Efficacy and Safety of BST-236 in Newly Diagnosed Acute Myeloid Leukemia Patients, Unfit for Standard Induction Therapy

Study Overview
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Brief Summary
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The purpose of this study is to assesses the benefit, safety, and pharmacokinetics (PK) of BST-236 in patients with newly-diagnosed Acute Myeloid Leukemia (AML) who are not eligible for standard induction chemotherapy due to advanced age or comorbidities. The Complete Remission (CR) rate following treatment with BST-236 will be compared to the CR rate reported in historical data in a similar population.

Detailed Description
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BST-236 is a cytarabine pro drug designed to release cytarabine inside the target cells with reduced systemic exposure to free cytarabine. As such, BST-236 may enable delivery of high doses of cytarabine to medically-unfit or older adults who otherwise cannot be treated with standard cytarabine therapy. This study aims to validate this hypothesis. The study is an open-label, single arm, single agent, multi-center study in adults with newly diagnosed AML who are unfit for standard therapy. The patients will receive up to 4 courses of six-days treatment with intravenous BST-236; 1 or 2 induction courses followed by 1 to 2 consolidation courses. The study participation will be 52 weeks including treatment and follow-up periods. An additional 1 year post study follow-up for the evaluation of survival is optional.

Official Title
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A Phase 2b Open-Label, Single Arm, Multi-Center Study to Assess the Efficacy and Safety of BST-236 as a Single Agent in Adults With Newly-Diagnosed Acute Myeloid Leukemia (AML), Not Eligible for Standard Induction Therapy

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: BST-236


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult ≥18 years of age AML according to the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: ≥20% blasts in peripheral blood or marrow de-novo AML or AML secondary to MDS or AML secondary to exposure to potentially leukemogenic therapies or agents (e.g. radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years Not eligible for standard induction chemotherapy; Age ≥75 years or Age ≥18 years with at least one of the following comorbidities: i. Clinically significant heart or lung comorbidities, as reflected by at least one of: Left ventricular ejection fraction (LVEF) ≤50% Lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected Forced expiratory volume in 1 second (FEV1) ≤65% of expected ii. Chronic stable angina or congestive heart failure controlled with medication iii. Other contraindication(s) to anthracycline therapy (must be documented) iv. Other comorbidity that the Investigator judges as incompatible with intensive remission induction chemotherapy, which must be documented Creatinine clearance (estimated by the Cockroft-Gault (C-G) or measured by 24 hours urine collection) ≥45 mL/min Liver enzymes (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 times the upper limits of normal (ULN) Total bilirubin ≤1.5 x ULN unless due to known history of Gilbert's disease Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening Prepared and able to give written (signed and dated) informed consent, which includes compliance with study requirements and restrictions prior to admission to the study Women of reproductive potential must have a negative serum pregnancy test within 48 hours of the first day of any BST-236 treatment course Women or men of reproductive potential must use (or have his/her partner use) two forms of effective birth control methods starting from 1 month prior to screening and until 3 months following the last BST-236 administration day (acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptives, contraceptive patch, long-acting injectable contraceptives, partner's vasectomy, or double-barrier method condom or diaphragm with spermicide) Patient must voluntarily sign and date an ICF, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures Patient must be able to adhere to the study visit schedule and other protocol requirements Exclusion Criteria: Patient has relapsed or refractory AML Patient has acute promyelocytic leukemia Any previous treatment for AML (except for hydroxyurea or up to one treatment course with hypomethylating agents (HMA)) Patient has history of myeloproliferative neoplasm (MPN) including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation Previous use (prior to study initiation) of drugs containing cytarabine as an active ingredient Use of any HMA for the treatment of MDS within 30 days of study Day 1 Participation in a previous clinical trial and/or use of an investigational drug within 90 days or at least 5 half-lives of tested drug (whichever is longer) of initial screening assessment Peripheral White Blood Cell (WBC) count >30,000 /µL in the 48 hours prior to first BST-236 dose administration. Hydroxyurea administration or leukapheresis is permitted to meet this criterion Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment) Any medical or surgical condition, presence of laboratory abnormalities or psychiatric illness that may preclude safe and complete study participation based on the Investigator's judgment Diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma of the skin without complications, in-situ carcinoma, or other local malignancy excised or irradiated with a high probability of cure and not treated with chemotherapy) Active malignant disease other than AML Leptomeningeal/central nervous system involvement of AML Myeloid sarcoma as a sole manifestation of AML Surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) in the 14 days prior to BST-236 administration Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 4 congestive heart failure Shortness of breath requiring continuous oxygen treatment for at least 15 hours per day in chronically hypoxemic patients History of allergic reactions attributed to compounds of similar chemical composition as BST-236 and/or cytarabine Life expectancy shorter than 3 months attributed to any known medical condition other than AML Active/chronic Hepatitis B Virus (HBV) infection (based on positive surface antigen (HBsAg)), Hepatitis C Virus (HCV) infection (HCV) (based on positive HCV antibody (Ab)), or Human Immunodeficiency Virus (HIV)-1 or HIV-2 (based on positive HIV antibody)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BST-236<br>BST-236 Intravenous, 4.5 g/m2/d or 2.5 g/m2/d, for 6 days | Drug: BST-236<br>* 1 to 4 courses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission | as BM blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC >1.0x 109/L (1,000/μL); platelet count >100 x 109/L (100,000/μL) | Day 28-35 of induction/re induction course | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Unfit for standard induction therapy, Cytarabine