Clinical Trial of BP1001(Liposomal Grb2 Antisense Oligonucleotide) in Combination With Decitabine in AML / High Risk MDS

The primary objective of this study is to assess whether the combination of BP1001 and decitabine provides greater efficacy (Complete Remission [CR], Complete Remission with incomplete hematologic recovery [CRi], Complete Remission with partial hematologic recovery [CRh], than decitabine alone (by historical comparison) in participants with AML / High Risk MDS that cannot or elect not to be treated with more intensive chemotherapy. The historical comparison to be used will be defined in the Statistical Analysis Plan (SAP) prior to database closure.

Inclusion Criteria

• Inclusion Criteria: At the time of Screening, participants must meet all of the following criteria to be considered eligible to participate in the study: 1. Adults ≥18 years of age 2. Females must be of non-childbearing potential, surgically sterile, postmenopausal, or practice adequate methods of contraception during the study and for 30 days after the last dose of study drug or decitabine 3. Males must agree to use an adequate method of contraception during the study and for at least 30 days after the last dose of study drug, or decitabine 4. Histologically documented diagnosis (based on the 2008 World Health Organization [WHO] Classification) (Vardiman 2009) of one of the following: 1. Newly diagnosed untreated AML; or 2. Untreated secondary AML, including AML that has progressed from MDS 3. In some cases of AML associated with specific genetic abnormalities, however, the diagnosis of AML may be made if the blast count is less than 20% (Dohner, 2017) - specifically AML with t(15;17), t(8;21), inv(16), or t(16;16)) 4. Relapsed or Refractory AML/High Risk MDS 5. Untreated High Risk MDS 5. Investigator considers participant ineligible for (or unwilling to receive) intensive induction therapy based on medical reasons, disease characteristics such as genetics, type of AML (untreated or secondary), or participant characteristics such as age, performance status, co-morbidities, organ dysfunctions, or patient election of low-intensity treatment. 6. Eligible for decitabine therapy, based on Investigator assessment; although decitabine is not approved by FDA for AML, it is commonly used in this patient population and is approved for MDS patients. 7. 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 glomerular filtration rate (eGFR) of at least 40 ml/min. These estimations can be calculated using the following methods (Appendix D): i. Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation OR ii. Cockcroft Gault equation OR iii. Modification of Diet in Renal Disease (MDRD study equation) OR iv. Creatinine clearance estimated by 24-hr urine collection for creatinine clearance 8. Documented Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 9. Recovered from the effects of any prior surgery, radiotherapy, or antineoplastic treatment (with the exception of alopecia), based on Investigator assessment 10. Willing and able to provide written informed consent Exclusion Criteria: At the time of Screening, participants who meet any of the following criteria will be excluded from participating in the study: 1. Active non-hematologic or lymphoid malignancy other than AML or High Risk MDS treated with immuno- or chemotherapy within the previous 12 months except active non-melanoma, non- invasive skin cancer will be allowed. 2. Known, active leptomeningeal leukemia requiring intrathecal therapy. NOTE: Patients 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 = 20% blasts in bone marrow aspirate or biopsy). Patients may have leukemia with lower blast counts (Dohner, 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 (CML) in any phase 6. Receipt of any anti-cancer therapy within 14 days prior to C1D1, with the exception of hydroxyurea or anagrelide (within 24 hours), TKI (within 1day), or single dose of cytarabine (for proliferative disease) 7. Palliative treatment for high WBCs with hydroxyurea (HU) is allowed. 8. Uncontrolled active, untreated, or progressive infection 9. Receipt of any investigational agent or study treatment within 30 days prior to C1D1 10. Females who are capable of becoming pregnant, test positive for pregnancy, or are breast-feeding during the Screening period, or intend to become pregnant or breast-feed during the course of the study or within 30 days after last dose of study drug 11. Serious intercurrent medical or psychiatric illness which, in the opinion of the Investigator, would interfere with the ability of the participant to complete the study 12. Known active or clinically significant hepatitis B infection (based on positive surface antigen [HBsAg]), hepatitis C infection (based on positive antibody [HCV Ab]), or human immunodeficiency virus (HIV-1 or HIV-2, based on positive antibody) 13. History of any hypersensitivity to decitabine, unless reaction is deemed irrelevant to the study by the Investigator and Medical Monitor 14. 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) 15. 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 16. Uncontrolled seizure disorder (i.e., seizures within the past 2 months) 17. Unable or unwilling to communicate or cooperate with the Investigator or follow the protocol for any reason

Improvement of clinical benefit in fragile AML and high risk MDS patients while maintaining tolerability is an important area of further clinical development. Modern aggressive combination chemotherapy can induce CR in a significant proportion of patients with previously untreated AML or high risk MDS, but relapse occurs in most unless patients undergo intensive allogeneic hematopoietic stem cell transplantation. Novel therapies are needed for these patients The Grb2 gene has been mapped to the human chromosome region 17q22-qter, a region that is duplicated in leukemias and solid tumors, which may result in an increased copy number of the Grb2 gene product. As Grb2 is important for the transformation of murine hematopoietic cells, and the proliferation of human leukemia cells that express high levels of oncogenic tyrosine kinases, inhibition of Grb2 may have a significant impact on the natural history of leukemias. The study drug (BP1001) may be able to inhibit the cells from making Grb-2. Researchers hope that without this protein, the leukemia cells will die. This represents an area in which targeted therapies might be of benefit to these patients. One such potential treatment is BP1001, liposomal anti-sense treatment directed against Growth Factor Receptor-Bound Protein 2 (Grb2). Decitabine is approved in Europe for the treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukemia (AML). In vitro studies in AML cells co-incubated with BP1001 and decitabine suggests that treatment of AML patients with decitabine followed by BP1001 may be a combination that could benefit patients with AML. This Phase IIa, multicenter, study of BP1001 in combination with decitabine will enroll participants with AML or high risk MDS who are not otherwise eligible for standard or high-intensity chemotherapy regimens or who have elected a low-intensity regimen. This trial will utilize an open label, two-stage design to assess the safety profile, PK, PD, and efficacy of of BP1001 in combination with decitabine to assess whether the combination of either provides greater efficacy than decitabine alone. This 2-arm combination cohort study of BP1001 with decitabine in either untreated or relapsed/refractory patients with AML or high risk MDS will have 19 evaluable patients enrolled per cohort, with a decision to stop or proceed to 54 patients per cohort, for a total of 108 additional patients.

Lead Organization
Bio-Path Holdings, Inc.