| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Solid Tumors and Gliomas with an IDH1 Mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Solid Tumors and Gliomas |
|
| 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 | PT |
| E.1.2 | Classification code | 10018338 |
| E.1.2 | Term | Glioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008734 |
| E.1.2 | Term | Chondrosarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073073 |
| E.1.2 | Term | Hepatobiliary cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10073077 |
| E.1.2 | Term | Intrahepatic cholangiocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Phase 1b:
Evaluate the safety and tolerability of FT-2102 as monotherapy and confirm the dose to be further examined in expansion cohorts as monotherapy and combination therapy.
Phase 2:
Evaluate the clinical activity of FT-2102 as monotherapy or in combination in patients with glioma, HBC, chondrosarcoma, and IHCC harboring an IDH1 mutation.
|
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b:
Evaluate the PK of FT-2102 as monotherapy and in combination with other anti-cancer agents.
Evaluate the clinical activity of FT-2102 as a single-agent or in combination in patients with glioma, HBC, chondrosarcoma, and IHCC harboring an IDH1 mutation.
Phase 2:
Evaluate the safety of FT-2102 administered as monotherapy and in combination in patients with glioma, HBC, chondrosarcoma, and IHCC harboring an IDH1 mutation.
Evaluate the PK of FT-2102 as monotherapy and in combination with other anti-cancer agents.
Evaluate additional measures of antitumor activity of FT-2102 as monotherapy and in combination with other anti-cancer agents. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All patients must meet the following criteria for inclusion:
1.≥18 years of age
2.Life expectancy of ≥4 months
3.Able to provide tumor tissue sample (archival)
4.Disease, defined as:
Disease-specific Cohorts
•Glioma (Cohort 1)
Histologically or cytologically confirmed IDH1 gene-mutated advanced glioma that has recurred or progressed following standard therapy, or that has not responded to standard therapy.
Glioblastoma multiforme with confirmed IDH1 gene-mutated disease with first or second recurrence.
HBC (Cohort 2)
Relapsed/refractory or intolerant to approved standard-of-care therapy (included: hepatocellular carcinoma, bile duct carcinoma, intrahepatic cholangiocarcinoma or other hepatobiliary carcinomas)
Histologically or cytologically confirmed IDH1 gene-mutated with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Child-Pugh Class A
Single Agent FT-2102: prior exposure to nivolumab is permitted
Combination Cohort 2b: patients may not have had prior exposure to nivolumab.
•Chondrosarcoma (Cohort 3)
Relapsed or refractory and either locally advanced or metastatic and not amenable tocomplete surgical excision
Histologically or cytologically confirmed IDH1 gene-mutated with measurabledisease per RECIST 1.1 criteria.
•IHCC (Cohort 4)
Advanced nonresectable or metastatic intrahepatic cholangiocarcinoma not eligiblefor curative resection or transplantation.
Single-Agent/Safety Lead-in of Combination Phase 2: ineligible for standardtherapies only
Combination Phase 2 (beyond Safety Lead-in): have received no more than 1 cycleof GemCis therapy
Histologically or cytologically confirmed IDH1 gene-mutated with measurabledisease per RECIST 1.1 criteria
•Other tumors (non-CNS) (Cohort 5)
Relapsed or refractory to standard-of-care therapy with no other available therapeuticoptions
Histologically or cytologically confirmed IDH1 gene-mutated with measurabledisease per disease appropriate response criteria.
5.Recovered to ≤Grade 2 or baseline toxicity (except alopecia) from prior therapy (per CTCAEv 4.03)
6.Eastern Cooperative Oncology Group (ECOG) performance status 0-2
7.Adequate bone marrow function
•Absolute neutrophil count (ANC) ≥1.5 x 109/L without any growth factors in prior7 days
•Hemoglobin ≥8.0 g/dL (with or without transfusion support)
Platelet count ≥75 × 109/L (with or without transfusion support); Cohort 4b (GemCiscombination): platelet count ≥100 × 109/L (with or without transfusion support)
8.Adequate hepatic function
•Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase)/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase) ≤2.5 ×institutional upper limit of normal (ULN). For patients with suspected malignancyrelated elevations, <5 × ULN.
• Total bilirubin ≤1.5 × ULN. For patients with suspected malignancy related elevation <3 × institutional ULN.
9. Adequate renal function
• Creatinine clearance per Cockcroft-Gault equation of ≥60 mL/min
10. For women of childbearing potential (WCBP): negative serum β human chorionic gonadotropin (β-hCG) pregnancy test within 1 week before first treatment (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally post-menopausal for at least 12 consecutive months for women >55 years of age)
11. Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of the study treatment, including 90 days after the last dose of study drug. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception. Males must agree not to donate sperm while participating in the study and for 90 days after the last dose of the study drug.
12. Ability to adhere to the study visit schedule and all protocol requirements
13. Signed and dated IRB/independent ethics committee (IEC)-approved informed consent form before any screening procedures are performed.
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|
| E.4 | Principal exclusion criteria |
Patients are to be excluded from the study if they meet any of the following criteria:
1. Previous solid organ or hematopoietic cell transplant
2. Prior anticancer treatment
• No prior treatment with small molecule, antibody, or other anticancer therapeutic within 21 days (or 5 half-lives), whichever is shorter of first dose of study treatment (6 weeks for nitrosoureas or mitomycin C). For patients enrolling in the Phase 2 (beyond Safety Lead-in with IHCC) a minimum of 14 days from GemCis therapy.
• No previous treatment with an IDH1 inhibitor (single agent FT-2102 cohorts only)
• No prior radiation therapy (including radiofrequency ablation) within 4 weeks prior to initiation of study treatment
• No prior stereotactic body radiation therapy within 2 weeks prior to initiation of study treatment
• No prior chemoembolization or radioembolization within 4 weeks
3. Congestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris; previous history of myocardial infarction within one year prior to study entry, uncontrolled hypertension, or uncontrolled arrhythmias
4. History of QT prolongation or baseline QT interval corrected with Fridericia’s method (QTcF) >450 ms (average of triplicate readings)
NOTE: criterion does not apply to patients with a right or left bundle branch block.
5. Concomitant medication(s) associated with QTc interval prolongation or Torsades de Pointes (TdP) initiated less than the duration required to reach steady-state plasma concentration (approximately five half-lives) before first dose of study drug (see Appendix 3) (medications used as needed [PRN] (e.g., Zofran) are exempt).
6. Pregnant or nursing women or WCBP not using adequate contraception; male patients not using adequate contraception
7. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ, stage 1, grade 1 endometrial carcinoma, or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years
8. Major surgery within 4 weeks of starting study treatment or not recovered from any effects of prior major surgery (uncomplicated central line placement or fine needle aspirate are not considered major surgery)
9. Patients receiving >6 mg/day of dexamethasone or equivalent
10. Patients with gastrointestinal disorders likely to interfere with absorption of the study medication
11. Known human immunodeficiency virus positivity (HIV)
12. Active infection with hepatitis B or C virus (Hep B or C viral load>100 international units/milliliter or local institutional equivalent)
13. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important medical or psychiatric illness or abnormal laboratory finding that would, in the Investigator’s judgment, increase the risk to the patient associated with his or her participation in the study
14. PD-1 combination only:
• Patients with active autoimmune disease
Note: patients with well controlled diabetes or hypothyroidism are eligible. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
• DLTs (Safety Lead-in Periods), AEs, and safety laboratory values
Phase 2:
• Objective response rate (ORR) as determined by applicable disease criteria, for disease-specific cohorts |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| DLTs will be evaluated during the Safety Lead-in Period during the first treatment cycle, patients will be monitored continuously for toxicity while on study drug and or all parts of the study, response and progression will be determined by Investigator assessment using the appropriate response criteria per disease at the time points shown in Table 8 of the protocol. |
|
| E.5.2 | Secondary end point(s) |
• AEs, and safety laboratory values (Phase 2)
• ORR (Phase 1b only)
• Progression-free survival (PFS), defined as the time from the first dose to disease progression as determined by applicable disease criteria or death due to any cause, whichever is sooner
• Time to progression (TTP), defined as the time from start of treatment until disease specified progression.
• Duration of response (DOR), defined as the time from the first response to documented disease progression as determined by applicable disease criteria
• Overall Survival (OS), defined as the time from the first dose to death due to any cause
• Time to Response (TTR), defined as the time from first dose to first response
• AEs and abnormal laboratory findings
• PK parameters derived from plasma/CSF FT-2102 concentrations
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients will be monitored continuously for toxicity while on study drug and or all parts of the study, response and progression will be determined by Investigator assessment using the appropriate response criteria per disease at the time points shown in Table 8 of the protocol. |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1b Safety Lead-in Period |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Australia |
| Canada |
| France |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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