Clinical Trials

Inclusion Criteria:

• The subject has a confirmed diagnosis of AML, MDS, or CMML (including de novo, secondary, and therapy-related disease) according to WHO 2008 classification, excluding acute promyelocytic leukemia (APL, FAB M3):
  • For Cohorts A and D, subjects must have either AML or higher-risk-MDS/CMML, defined for MDS as meeting IPSS criteria for categorization > IR-2 and defined for CMML as meeting WHO criteria for CMML-2;
  • For Cohort C, subjects must have lower-risk MDS/CMML, defined for MDS as meeting IPSS criteria for categorization < IR-2 and defined for CMML as meeting WHO criteria for CMML-0 or CMML-1. To ensure adequate bone marrow reserve, all subjects in Cohort C must also have platelet counts of ≥ 50,000 mm^3 in the absence of transfusion for 8 weeks;
  • For the MDS expansion cohort, subjects must be lower-risk MDS, defined as low or intermediate-1 risk categorization per IPSS criteria (Greenberg et al., 1997) that carries a missense SF3B1 mutation (i.e., mutations in codons E622, Y623, R625, N626, H662, T663, K666, K700, V701, I704, G740, K741, G742, D781) at a variant allele frequency of 5% or higher. Mutation assessment will be provided either by a local Sponsor-approved laboratory or by a central Sponsor-provided laboratory prior to enrollment.
  • For the Dose-optimization cohort, subjects must be transfusion-dependent, lower-risk MDS, defined as very-low to intermediate risk categorization by IPSS-R (Greenberg et al., 2012) that carries a messense SF3B1 mutation (i.e., mutations in codons E622, Y623, R625, N626, H662, T663, K666, K700, V701, I704, G740, K741, G742, D781) at a variant allele frequency of 5% or higher. Mutation assessment will be provided either by a local Sponsor-approved laboratory or by a central Sponsor-provided laboratory prior to enrollment. Local lab results indicating presence of SF3B1 missense mutations must be completed within 6 months prior to signing informed consent.

The subject must meet the following criteria relevant to their specific diagnosis:

• Subjects 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;
• For enrollment in the dose escalation portion, subjects with lower-risk MDS/CMML must be transfusion-dependent for red blood cells or platelets (as determined by instructional practices or local standard of care). For enrollment in the MDS expansion cohort, lower risk MDS subjects must be RBC transfusion dependent according to IWG 2006 criteria (having received at least 4 U of RBCs within 8 weeks for hemoglobin (Hb) of < 9 g/dL prior to first dose of H3B-8800 (RVT-2001). Subjects who are RBC transfusion-dependent must also have failed erythropoiesis stimulating agents (ESA) (primary resistance or relapse after a response) or have serum erythropoietin (EPO) levels > 500 U/L;
• For enrollment in the Dose-optimization cohort, lower-risk MDS subjects must be RBC transfusion-dependent at baseline defined as ≥ 3 RBC units (concentrates) in 16 weeks in at least 2 transfusion episodes prior to the first dose of H3B-8800 (RVT-2001). Subjects who are RBC 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. Any ESA use should be discontinued > 6 weeks prior to enrollment.
• Subjects with AML must either refuse or not be considered candidates for intensive induction chemotherapy using consensus criteria for defining such subjects. Previously treated subjects should have evidence of persistent or recurrent AML in the peripheral blood and/or bone marrow that is refractory to, or has relapsed from, their most recent prior line of treatment. For AML, subjects must have WBC < 15 × 10^9 /L.;
• Subjects with CMML must have been treated with at least 1 prior therapy (hydroxyurea or an HMA);
• Peripheral blood sample requirements:
  • For dose escalation cohorts screening visit peripheral blood must be available for retrospective analysis of spliceosome mutations of interest.
• Male or female, age ≥ 18 years old at the time of consent.
• ECOG performance score (PS) of 0-2. 5.
• MDS Expansion and Dose-optimization cohorts: Absolute neutrophil count (ANC) > 500/μL (0.5 x 10^9 /L).
• MDS Expansion and Dose-optimization cohorts: Platelet count ≥ 50,000/μL (50 x 10^9 /L).
• Dose-optimization cohort: No prior HMA or lenalidomide in subjects with lower-risk MDS.
• Adequate baseline organ function, including renal, and hepatic function:
  • Serum creatinine ≤ 1.7 mg/dL or calculated creatinine clearance ≥ 50 mL/min per the Cockcroft and Gault formula;
  • Direct bilirubin ≤ 1.5 × upper limit of normal (ULN);
  • AST and ALT ≤ 3.0 × ULN;
  • Albumin ≥ 2.5 mg/dL.
• Willing and able to comply with all aspects of the protocol.
• Provide written informed consent prior to any study-specific Screening procedures.

Exclusion Criteria:

• Females who are breastfeeding or pregnant at Screening or baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative Screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing):
  • Females of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment and for at least 1 month and 1 week after finishing treatment;
  • Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period, for 1 week after study drug discontinuation and for an additional 30 days after;
  • Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study, for 1 week after study drug discontinuation and for an additional 30 days after. Women using oral hormonal contraceptives should add a barrier method.
• Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period, for 1 week after study drug discontinuation and for an additional 3 months after). No sperm donation is allowed during the study period, for 1 week after study drug discontinuation and for an additional 3 months after.
• Diagnosis of a core binding factor leukemia (t(8;21), t(16;16); or inv(16)). Diagnosis of acute promyelocytic leukemia (t(15;17)).
• Subject is deemed a candidate for hematopoietic stem cell transplants at the time of enrollment. This exclusion criteria applies only to AML subjects.
• 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 subject has tested negative for the mutation(s).
• Known prior or current retinal or optic nerve disease (e.g., Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) not stable for at least 6 months.
• History of clinically significant, uncorrected vitamin B12 or folate deficiency. Re-screening following repletion therapy is acceptable.
• Alcohol dependency within the previous 6 months of first dosing.
• 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 subject can discontinue or switch medications.
• Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of H3B-8800 (RVT-2001) or absorption of vitamins.
• Persistent clinically significant ≥ Grade 2 toxicities from previous chemotherapy (excluding alopecia, nausea, fatigue, anemia, and liver function tests [as mandated in the inclusion criteria]).
• 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. Subjects with the following neoplastic diagnoses are eligible: early-stage cancer with curative resection not requiring systemic therapy (review with Sponsor), 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 (e.g., uncontrolled congestive heart failure, uncontrolled angina, history of myocardial infarction within the 6 months, unstable angina or stroke within 30 days of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
• A clinically significant ECG abnormality, including a marked baseline prolonged QTcF (QT corrected for heart rate using Fridericia’s formula) interval (e.g., a repeated demonstration of a QTc interval > 480 ms).
• Uncontrolled, clinically significant pulmonary disease (e.g., COPD, pulmonary hypertension, continuous dependency on supplemental oxygen) that in the opinion of the Investigator would put the subject at significant risk for pulmonary complications during the study.
• Known active or suspected CNS leukemia. If suspected, CNS leukemia should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit adherence to study requirements.
• Known history of human immunodeficiency virus (HIV), or active Hepatitis B or C.
• Known intolerance to the study drug or chemical derivative or any of the excipients.
• Currently enrolled in another clinical study or used any investigational drug or device within 28 days or 5 × the half-life (whichever is longger), preceding informed consent.
• Dose-optimization cohort: Prior exposure to an SF3B1 inhibitor or other spliceosome inhibitors.