E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fibroblast growth factor receptor (FGFR) aberrations |
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E.1.1.1 | Medical condition in easily understood language |
solid tumors or gastric cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007050 |
E.1.2 | Term | Cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Cohorts A nd B :The primary objective is to evaluate the objective response rate (ORR) in patients with solid tumors harboring FGFR rearrangements or gastric cancer (including GEJ cancer) harboring FGFR2 amplifications based on independent central review of radiologic images (IRC).
Cohort C: The overall objective of Cohort C is to assess the clinical activity of futibatinib as monotherapy in the treatment of patients with myeloid/lymphoid neoplasms (MLN) harboring FGFR1 rearrangements. |
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E.2.2 | Secondary objectives of the trial |
Cohorts A and B Secondary objectives include assessment of: - ORR based on Investigator assessment; - Disease control rate (DCR); - Duration of response (DOR); - Progression-free survival (PFS); - Overall survival (OS); and - Safety and tolerability.
Cohort C Secondary objectives include assessment of: -ORR -CR + complete response, and overall survival with incomplete hematological recovery (CRi) rate -Complete or partial cytogenetic responses (CCyR or PCyR) rate -Duration of CR -Duration of CR+CRi -DOR -Time-to-events -To assess the safety and tolerability
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provide documented informed consent 2. ≥18 years of age (or meets the country's regulatory definition for legal adult age, whichever is greater) 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 4. Has recovered from the acute toxic effects of prior anticancer therapy to baseline or Grade 1 (except toxicities which are not clinically significant such as alopecia) 5. Known FGFR aberration status and tumor type that meet all of the criteria for one of the following cohorts: a. Cohort A I. Histologically-confirmed, locally-advanced, advanced, or metastatic solid tumors harboring a FGFR1-4 rearrangement determined in tumor tissue using next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), or other assays that can determine gene rearrangements in tumor tissues. Patients with primary brain tumor or iCCA are not eligible. ii. Measurable disease per RECIST 1.1 iii. Had disease progression/recurrence after standard treatment for their advanced or metastatic cancer b. Cohort B I. Histologically-confirmed, locally-advanced, advanced, or metastatic gastric or GEJ adenocarcinoma harboring a FGFR2 amplification. The tumor must have an FGFR2/CEN10 ratio of ≥5 or an FGFR2 copy number ≥10 signals per cell determined in tumor tissue using NGS, FISH, or other assays that can determine gene amplification in tumor tissues. ii. Measurable disease per RECIST 1.1 iii. Received at least 2 prior systemic regimens for advanced/metastatic disease iv. Experienced disease progression/recurrence during or after the most recent prior systemic treatment for advanced/metastatic gastric or GEJ cancer c. Cohort C I. Confirmed MLN with a FGFR1 rearrangement as defined by WHO criteria ii. Not a candidate for hematological stem cell transplant (HSCT) or relapsed after HSCT and donor lymphocyte infusion, and progressed and not a candidate for other therapies 6. Has archival or fresh tumor tissue (preferably in block format) for Cohorts A and B and bone marrow tissue for Cohort C available to send to central laboratory. 7. Adequate organ function as defined by the following criteria: a. Cohorts A and B: I. Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L ii. Platelet count ≥ 75,000/mm3 (≥ 75 x 10^9/L) iii. Hemoglobin ≥ 9.0 g/dL iv. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5.0 × ULN. v. Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert's syndrome. vi. Creatinine clearance (CrCl) (calculated or measured value): ≥40 mL/min. For calculated CrCl, use the Cockcroft-Gault formula (Section 6). vii. Phosphorus <1.5 ULN b. Cohort C I. ALT and AST ≤ 3.0 × ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5.0 × ULN. ii. Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert'ssyndrome. iii. CrCl (calculated or measured value): ≥40 mL/min. For calculated CrCl, use the Cockcroft-Gault formula (Section 6). iv. Phosphorus <1.5 ULN 8. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of futibatinib. Female patients are not considered to be of child-bearing potential if they are post-menopausal, defined as no menses for 12 months without an alternative medical cause or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). 9. Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose and for 90 days after the last dose or longer based on local requirements. 10. Ability to take medications orally (feeding tube is not permitted). 11. Willing and able to comply with scheduled visits and study procedures.
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E.4 | Principal exclusion criteria |
1. Currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study. If a patient is currently enrolled in a clinical trial involving non-approved use of a device, then agreement with the Investigator and the Sponsor's Medical monitor is required to establish eligibility. 2. History and/or current evidence of any of the following disorders: a. Non-tumor related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the Investigator b. Ectopic mineralization/calcification including, but not limited to, soft tissue, kidneys, intestine, or myocardia and lung, considered clinically significant in the opinion of the Investigator c. Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator. 3. Corrected QT interval using Fridericia's formula (QTcF) >470 msec. Patients with an atrioventricular pacemaker or other condition (for example, right bundle branch block) that renders the QT measurement invalid are an exception and the criterion does not apply. 4. Treatment with any of the following within the specified time frame prior to the first dose of futibatinib: a. Major surgery within 4 weeks (surgical incision should be fully healed) b. Radiotherapy for extended field within 4 weeks or limited field radiotherapy within 2 weeks c. A drug that has not received regulatory approval for any indication within 14 or 21 days of treatment for a nonmyelosuppressive or myelosuppressive agent, respectively. 5. Received strong inhibitors or inducers of CYP3A4 within 2 weeks of first dose 6. Prior treatment with an FGFR inhibitor 7. A serious illness or medical condition(s) including, but not limited to, the following: a. Known acute systemic infection b. Myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure within the previous 6 months c. History or current evidence of uncontrolled ventricular arrhythmia d. Chronic diarrhea diseases considered to be clinically significant in the opinion of the Investigator e. Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death f. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or futibatinib administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study 8. Active central nervous system (CNS) metastasis and/or carcinomatous meningitis. Patients with previously treated brain metastases that are clinically and radiologically stable (for at least 4 weeks prior to enrollment) are eligible. 9. Known additional malignancy that is progressing or has required active treatment within the past 2 years. Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 10. Pregnant or breastfeeding.
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohorts And B ORR, defined as the proportion of patients experiencing a best overall response of partial response (PR) or complete response (CR) (per Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST 1.1]), based on IRC
Cohort C Complete response rate defined as the proportion of patients who achieved a CR |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Cohort A and B: 6 months from Cycle 1 Day 1 - Cohort C: 6 months from Cycle 1 Day 1 |
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E.5.2 | Secondary end point(s) |
Cohorts And B : Secondary Endpoints DOR defined as the time from the first documentationof response (CR or PR per RECIST 1.1 based on IRC) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first, based on IRC ORR, defined as the proportion of patients experiencing a best overall response of partial response of PR or CR (per RECIST 1.1), based on Investigator assessment DCR, defined as the proportion of patients experiencing a best overall response of stable disease (SD), PR, or CR (per RECIST 1.1), based on IRC PFS, defined as the time from first dose of study drug to the date of death (any cause) or disease progression (based on IRC), whichever occurs first OS, defined as the time from the date of first dose to the death date Safety based on reported AEs and on-study laboratory parameters, graded according to the National Cancer Institute—Common Terminology Criteria for Adverse Events, Version 5.0 (NCI-CTCAE V5.0). Cohort C ORR, defined as the proportion of patients who achieved a CR, CRi, or PR CR+CRi rate, defined as the proportion of patients who achieved a CR or CRi CCyR rate, defined as the proportion of patients who achieved CCyR PCyR rate, defined as the proportion of patients who achieved PCyR Duration of CR defined as the time from the first documentation of CR to the first documentation of objective tumor progression or death due to any cause, whichever occurs first Duration of CR+CRi defined as the time from the first documentation of CR/CRi to the first documentation of objective tumor progression or death due to any cause, whichever occurs first DOR defined as the time from the first documentation of CR, CRi, or PR to the first documentation of objective tumor progression or death due to any cause, whichever occurs first PFS, defined as the time from first dose of study drug to the date of death (any cause) or disease progression, whichever occurs first Relapse-free survival (RFS), defined as the time from the first documentation of CR to the first documentation of disease relapse or death due to any cause, whichever occurs first. Event-free survival (EFS) (leukemia presentation only), defined as the time from first dose of study drug to treatment failure, disease relapse after CR, or patient death from any cause. OS, defined as the time from the date of first dose to the death date. Safety based on reported AEs and on-study laboratory parameters, graded according to the NCI-CTCAE V5.0 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Cohort A and B: 6 months from Cycle 1 Day 1 - Cohort C: 6 months from Cycle 1 Day 1 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Sweden |
Netherlands |
Spain |
Germany |
Italy |
Belgium |
Denmark |
Portugal |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Treatment will continue until disease progression, unacceptable toxicity, or any other of the criteria for treatment discontinuation is met (Protocol Section 4.4). The study will be considered complete when: • Survival events (deaths) have been reported for at least 75% of enrolled patients in either Cohort A, B or C, whichever comes last; or • The study is halted early for any reason. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |