| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the blood and bone marrow cells |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060558 |
| E.1.2 | Term | Acute myeloid leukemia recurrent |
| 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 1:
•To determine the maximum tolerated doses (MTDs) or the maximum evaluated doses (MEDs), dose-limiting toxicities (DLTs), and the Phase 2 dose(s) of FT-2102 as a single agent, in combination with azacitidine, and in combination with cytarabine in patients with AML or MDS, harboring the IDH1-R132 mutation.
Phase 2:
•To evaluate the antileukemic and antimyelodysplastic activity of FT-2102 as a single agent or in combination with azacitidine in patients with AML or MDS, harboring an IDH1-R132 mutation
|
|
| E.2.2 | Secondary objectives of the trial |
Phase 1:
•To determine the pharmacokinetics (PK) of FT-2102 as a single agent and in combination with azacitidine or cytarabine.
•To observe patients for any evidence of antileukemic or antimyelodysplastic activity of FT 2102 as a single agent and in combination with azacitidine or cytarabine.
Phase 2:
•To confirm the safety of FT-2102 as a single agent and in combination with azacitidine.
•To evaluate additional measures of the antileukemic or antimyelodysplastic activity of FT-2102 as a single agent and in combination with azacitidine.
•To determine the PK of FT-2102 as a single agent and in combination with azacitidine.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Pathologically proven AML (except acute promyelocytic leukemia with the t(15;17) translocation) or intermediate, high risk or very high risk MDS as defined by the World Health Organization (WHO) criteria or
Revised International Prognostic Scoring System (IPSS-R) harboring IDH1-R132 mutations, and one of the following based on enrollment stage or treatment cohort:
a. Single Agent Phase 1 Cohorts including Dose-Escalation/Dose-Expansion: AML/MDS either R/R to standard therapy, or for whom standard treatments are contraindicated
b. Combination (FT-2102 + azacitidine) Phase 1 Dose-Escalation/ Dose-Expansion (patients must meet one of the following):
i. Patients with AML that is either R/R to standard therapy, or for whom standard treatments are contraindicated
ii. Patients that have MDS that is either R/R to standard therapy, or are treatment-naïve, who are eligible for azacitidine therapy
c. Combination (FT-2102 + Cytarabine) Phase 1 Dose-Escalation/Dose- Expansion Cohort: Patients ≥ 60 years with treatment-naïve AML for whom standard treatments are contraindicated
d. Phase 2 Cohort 1 (Single Agent) only: AML R/R to standard therapy
e. Phase 2 Cohort 2 (Single Agent) only: AML in morphologic CR/CRi after prior therapy (+/- HSCT) with residual IDH1-R132 mutation (≥ 0.01%) detected in the bone marrow
f. Phase 2 Cohort 3 (Single Agent) only: R/R AML/MDS that have been previously treated with FT-2102 AND for whom standard treatments are contraindicated
g. Phase 2 Cohort 4 (FT-2102 + Azacitidine) only: Patients < 60 years old with R/R AML/MDS with no prior hypomethylating agent therapy AND no prior IDH-1 inhibitor therapy
h. Phase 2 Cohort 5 (FT-2102 + Azacitidine) only: R/R AML/MDS that have inadequately responded to or have progressed on prior treatment with a hypomethylating agent
i. Phase 2 Cohort 6 (FT-2102 + Azacitidine) only: R/R AML/MDS that have been previously treated with a single agent FT-2102 as their last therapy prior to study enrollment
j. Phase 2 Cohort 7 (Single Agent) only: Treatment naïve AML patients for whom standard treatments are contraindicated
k. Phase 2 Cohort 8 (FT-2102 + Azacitidine) only: Treatment naïve AML patients who are candidates for azacitidine first line treatment.
Note for Phase 2 Cohort 7 and Phase 2 Cohort 8: Treatment naïve is defined as no prior treatment for AML. Patients may have received a prior treatment for another hematologic malignancy.
2. Patients must have documented IDH1-R132 gene-mutated disease as
evaluated by the site
3. Patients ≥ 18 years old
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (see Appendix 3)
5. Signed informed consent prior to beginning study and undergoing
procedures
6. No prior solid organ allograft
7. Acceptable liver function:
a. Bilirubin ≤ 2 times upper limit of normal (ULN) (≤ 3 times ULN in
patients with Gilbert Syndrome)
b. Aspartate transaminase (AST, also referred to as SGOT), alanine
transaminase (ALT, also referred to as SGPT) and alkaline phosphatase
(ALP) ≤ 3 times ULN
8. Acceptable renal function:
a. Serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance ≥
50 mL/min (Cockcroft and Gault 1976)
9. Recovery from the non-hematologic toxic effects of prior treatment to Grade ≤ 1, or baseline value according to NCI CTCAE classification (excluding infertility, alopecia, or Grade 1 neuropathy)
10. Baseline QTcF ≤ 450 msec (average of the QTcF values of screening triplicate ECGs) Note: This criterion does not apply to patients with a bundle branch block (BBB); for patients with BBB, a cardiology consult is recommended to ensure that QTcF is not prolonged.
11. Negative serum pregnancy test if female of childbearing potential
12. For fertile men and women, agreement to use highly effective contraceptive methods for the duration of study participation and 90 days after the last dose of study medication (Section 5.6.1).
13. Agreement for male patients not to donate sperm and for female patients of childbearing potential not to donate ova during the study and for 90 days after the final dose of study drug (Section 5.6.2).
14. Phase 2 Cohorts 1-8 (SA and combination) only: Pre-treatment peripheral blood and bone marrow aspirate available for retrospective central confirmation of IDH1-R132 mutation is required
Note: Central confirmation |
|
| E.4 | Principal exclusion criteria |
1. Phase 1 single agent dose-escalation/dose expansion cohorts and Phase 2 Cohorts 1, 4, 5, 7 and 8 only: Patients who have been treated with an IDH1 targeted therapy
2. Phase 2 Single Agent Cohorts 1-3 and 7 only: Patients with IDH2 mutation detection at baseline or history of IDH2m inhibitor treatment
3. History of prior malignancy unless disease-free for ≥ 12 months or considered surgically cured; patients with nonmelanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis
(including concomitant diagnoses)
4. Patients with symptomatic central nervous system (CNS) metastases or other tumor location (such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.)
necessitating an urgent therapeutic intervention, palliative care, surgery or radiation therapy
5. Patients with previous allogeneic HSCT if they meet any of the following criteria: < 100 days from time of HSCT; active acute or chronic graft vs. host disease (GvHD); or receiving immunosuppressive therapy as
treatment or prophylaxis against GvHD
Note: Doses < 20 mg methylprednisolone (or its equivalent) daily are not an exclusion criterion.
6. Treatment with radiation therapy, major surgery (requiring general anesthesia) within one month prior to study drug dosing
7. Treatment with chemotherapy or small molecule anticancer therapeutic within five halflives of the agent or within 21 days if the half-life is unknown. Patients re-enrolling in Cohort 6 after relapse/progression on Cohort 1 are exempt from this washout requirement (i.e. can continue FT-2102 treatment until re-enrollment)
8. Treatment with an anticancer therapeutic antibody less than four weeks before first dose of study drug
9. Treatment with other experimental therapies or participation in another clinical trial within a period of time that is less than the cycle length or within 21 days prior to starting study drug, whichever is shorter
10. Patients unable to swallow oral medications, or patients with gastrointestinal conditions (e.g., malabsorption, resection, etc.) deemed by the Investigator to jeopardize intestinal absorption
11. 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 (see Appendix 5)
12. Patients with a family history of QT prolongation
13. Concomitant medication(s) known to cause 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 5) (medications used as needed [PRN] (e.g. Zofran) are exempt)
14. Concurrent treatment with chronic corticosteroids except if chronic treatment with < 20 mg of methylprednisolone daily or equivalent (pulse steroids for treatment or prophylaxis are allowed [e.g., for transfusion or medication reactions])
15. Known HIV positivity
16. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy (prophylactic systemic antimicrobials permitted)
17. Uncontrolled disease-related metabolic disorder (e.g., hypercalcemia)
18. Pregnant or nursing women or women of childbearing potential not using adequate contraception; male patients not using adequate contraception
Note: Women of childbearing potential (see Section 5.6) and men must
agree to use highly effective conntraception (see Section 5.6.1) prior to study entry and for the duration of study participation and 90 days after. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
19. Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor
20. Unwillingness or inability to comply with procedures either required in this protocol or considered standard of care
21. Medical, uncontrolled disease-related metabolic disorder, psychiatric, cognitive, or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply
with the study protocol, or complete the study
22. History of severe allergic reaction to azacitidine (if patient enrolling into azacitidine combination cohort) or low-dose cytarabine (if patient enrolling into cytarabine combination cohort)
23. Prisoners or patients who are involuntarily incarcerated or are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness Note: Under certain specific circumstances, a person who has been imprisoned may be included or permitted to continue as a patient, if local regulations permit. Strict conditions apply and Forma's approval is required. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
• Incidence and severity of adverse events (AEs), clinical laboratory
abnormalities and changes in electrocardiogram (ECG) parameters
Phase 2:
All cohorts except Cohort 2: Complete Response rate (best overall response [BOR] of complete remission [CR]/ complete remission with partial hematological recovery [CRh]) as determined by the investigator per disease-specific criteria. Refer to Appendix for AML and Appendix 7 for MDS response criteria
Cohort 2: Four-month relapse free survival (RFS) rate
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients are assessed for response at the Cycle 2 Day 1, Day 1 of Cycle 3 (if not assessed on Day 1 of Cycle 2) and every subsequent cycle and end of study visit. |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
• PK parameters derived from FT-2102 concentrations
• Antileukemic or antimyelodysplastic activity as determined by CR, CRh,
CRi, MLFS, Marrow CR, PR, and SD
Phase 2:
• Evidence of clinical benefit (complete remission with incomplete blood count recovery [CRi], morphologic leukemia-free state [MLFS], Marrow CR, Overall Response [OR], Time to Response [TTR], Duration of Response [DOR], event free survival [EFS], RFS, overall survival [OS], and other definitions of response, including Stable Disease [SD])
• Incidence and severity of adverse events (AEs), clinical laboratory abnormalities and changes in ECG parameters
• PK parameters derived from plasma FT-2102 concentrations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Patients are assessed for response at the Cycle 2 Day 1, Day 1 of Cycle 3 (if not assessed on Day 1 of Cycle 2) and every subsequent cycle and end of study visit |
|
| 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 | Yes |
| 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) | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Korea, Republic of |
| United States |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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