Advanced Hematologic Malignancy, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Relapsed Myelodysplastic Syndromes, Refractory Myelodysplastic Syndromes, Relapsed Chronic Myelomonocytic Leukemia, Refractory Chronic Myelomonocytic Leukemia
Conditions
Keywords
AML, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, MDS, Relapsed Myelodysplastic Syndromes, Refractory Myelodysplastic Syndromes, Phase 1, FHD-286, Foghorn, CMML, Refractory Chronic Myelomonocytic Leukemia, Relapsed Chronic Myelomonocytic Leukemia
Brief summary
This Phase 1, multicenter, open-label, dose escalation study is designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FHD-286 administered orally as monotherapy or combination therapy, in subjects with advanced hematologic malignancies.
Detailed description
This study is primarily intended to evaluate the safety and tolerability of FHD-286 when administered orally as monotherapy or in combination with either LDAC or decitabine to subjects with R/R AML, R/R MDS, and R/R CMML not in blast crisis. In each arm of the study, successive cohorts of participants will receive increasing oral doses of FHD-286 as a single agent or in combination with LDAC or decitabine to determine the RP2D(s) in this population. The data from this study in subjects with advanced hematologic malignancies, including safety, tolerability, PK/PD findings, and antitumor activity, will form the basis for subsequent clinical development of FHD-286.
Interventions
DRUGFHD-286
FHD-286 administered orally
LDAC administered subcutaneously (SC)
DRUGDecitabine
Decitabine administered intravenously
Sponsors
Foghorn Therapeutics Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Subject must be ≥16 years of age. 2. Subject must: * Have a confirmed diagnosis of R/R AML, R/R MDS, or R/R CMML not in blast crisis AND * Have received ≤4 prior lines of systemic anticancer therapy for their disease under study; subjects who have received \>4 prior lines of systemic anticancer therapy for their disease under study must receive Sponsor approval. AND * Be an appropriate candidate for treatment with LDAC (Arm A) or decitabine (Arm B) 3. Subject or their parent or legal guardian (when applicable) must be able to understand and be willing to sign an informed consent and, when applicable, subject must sign an assent form. 4. Subject must be willing and able to comply with scheduled study visits and treatment plans. 5. Subject must be willing to undergo all study procedures unless contraindicated due to medical risk. 6. Subject must have an ECOG PS of ≤2. 7. Subject must have a life expectancy of ≥3 months. 8. Subject must have adequate hepatic function. 9. Subject must have adequate renal function. 10. Subject must have a WBC count ≤20×109/L; treatment with a stable dose of hydroxyurea or other cytoreductive agent (eg, cytarabine) to achieve this count is allowed. 11. Subject must have adequate cardiovascular, respiratory, and immune system function. 12. Subject must agree to abide by dietary and other considerations required during the study. 13. Subject must meet timing requirements with respect to prior therapy and surgery 14. Toxicity related to prior therapy must have returned to Grade ≤2 by CTCAE by approximately 14 days before the start of study treatment or be deemed irreversible and stable by the Investigator. Exceptions include alopecia, neuropathy, appropriately controlled endocrine toxicities, and other well-controlled stable toxicities with discussion with the Sponsor. 15. Female subjects must be: * postmenopausal; or * permanently sterile, or, if sexually active with male partners, these partners must be azoospermic; or * nonpregnant, nonlactating, and, if sexually active with fertile male partners, having agreed to use a highly effective method of contraception 16. Male subjects must have documented azoospermia or, if fertile and sexually active, must agree to use a highly effective method of contraception with their partners of childbearing potential Key
Exclusion criteria
1. Subject is unable to provide informed consent and/or to follow protocol requirements. 2. Subject: * Has undergone chimeric antigen receptor T cell therapy or HSCT within 60 days of the first dose of study treatment OR * Has clinically significant GVHD 3. Subject has evidence (or suspicion) of extramedullary involvement, unless approved by Sponsor. 4. Subject has an immediately life-threatening, severe complication(s) of advanced myeloid malignancy, such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation. 5. Subject has other malignancy that may interfere with the diagnosis and/or treatment of advanced hematologic malignancies. 6. Subject has active HBV or HCV infections; Subject has known positive HIV antibody results, or AIDS-related illness. 7. Subject has an active severe infection that requires anti-infective therapy or has an unexplained temperature of \>38.5°C during screening visits or on their first day of study treatment. 8. Subject has an uncontrolled intercurrent illness. 9. Subject has QTcF \>470 msec or other factors that increase the risk of QTc prolongation or arrhythmic events. 10. Subject has any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent/assent, cooperate, or participate in the study. 11. Subject has known allergies or hypersensitivities to: * All subjects: components of the FHD-286 formulation * Arm A: cytarabine or any of the excipients * Arm B: decitabine or any of the excipients 12. Subject is unable to tolerate the administration of oral medication or has GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of FHD-286. 13. Subject is receiving any other anticancer investigational agents. Investigational agents to treat non-cancer indications may be permitted with Sponsor approval. 14.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of AEs, dose-limiting toxicities (DLTs), serious AEs (SAEs), AEs leading to discontinuation, and adverse events of special interest (AESIs); safety laboratory assessments | Up to 18 months |
Secondary
| Measure | Time frame |
|---|---|
| AML: Duration of CR | Up 18 months |
| AML: CR + CR with partial hematologic recovery (CRh) rate | Up 18 months |
| AML: Duration of CR + CRh | Up 18 months |
| AML: Transfusion independence rate | Up 18 months |
| AML: Event free survival (EFS) | Up 42 months |
| AML: Overall survival (OS) | Up to 42 months |
| MDS: CR rate | Up to 18 months |
| MDS & CMML: Duration of CR | Up to 18 months |
| AML: Complete remission (CR) rate | Up to 18 months |
| MDS & CMML: Duration of PR | Up to 18 months |
| MDS & CMML: CR + PR | Up to 18 months |
| MDS & CMML: Duration of CR + PR | Up to 18 months |
| MDS & CMML: Hematologic Improvement rate | Up to 18 months |
| MDS & CMML: EFS | Up to 42 months |
| MDS: OS | Up to 42 months |
| PK parameter: Area under the plasma concentration time curve (AUC) | Day 1 and day 8 of cycle 1 (each cycle is 28 days) |
| Plasma concentration vs. time profiles | Day 1 and day 8 of cycle 1 (each cycle is 28 days) |
| MDS & CMML: Partial remission (PR) rate | Up to 18 months |
Countries
United States
Outcome results
None listed