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
The main goal of this study is to learn about the safety of H3B-8800 in humans and to understand how it works in MDS, AML, and CMML. There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerable dose of H3B-8800 that can be given to patients with MDS, AML, or CMML. The goal of Part 2 of this study is to learn if the dose of H3B-8800 found in Part 1 can help to control the disease in patients with certain types of genetic mutations (changes). The safety of H3B-8800 will also be studied in both parts. This is the first study using H3B-8800 in humans.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: H3B-8800
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Eisai Inc.,H3 Biomedicine Inc
Primary Objective The primary objectives of the study are to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of H3B-8800 administered orally in subjects with MDS, AML, or 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 subjects with MDS, AML, or CMML. Secondary Objectives The secondary objectives of the study are: 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 The exploratory objectives of the study are: 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. To explore the metabolite profile of H3B-8800 in plasma and urine.
IRB Review and Approval Date: 03/24/2017
Recruitment Status: Open
Projected Accrual: Approximately 110
1) The subject has a confirmed diagnosis of MDS, CMML, or AML (including
de novo, secondary and therapy-related) according to WHO 2008
classification excluding acute promyelocytic leukemia (APL, FAB M3).
2) The subject must meet the following criteria relevant to their specific diagnosis: a. 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 x 10^9 cells/L. b. For International Prognostic Staging System (IPSS) high-risk or intermediate-2 MDS, subjects must be intolerant of hypomethylating agents 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 a hypomethylating agent (HMA).
3) CONTINUED: For IPSS intermediate-1 or low-risk MDS, subjects must be transfusion dependent for red blood cells or platelets (as determined by instructional practices or local standard of care). Subjects 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. d. For CMML subjects must have been treated with at least one prior therapy (hydroxyurea or an HMA).
4) Peripheral blood samples: a. Cohort A: Screening visit peripheral blood must be available for retrospective analysis of spliceosome mutations of interest. b. Cohort B and Expansion: Screening visit peripheral blood must be submitted for central analysis to identify spliceosome hotspot mutations in SF3B1, SRSF2, U2AF1, mutations in ZRSR2 and SRSF2 deletion including amino acid P95. The table below (located in Proposed Treatment Plan) identifies the specific mutations which are required for enrollment. Additional mutations (not identified in this table) may be considered in consultation with the medical monitor.
5) Male or female, age >/= 18 years old at the time of consent.
6) ECOG performance score (PS) of 0-2.
7) Adequate baseline organ function, including renal, and hepatic function: a. Serum creatinine </= 1.7 mg/dL or calculated creatinine clearance >/=50mL/min per the Cockcroft and Gault formula b. Direct bilirubin </= 1.5 x upper limit of normal (ULN) c. AST and ALT </= 3.0 x ULN d. Albumin >/= 2.5 mg/dL
8) Willing and able to comply with all aspects of the protocol.
9) Provide written informed consent prior to any study-specific screening procedures
1) Females who are breastfeeding or pregnant at Screening or Baseline
(as documented by a positive beta-human chorionic gonadotropin [b-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.
2) 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 (ie, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing).
3) Females of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment and for at least 1 month 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 (eg, total abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. 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 and for 30 days after study drug discontinuation. Women using oral hormonal contraceptives should add a barrier method.
4) Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period or for 3 months after study drug discontinuation). No sperm donation is allowed during the study period or for 3 months after study drug discontinuation.
5) Diagnosis of a core binding factor leukemia (t(8;21), t(16;16) or inv(16)).
6) Subject is deemed a candidate for hematopoietic stem cell transplants at the time of enrollment.
7) 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).
8) Known prior or current retinal or optic nerve disease (e.g. Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) based on screening ophthalmology assessment for eligibility.
9) Corrected vision is worse than 20/40 unless due to cararacts.
10) Vitamin B12, folate or vitamin A deficiency. Rescreening following repletion therapy is acceptable.
11) Alcohol dependency within the previous 6 months of first dosing.
12) 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.
13) 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 of enrollment.
14) Use of concomitant medications that are known to be strong inhibitors or inducers of CYP3A4 enzymes unless subject can discontinue or switch medications.
15) Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the bioavailability of H3B-8800 or absorption of vitamins.
16) Persistent clinically significant Grade >/= 2 toxicities from previous chemotherapy (excluding alopecia, nausea, fatigue, anemia, and liver function tests [as mandated in the inclusion criteria]).
17) Received treatment with chemotherapy, wide-field radiation, or anti-cancer biologic therapy including investigational agents within 14 days of study entry.
18) An active malignancy and/or cancer history for at least 2 years that may confound the assessment of the study endpoints. Subjects with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease.
19) Clinically severe cardiovascular disease (eg, uncontrolled congestive heart failure, uncontrolled angina, history of myocardial infarction within the six months, unstable angina or stroke within 30 days of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
20) Cardiac troponin (cTn) levels above the upper limit of normal (grade 1 or higher)
21) A clinically significant ECG abnormality, including a marked baseline prolonged QTcF interval (eg, a repeated demonstration of a QTc interval >480 ms).
22) 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 patient at significant risk for pulmonary complications during the study.
23) Known active or suspected CNS leukemia. If suspected, CNS leukemia should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.
24) 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.
25) Known history of human immunodeficiency virus (HIV), or active Hepatitis B or C.
26) Known intolerance to the study drug or chemical derivative or any of the excipients.
27) Currently enrolled in another clinical study or used any investigational drug or device within 28 days or 5x the half-life, whichever is longer) preceding informed consent
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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