Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia Refractory
Conditions
Brief summary
This study evaluates the safety and tolerability of escalating doses of BP1002 (Liposomal Bcl-2 Antisense Oligodeoxynucleotide) in patients with refractory/relapsed AML. The study is designed to assess the safety profile, identify DLTs, biologically effective doses, PK, PD and potential anti-leukemic effects of BP1002 as single agent (dose escalation phase) followed by assessing BP1002 in combination with decitabine (dose expansion phase).
Interventions
DRUGBP1002; Liposomal Bcl-2 Antisense Oligodeoxynucleotide
Dose escalation of BP1002 monotherapy
DRUGDecitabine (in combination with BP1002)
Dose expansion of BP1002 in combination with decitabine
Sponsors
Bio-Path Holdings, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults ≥18 years of age, with histologic evidence of refractory/relapsed AML who have failed treatment with available therapies known to be active for refractory/relapsed AML 2. Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0, 1 or 2 3. For the dose expansion phase, participants with documented diagnosis of AML who are eligible for decitabine therapy 4. Participants must have adequate hepatic and renal functions as defined by: 1. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 times the upper limit of normal (ULN); and 2. Usually total bilirubin ≤ 1.5 ULN. In specific cases the PI may request a waiver of this requirement with medical justification and agreement with the medical monitor and Bio-Path Holdings. And; 3. Estimated creatinine clearance of at least 60 mL/min. These estimations are calculated using the Cockcroft-Gault equation. 5. Female participants of childbearing potential must agree to use an acceptable method of birth control (i.e. a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide or abstinence) for the duration of the study and for at least 6 months after the last dose of study drug or decitabine 6. Male participants must agree to use an acceptable method of contraception for the duration of the study 7. Recovered from the effects of any prior surgery, radiotherapy, or antineoplastic treatment (with the exception of alopecia), based on Investigator assessment 8. Participants must be willing and able to provide written informed consent
Exclusion criteria
1. Active non-hematologic or lymphoid malignancy other than AML treated with immunotherapy, targeted therapy or chemotherapy within the previous 12 months 2. Known, active leptomeningeal leukemia requiring intrathecal therapy. NOTE: Participants with a history of CNS disease may be allowed to participate based on at least 1 documented, negative spinal fluid assessment within 28 days prior to Screening 3. Isolated potentially treatable extramedullary leukemia without also meeting bone marrow criteria for acute leukemia (for AML usually ≥ 5% blasts in BMA or biopsy). Participants may have leukemia with lower blast counts (Döhner 2017). Bio-Path Holdings and Investigator concurrence required. 4. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) PML-RARA 5. Chronic myeloid leukemia in any phase 6. Receipt of any anti-cancer therapy within 14 days prior to C1D1, with the exception of hydroxyurea or leukapheresis 7. Participants may not be receiving any other investigational agents 8. Female participants who are pregnant or breast-feeding 9. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results 10. Participants with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts \< 350 cells/mcL or with clinically active hepatitis B or C infection 11. History of any hypersensitivity to hypomethylating agents, unless reaction is deemed irrelevant to the study by the Investigator and Medical Monitor 12. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy or procedure, excluding alopecia 13. Presence of concurrent conditions that, in the opinion of the Investigator and/or Medical Monitor, may compromise the participant's ability to tolerate study treatment or interfere with any aspect of study conduct or interpretation of results. This includes, but is not limited to, unstable or uncontrolled angina, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled and sustained hypertension, clinically significant cardiac dysrhythmia or clinically significant baseline ECG abnormality (e.g., QTcF \>470 msec) 14. Within the past 6 months, has had any of the following: myocardial infarction, unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack 15. Uncontrolled seizure disorder (i.e., seizures within the past 2 months) 16. Unable or unwilling to communicate or cooperate with the Investigator or follow the protocol for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine anti-drug antibody (ADA) levels of BP1002 | 30 days | Evaluate ADA via peripheral blood |
| Identify and grade treatment-emergent laboratory abnormalities of escalating doses of BP1002 | 30 days | Identify and grade treatment-emergent laboratory abnormalities of escalating doses of BP1002 using non-hematologic and hematologic measure per NCI CTCAE criteria |
| Recommended Phase 2 (RP2D) of BP1002 | 210 days | Determine RP2D by evaluating Maximally Tolerated Dose (MTD) data |
| Determine plasma pharmacokinetics (PK) of BP1002 using maximum plasma drug concentration | 30 days | Evaluate plasma PK of BP1002 using maximum plasma drug concentration (Cmax) |
| Determine plasma pharmacokinetics (PK) of BP1002 using volume of distribution | 30 days | Evaluate in vivo PK of BP1002 using volume of distribution (Vd) |
| Determine plasma pharmacokinetics (PK) of BP1002 using elimination rate constant | 30 days | Evaluate in vivo PK of BP1002 using elimination rate constant |
| Determine half-life plasma pharmacokinetics (PK) of BP1002 | 30 days | Evaluate in vivo PK of BP1002 half-life (t1/2) |
| Identify conduction and rhythm changes (treatment emergent QTc elevations or other treatment emergent changes in ECG intervals) of escalating doses of BP1002 | 30 days | Collection of 12-lead ECGs at defined intervals to identify conduction and rhythm changes (treatment emergent QTc elevations or other treatment emergent changes in ECG intervals) |
| Determine pharmacodynamics (PD) of BP1002 | 30 days | Flow cytometry will be performed using peripheral blood to evaluate Bcl-2 target inhibition by BP1002 on pre and post treatment samples |
| Identify Dose Limiting Toxicity (DLT) of BP1002 | 30 days | Identify DLT of BP1002 using non-hematologic and hematologic measures per NCI CTCAE criteria |
| Identify and grade treatment-emergent adverse events (TEAE) of escalating doses of BP1002 | 30 days | Identify TEAE of BP1002 using non-hematologic and hematologic measures per NCI CTCAE criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To determine progression-free survival (PFS), overall survival (OS), and duration of response | 180 days | To assess progression-free survival (PFS), overall survival (OS), and duration of response from date of study entry to study closure or death |
| Determine evidence of response by bone marrow aspirate | 180 days | Assess complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with partial hematologic recovery (CRh) per Döhner 2017 |
| Determine evidence of response by complete blood counts using peripheral blood | 180 days | Assess complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with partial hematologic recovery (CRh) per Döhner 2017 |
| Assessment of morphologic leukemia free state (MLFS) and partial remissions by bone marrow aspirate and complete blood counts | 180 days | To assess percentage of participants with MLFS and partial remissions per Döhner 2017 |
| Assessment of morphologic leukemia free state (MLFS) and partial remissions by bone marrow aspirate | 180 days | To assess percentage of participants with MLFS and partial remissions per Döhner 2017 |
| Assessment of blast count reductions by complete blood counts using peripheral blood | 180 days | To assess blast count reductions per Williams 2016 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory objective to correlate treatment response with cytogenetic characteristics | 30 days | Flow cytometry assays to determine the effects of BP1002 on Bcl-2 protein expression |
| Exploratory objective to correlate treatment response with molecular characteristics | 30 days | Flow cytometry assays to determine the effects of BP1002 on Bcl-2 protein expression |
Countries
United States
Contacts
Primary ContactMichael Hickey
Outcome results
None listed