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Clinical Trial 18939

Cancer Type:
Interventions:H3B-8800

Study Type: Treatment
Phase of Study: Phase I
Investigators:

  • Rami Komrokji

Call 813-745-6100
or 1-800-679-0775
Overview

Study Title

An Open-label, Multicenter Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

Summary

This study will include a Phase 1 dose-finding portion and a four-arm expansion portion. The primary objectives of the study are to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of H3B-8800 administered orally in participants with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML) and to assess the safety and tolerability of H3B-8800 as a single agent administered orally once daily on a 5 days on/9 days off repeated dosing schedule in 28-day cycles in participants with MDS, AML, or CMML.

Objective

Primary Objectives: Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of H3B-8800 administered orally in subjects with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). Assess the safety and tolerability of H3B-8800 as a single agent administered orally once daily on a 5 days on/9 days off repeated dosing schedule in 28-day cycles in subjects with MDS, AML, or CMML. Secondary Objectives: Characterize the plasma pharmacokinetics (PK) of H3B-8800 in subjects with MDS, AML, or CMML. Evaluate the preliminary antitumor activity of H3B-8800 at the RP2D and schedule in subjects with MDS, AML, and CMML with spliceosome mutations of interest in SF3B1, SRSF2, U2AF1 and/or ZRSR2. Exploratory Objectives: Evaluate the pharmacodynamic (PD) effects of H3B-8800 in blood and marrow cells including, but not limited to, effects on splicing and variant allele fraction (in cases of mutation-positive patients). Assess candidate biomarkers predictive of response to H3B-8800 that may include, but are not limited to, pre-treatment splicing patterns and methylation patterns. Evaluate potential mechanisms of treatment-emergent resistance to H3B-8800 therapy. Explore the metabolic profile of H3B-8800 in plasma and urine.

Inclusion Criteria

  • Confirmed diagnosis of Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML). For Cohorts A and D, participants must have either AML or higher-risk-MDS/CMML.For Cohort C, participants must have lower-risk MDS/CMML. To ensure adequate bone marrow reserve, all participants in Cohort C must also have platelet counts of ≥ 50,000 mm3 in the absence of transfusion for 8 weeks.
  • Must meet the following criteria relevant to their specific diagnosis: Participants with higher-risk MDS/CMML must be intolerant of hypomethylating agents (HMAs) or not have responded to 4 treatment cycles of decitabine or 6 treatment cycles of azacitidine, or must have progressed at any point after initiation of an HMA. Participants with lower-risk MDS/CMML must be transfusion-dependent for red blood cells or platelets. Participants who are red blood cell transfusion-dependent must also have failed erythropoiesis stimulating agents (ESA) (primary resistance or relapse after a response) or have serum EPO levels > 500 U/L. These lower-risk patients must have platelet counts above 50,000 mm3 in the absence of transfusion for 8 weeks.
  • AML: Participants with AML must either refuse or not be considered candidates for intensive induction chemotherapy. Previously treated participants should have evidence of persistent or recurrent AML in the peripheral blood and/or bone marrow. Participants must have white blood cell (WBC) > Participants with CMML must have been treated with at least 1 prior therapy (hydroxyurea or an HMA).
  • Peripheral Blood Samples must be available
  • Male or female, age ≥ 18 years old at the time of consent.
  • Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
  • Adequate baseline organ function.
  • Provide written informed consent.

  • Exclusion Criteria

  • Females who are breastfeeding or pregnant.
  • Males who have not had a successful vasectomy or do not practice highly effective contraception as outlined in the protocol.
  • Diagnosis of a core binding factor leukemia (t(8;21), t(16;16) or inv(16)).
  • Participant is candidate for hematopoietic stem cell transplants at the time of enrollment.
  • Family history of Leber Hereditary Optic Neuropathy, Autosomal Dominant Optic Atrophy, Late-Onset Retinal Degeneration, Familial Dysautonomia or other hereditary mitochondrial disease, unless the causative mutation(s) in the family have been determined and the participant has tested negative for the mutation(s).
  • Known prior or current retinal or optic nerve disease (e.g., Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) based on screening ophthalmology assessment for eligibility.
  • Corrected vision is worse than 20/40 unless due to cataracts.
  • Vitamin B12, folate or vitamin A deficiency. Re-screening following repletion therapy is acceptable.
  • Use of concomitant medications with evidence for an association with drug-induced mitochondrial optic neuropathy including systemic administration of ethambutol, chloramphenicol, linezolid, erythromycin, streptomycin, and zidovudine.
  • Prior exposure to cisplatin, 5-fluorouracil, tamoxifen, and/or MEK inhibitors within 3 months of enrollment and/or ethambutol and/or hydroxychloroquine within 12 months.
  • Use of concomitant medications that are known to be strong inhibitors or inducers of CYP3A4 enzyme unless participant can discontinue or switch medications.
  • Received treatment with chemotherapy, wide-field radiation, or anticancer biologic therapy within 14 days of study entry.
  • An active malignancy and/or cancer history within the prior 2 years. Participants with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, and organ-confined prostate cancer with no evidence of progressive disease.
  • Clinically severe cardiovascular disease or clinically significant electrocardiogram (ECG) abnormality.
  • Uncontrolled, clinically significant pulmonary disease.
  • Known active or suspected central nervous system (CNS) leukemia.
  • Uncontrolled intercurrent illness.
  • Known history of human immunodeficiency virus (HIV), or active Hepatitis B or C.
  • Cardiac troponin (cTn) levels above the upper limit of normal.
  • Currently enrolled in another clinical study or used any investigational drug or device within 28 days or 5 × the half-life (whichever is longer), preceding informed consent.