Clinical Trials /

Clinical Trial of BP1001 in Combination With With Venetoclax Plus Decitabine in AML

NCT02781883

Description:

The primary objectives of this study are to assess: (1) whether the combination of BP1001 plus venetoclax plus decitabine provides greater efficacy (Complete Remission [CR], Complete Remission with incomplete hematologic recovery [CRi], Complete Remission with partial hematologic recovery [CRh], than venetoclax plus decitabine alone (by historical comparison) in participants with untreated AML that cannot or elect not to be treated with more intensive chemotherapy; (2) whether BP1001-based treatment provides greater efficacy (CR, CRi, CRh) than intensive chemotherapy (by historical comparison) in participants with refractory/relapsed AML.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Clinical Trial of BP1001(Liposomal Grb2 Antisense Oligonucleotide) in Combination With Decitabine in AML / High Risk MDS
  • Official Title: A Phase IIa, Open-label, Clinical Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of BP1001 in Combination With Decitabine in AML or High Risk MDS Patients Who Are Ineligible for Intensive Induction Therapy

Clinical Trial IDs

  • ORG STUDY ID: BP1001-201-AML
  • NCT ID: NCT02781883

Conditions

  • Acute Myeloid Leukemia (AML)
  • High-risk Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
BP1001 in combination with decitabineLiposomal Grb-2, L-Grb-2Refractory/Relapsed AML/High Risk MDS

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Untreated AML/High Risk MDSExperimentalBP1001 in combination with decitabine
  • BP1001 in combination with decitabine
Refractory/Relapsed AML/High Risk MDSExperimentalBP1001 in combination with decitabine
  • BP1001 in combination with decitabine

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assessment of efficacy by bone marrow aspirate or biopsy
Time Frame:180 days
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Assessment of safety of BP1001 in combination with decitabine
Time Frame:30 days
Safety Issue:
Description:Evaluate safety and toxicity of the combination of BP1001 with decitabine using non-hematologic and hematologic measures per NCI CTCAE criteria (with a safety run-in)
Measure:Assessment of the pharmacokinetics (PK) of BP1001 when given in combination with decitabine
Time Frame:30 days
Safety Issue:
Description:Evaluate the in vivo PK using plasma to compute half life and elimination.
Measure:Assessment of Minimal Residual Disease (MRD) status in patients who achieve CR/CRi/CRh with BP1001 + decitabine;
Time Frame:30 days
Safety Issue:
Description:Assess time to response from administration of BP1001+decitabine to CR, CRi, or CRh, negative MRD status as defined by the site and as available (Usually ≤ 0.1% by multi-parameter flow cytometry).
Measure:Assessment of Partial Remissions and blast count reductions.
Time Frame:30 days
Safety Issue:
Description:Assessment of Partial Remissions (per Cheson, 2003), and blast count reductions (per Williams, 2016)
Measure:Assessment of overall survival
Time Frame:180 days
Safety Issue:
Description:To assess event-free survival, overall survival, time to response, and duration of response from date of study entry to study closure or death.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bio-Path Holdings, Inc.

Trial Keywords

  • Liposomal Grb-2 treatment of AML or High Risk MDS
  • Liposomal Grb-2 with decitabine for AML or High Risk MDS

Last Updated

June 11, 2019