FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies
FHD-286 as Monotherapy or Combination Therapy in Subjects With Advanced Hematologic Malignancies
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.
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.
Leukemia,
Myelodysplastic Syndrome,
Phase I
Phase I
Adults
Chemotherapy - cytotoxic,
Mol. targeted/Immunotherapy/Biologics
Decitabine,
FHD-286,
Low-dose cytarabine (LDAC)
Kishtagari, Ashwin
National
Vanderbilt University
07-28-2021
Eligibility
16 Years
BOTH
NO
Inclusion Criteria:
Subject must be 16 years of age.
Subject must: Have a confirmed diagnosis of R/R AML, R/R MDS, or R/R CMML not in blast crisis AND Be an appropriate candidate for treatment with LDAC (Arm A) or decitabine (Arm B)
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.
Subject must be willing and able to comply with scheduled study visits and treatment plans.
Subject must be willing to undergo all study procedures unless contraindicated due to medical risk.
Subject must have an ECOG PS of 2.
Subject must have a life expectancy of 3 months.
Subject must have adequate hepatic function
Subject must have adequate renal function
Subject must have a WBC count 20109/L
Subject must have adequate cardiovascular, respiratory, and immune system function
Subject must agree to abide by dietary and other considerations required during the study
Subject must meet timing requirements with respect to prior therapy and surgery
Toxicity related to prior therapy must have returned to Grade 2 by CTCAE by approximately 14 days before the start of study treatment
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
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
Exclusion Criteria:
Subject is unable to provide informed consent and/or to follow protocol requirements.
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
Subject has clinical symptoms suggesting active CNS leukemia or known CNS leukemia.
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.
Subject has other malignancy that may interfere with the diagnosis and/or treatment of advanced hematologic malignancies.
Subject has active HBV or HCV infections; Subject has known positive HIV antibody results, or AIDS-related illness;
Subject has an active severe infection that requires anti-infective therapy or has an unexplained temperature of >38.5C during screening visits or on their first day of study treatment
Subject has an uncontrolled intercurrent illness.
Subject has QTcF >470 msec or other factors that increase the risk of QTc prolongation or arrhythmic events
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.
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
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.
Subject is receiving any other investigational agents.
At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since last administration of a prior investigational drug at the start of study treatment. Exceptions include participation in any observational or nontherapeutic clinical trials.
Subject is on medications classified as:
Strong CYP3A inhibitors
Triazole antifungal agents, including those classified as strong CYP3A inhibitors , are permitted.
Strong CYP3A inducers
Sensitive CYP3A substrates with narrow TIs
Subject is on medications with narrow TIs that are sensitive P-gp or BCRP substrates and are administered orally or on medications classified as strong inhibitors of P-gp or BCRP.
Administration of PPIs should be stopped or switched to another ARA 7 days before administration of FHD-286.
Subject is requiring clinically significant or increasing doses of systemic steroid therapy or any other systemic immunosuppressive medication. Local or targeted steroid and immunosuppressive therapies are acceptable. Appropriate steroid replacement to manage endocrine toxicities resulting from prior anticancer systemic therapy is permitted.
Subject has undergone any prior treatment with a BRG1/BRM inhibitor.
Subject is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment.
Subject must be 16 years of age.
Subject must: Have a confirmed diagnosis of R/R AML, R/R MDS, or R/R CMML not in blast crisis AND Be an appropriate candidate for treatment with LDAC (Arm A) or decitabine (Arm B)
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.
Subject must be willing and able to comply with scheduled study visits and treatment plans.
Subject must be willing to undergo all study procedures unless contraindicated due to medical risk.
Subject must have an ECOG PS of 2.
Subject must have a life expectancy of 3 months.
Subject must have adequate hepatic function
Subject must have adequate renal function
Subject must have a WBC count 20109/L
Subject must have adequate cardiovascular, respiratory, and immune system function
Subject must agree to abide by dietary and other considerations required during the study
Subject must meet timing requirements with respect to prior therapy and surgery
Toxicity related to prior therapy must have returned to Grade 2 by CTCAE by approximately 14 days before the start of study treatment
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
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
Exclusion Criteria:
Subject is unable to provide informed consent and/or to follow protocol requirements.
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
Subject has clinical symptoms suggesting active CNS leukemia or known CNS leukemia.
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.
Subject has other malignancy that may interfere with the diagnosis and/or treatment of advanced hematologic malignancies.
Subject has active HBV or HCV infections; Subject has known positive HIV antibody results, or AIDS-related illness;
Subject has an active severe infection that requires anti-infective therapy or has an unexplained temperature of >38.5C during screening visits or on their first day of study treatment
Subject has an uncontrolled intercurrent illness.
Subject has QTcF >470 msec or other factors that increase the risk of QTc prolongation or arrhythmic events
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.
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
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.
Subject is receiving any other investigational agents.
At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since last administration of a prior investigational drug at the start of study treatment. Exceptions include participation in any observational or nontherapeutic clinical trials.
Subject is on medications classified as:
Strong CYP3A inhibitors
Triazole antifungal agents, including those classified as strong CYP3A inhibitors , are permitted.
Strong CYP3A inducers
Sensitive CYP3A substrates with narrow TIs
Subject is on medications with narrow TIs that are sensitive P-gp or BCRP substrates and are administered orally or on medications classified as strong inhibitors of P-gp or BCRP.
Administration of PPIs should be stopped or switched to another ARA 7 days before administration of FHD-286.
Subject is requiring clinically significant or increasing doses of systemic steroid therapy or any other systemic immunosuppressive medication. Local or targeted steroid and immunosuppressive therapies are acceptable. Appropriate steroid replacement to manage endocrine toxicities resulting from prior anticancer systemic therapy is permitted.
Subject has undergone any prior treatment with a BRG1/BRM inhibitor.
Subject is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment.
