| 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.1.3 | 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 written 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 1 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 cancer 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) 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’s syndrome.
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 Taiho 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 and 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 A and B
Objective response rate is defined as the proportion of patients with objective evidence of CR or PR. The primary evaluation of ORR will be based on an independent central review of radiologic images. At the analysis stage, the best objective response will be assigned for each patient as the best response recorded after initiation of study treatment and confirmed at least 4 weeks later. If applicable, responses recorded after disease progression or initiation of new anticancer treatment will be excluded. The exact 2-sided CI based on Clopper-Pearson methodology will be derived for ORR.
Cohort C
Complete response rate defined as the proportion of patients who achieved a CR will be calculated and the exact 2-sided CI will also be derived using the Clopper Pearson methodology. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
A patient will be discontinued from all study therapy for any of the following reasons:
1.Disease progression
2.Unacceptable AEs, or change in underlying condition such that the patient can no longer tolerate therapy, as evidenced by a dose delay > 28 days from the scheduled start date of the next cycle or need for more than 2 dose reductions outlined in this protocol
3.Physician’s decision, including need for other anticancer therapy not specified in the protocol or surgery or radiotherapy to the only site(s) of disease being followed in the study
4.Pregnancy
5.Termination of the study by the Sponsor, or
6.At the patient’s request at any time irrespective of the reason.
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| E.5.2 | Secondary end point(s) |
Cohorts A and B : Secondary Endpoints
-Overall response rate based on investigator assessment will be determined as described above for the primary analysis of ORR based on independent central review of radiologic images
-Disease control rate will be analyzed using the same methodology as ORR
-Duration of response will only be evaluated in patients with an objective response of CR or PR. Patients who are alive and progression-free as of the analysis cut-off date will be censored at their last evaluable tumor response assessment prior to initiation of any new anticancer treatment. Patients who start subsequent anticancer therapy without a prior reported progression will be censored at the last tumor assessments prior to initiation of the subsequent anticancer therapy
-Progression-free survival will be estimated using the Kaplan-Meier method. Patients who die without a reported disease progression will be considered to have progressed on the date of their death. Patients who did not progress or die will be censored on the date of their last tumor assessment. Patients who did not have any on-study assessments and did not die will be censored on the first dosing date. Patients who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy.
-Overall survival will be analyzed in a similar manner to PFS. In the absence of confirmation of death or for patients who are alive as of the OS cut-off date, survival time will be censored at the last known date that the patient was alive.
Cohort C: Secondary Endpoints
-The overall response, CR+CRi (leukemia presentation only), CCyR, and PCyR rates will be calculated and the exact 2-sided CIs will also be derived using the Clopper-Pearson methodology.
-Duration of CR (only in patients who achieved a CR), duration of CR+CRi (only in patients who achieved a CR/CRi [leukemia presentation only]), and duration of response (only in patients with an objective response of CR, CRi [leukemia presentation only], or PR) will be estimated using the Kaplan-Meier method. Patients who are alive and progression-free as of the analysis cut-off date will be censored at their last evaluable tumor response assessment prior to initiation of any new anticancer treatment. Patients who start subsequent anticancer therapy without a prior reported progression will be censored at the last tumor assessments prior to initiation of the subsequent anticancer therapy.
-Progression-free survival will be estimated using the Kaplan-Meier method. Patients who die without a reported disease progression will be considered to have progressed on the date of their death. Patients who did not progress or die will be censored on the date of their last tumor assessment. Patients who did not have any on-study assessments and did not die will be censored on the first dosing date. Patients who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy.
-Relapse-free survival will only be evaluated in patients with an objective response of CR and measured from the first date of achieving CR until the first date of relapsed disease or death from any cause, whichever occurs first. Patients who die without a reported disease relapse will be considered to have relapsed on the date of their death. Patients who did not relapse or die will be censored on the date of their last tumor assessment. Patients who started any subsequent anti-cancer therapy without a prior reported relapse will be censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy.
-Event-free survival will be estimated only for patients with leukemia presentation using the Kaplan-Meier method. EFS is defined as the time from first dose of study therapy to treatment failure, relapse after CR (if applicable), or death from any cause, whichever occurs first. For a patient with none of these events before the end of study follow-up, observation of EFS is censored at the date of last contact prior to the analysis cut-off date. If the patient does not achieve a CR, EFS is defined as the point of treatment failure or death, whichever comes first. Treatment failure for EFS is defined as PD in this study.
-Overall survival will be analyzed in a similar manner to PFS. In the absence of confirmation of death or for patients who are alive as of the OS cut-off date, survival time will be censored at the last known date that the patient was alive. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Treatment will continue until disease progression, unacceptable toxicity, or any other of the criteria for treatment discontinuation is met. |
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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 | 9 |
| 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 |
| Belgium |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Portugal |
| Singapore |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
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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 75% of enrolled patients; or
• The trial 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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