals include cyclodextrins, or complexes with metals.
  • the treatment cycle as used herein is a 28 day cycle.
  • the patient in particular the cancer patient, or the subject in need of erdafitinib treatment, as used herein, is a human.
  • a Phase 2, multicenter, open-label study is being conducted to evaluate the efficacy and safety of erdafitinib in subjects with metastatic or surgically unresectable urothelial cancer harboring select FGFR genetic alterations (FGFR translocations or mutations).
  • the study comprises a Screening Phase (molecular screening at any time prior to first dose and study screening within 30 days of first dose), a treatment phase, and a post-treatment follow-up phase.
  • the treatment phase comprises the period from first dose until the end-of- treatment visit.
  • the follow-up phase will extend until the subject has died, withdraws consent, is lost to follow-up, or the end of study, whichever comes first.
  • Study treatment is administered on 28-day cycles. Prior to interim analysis 1, there were 2 treatment regimens. Patients were randomized 1 : 1 to 28 day cycles to the following 2 regimens until a regimen was selected for further study : Regimen 1 (10 mg once daily intermittent (7 days on/7 days); Regimen 2 (6 mg once daily continuous).
  • the protocol was amended to increase the starting dose to 8 mg/day continuous dosing (Regimen 3) with an up-titration to 9 mg/day at day 14 in patients who did not reach target serum phosphate levels at this timepoint (patients with serum phosphate levels ⁇ 5.5 mg/dL) and in whom no treatment-related adverse events were observed).
  • Dose reductions based on observed toxicity was foreseen in the protocol.
  • RNA from formalin- fixed, paraffin-embedded tumor samples were required to have at least 1 FGFR2/FGFR3 mutation or fusion per central lab testing of RNA from formalin- fixed, paraffin-embedded tumor samples, using a custom assay.
  • PFS progression- free survival
  • DoR duration of response
  • Overall Survival safety, predictive biomarker evaluation, and pharmacokinetics.
  • Tumor responses were assessed by investigators according to RECIST version 1.1
  • Chemotherapy-refractory patients were those who had progressed during or following > 1 line of prior systemic chemotherapy or within 12 months of adjuvant or neoadjuvant chemotherapy.
  • c Chemotherapy-naive patients were those who were ineligible for cisplatin. Ineligibility for cisplatin was based on impaired renal function defined as 1) glomerular filtration rate ⁇ 60 mL/min/1.73 m2 by 24-hour urine measurement; 2) calculated by Cockcroft-Gault; or 3) grade 2 or higher peripheral neuropathy (CTCAE version 4.0).
  • the confirmed Objective Response Rate was 35% (95% CI, 28%- 43%)), with the highest rate among patients who were treated with 8 mg/d continuous erdafitinib in Regimen 3 (Table 6).
  • the confirmed disease control rate was 76% among all patients.
  • the majority of patients treated with 8 mg/d continuous erdafitinib had reduction in tumor burden (44/59 [75%] had reduction in the sum of target lesion diameters; Figure 2).
  • Median Progression Free Survival was 5.1 months and was most prolonged among patients who were treated with 8 mg/d continuous erdafitinib in Regimen 3 (Table 6).
  • the median time to response in the subset of 59 patients on Regimen 3 was 1.41 months, with a range of 1.1 to 5.5 months.
  • Hyperphosphatemia > 5.5 mg/dL was managed with a phosphate-binding agent when medically warranted.

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Abstract

La présente invention concerne un procédé de traitement du cancer par l'erdafitinib.
PCT/EP2018/052694 2017-02-06 2018-02-02 Traitement du cancer Ceased WO2018141921A1 (fr)

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TWI798199B (zh) 2023-04-11
TW201839399A (zh) 2018-11-01
MA47408A (fr) 2019-12-11

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