Clinical Trials /

Clinical Trial of BP1001 (Liposomal Grb2 Antisense Oligonucleotide) in Combination With Dasatinib in Patients With Ph + CML Who Have Failed TKI, Ph+ AML, Ph+ MDS

NCT02923986

Description:

The primary objective of the Phase Ib study is to determine the dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of BP1001 in combination with dasatinib in patients with with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) including chronic phase patients who have failed initial tyrosine kinase inhibitor (TKI) therapy, accelerated or blast phase, Ph+ Acute Myeloid Leukemia (AML) or High-risk Ph+ Myelodysplastic Syndrome (MDS). The primary objective of the Phase IIa study is to assess the efficacy of the combination of BP1001 and dasatinib in patients with Ph+ CML, Ph+AML, or high-risk Ph+ MDS.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Clinical Trial of BP1001 (Liposomal Grb2 Antisense Oligonucleotide) in Combination With Dasatinib in Patients With Ph + CML
  • Official Title: A Phase Ib/IIa Single-arm, Open-label Clinical Trial to Evaluate the Safety, Pharmacokinetics, and Efficacy of BP1001 (a Liposomal Grb2 Antisense Oligonucleotide) in Combination With Dasatinib (Das) in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) in Accelerated or Blast Phase

Clinical Trial IDs

  • ORG STUDY ID: BP1001-202-CML
  • NCT ID: NCT02923986

Conditions

  • Chronic Myelogenous Leukemia, Ph1-Positive

Interventions

DrugSynonymsArms
BP1001 (varying dose)Liposomal Grb-2, L-Grb-2BP1001 (varying dose) + Dasatinib
BP1001 (fixed dose)Liposomal Grb-2, L-Grb-2BP1001 (fixed dose) + Dasatinib
DasatinibDasBP1001 (varying dose) + Dasatinib

Purpose

The primary objective of the Phase 1b study is to determine the dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of BP1001 and Dasatinib (Das) in patients with Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML) in accelerated or blast phase. The primary objective of the Phase IIa study is to assess the efficacy of the combination of BP1001 and Das in patients with Ph+ CML.

Detailed Description

      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.

      Dasatinib (Das) has been a well established therapeutic regimen in the treatment of Ph+ CML
      patients who are in accelerated of blast phase. Researchers hope that the combination of
      BP1001 and Das will provide a benefit to CML patients in accelerated or blast phase, who
      typically do not respond to the front-line treatment, imatinib.

      This is a Phase Ib/IIa, multicenter, study of BP1001 in combination with Das in participants
      with Ph+ CML who are in accelerated or blast phase.

      This trial will utilize a single arm, open label design to assess the safety profile, DLT,
      MTD, PK, and efficacy of BP1001 in combination with Das.

      Phase Ib portion of the study: The Phase Ib study employs an open-label, sequential,
      dose-escalation design to assess safety, tolerability and toxicity, tumor response and
      anti-leukemic activity.

      A standard "3+3" design will be used in which successive cohorts of patients with CML are
      being treated with BP1001 at the MTD (or highest tested dose [HTD] if the MTD is not defined)
      and 1 level below the MTD (or HTD) in combination with a fixed dose of Das to characterize
      safety and biological effect, as well as identify the recommended Phase IIa dose.

      Phase IIa portion of the study: The Phase IIa study is an open-label, single-dose level
      study. All participants who are eligible to receive treatment on study will receive the same
      dose level for both BP1001 (the HTD or 1 level below the HTD) as determined by the Phase Ib
      study and Das (140 mg). There will be no randomization for this study. The Phase IIa study
      will compare the efficacy of the BP1001 in combination with Das to historical response rates
      documented for Das alone, and will evaluate the PK of BP1001, when given alone or in
      combination with Das.

      Approximately 40 evaluable participants will receive the combination of BP1001 with Das in
      Phase IIa.
    

Trial Arms

NameTypeDescriptionInterventions
BP1001 (varying dose) + DasatinibExperimentalPhase 1b: BP1001 (varying dose levels) in combination with Das
  • BP1001 (varying dose)
  • Dasatinib
BP1001 (fixed dose) + DasatinibExperimentalPhase IIa: BP1001 (fixed dose based on Phase 1b) in combination with Das
  • BP1001 (fixed dose)
  • Dasatinib

Eligibility Criteria

        Inclusion Criteria:

          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 Das

          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 Das

          4. Histologically documented diagnosis of Ph+ CML, in accelerated or blast phase.

             One of the following parameters is required to meet criteria for accelerated CML:

               -  Blasts in Peripheral Blood or Bone Marrow ≥15% (either myeloid or lymphoid
                  blasts)

               -  Promyelocytes and Blasts in Peripheral Blood or Bone Marrow ≥30%

               -  PB or BM basophils ≥20%

               -  Thrombocytopenia <100 x 103/ml, not resulting from therapy

               -  Cytogenetic clonal evolution Blast phase is defined as ≥30% blasts in peripheral
                  blood or bone marrow, or presence of extramedullary disease, except for liver or
                  spleen.

          5. 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. Total bilirubin ≤1.5 times ULN; and

               3. Estimated glomerular filtration rate (eGFR) of at least 50 ml/min; the Cockcroft
                  Gault formula will be utilized to determine eGFR when blood urea nitrogen (BUN)
                  and creatinine testing are performed at baseline. The combination of eGFR serum
                  creatinine and BUN will be used to evaluate patient's renal function for safety
                  assurance.

          6. Documented Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          7. Recovered from the effects of any prior surgery, radiotherapy, or antineoplastic
             treatment (with the exception of alopecia), based on Investigator assessment

          8. Willing and able to provide written informed consent

        Exclusion Criteria:

          1. Patients with T315I mutation will not be excluded, but their response will be analyzed
             separately.

          2. Another primary malignancy other than CML within the past 2 years except non-melanoma
             skin cancer, or carcinoma in situ of the cervix.

          3. Known, active leptomeningeal leukemia requiring intrathecal therapy. NOTE: Patients
             with a history of CNS disease may be allowed to participate based on at least 2
             consecutive documented, negative spinal fluid assessment prior to Screening

          4. Isolated extramedullary leukemia without also meeting bone marrow criteria for
             leukemia

          5. Receipt of any anti-cancer therapy within 14 days of starting BP1001, with the
             exception of hydroxyurea or anagrelide, or TKI (within 2 days)

          6. Uncontrolled active, untreated, or progressive infection

          7. Receipt of any investigational agent within 14 days or 5 half-lives of starting BP1001

          8. Females who are 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

          9. Prior exposure to BP1001

         10. Patients with a history of intolerance to Das or for whom Das might not be appropriate

         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. Active/chronic 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. 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 ECG abnormality (eg, QTcF >470 msec)

         14. Within the past 6 months, has had any of the following: pleural effusion, myocardial
             infarction, unstable angina pectoris, coronary/peripheral artery bypass graft,
             cerebrovascular accident or transient ischemic attack

         15. Uncontrolled seizure disorder (ie, seizures within the past 2 months).

         16. 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:Dose Limiting Toxicity of BP1001 using non-hematologic and hematologic parameters per NCI CTCAE criteria
Time Frame:180 days
Safety Issue:
Description:Phase 1b portion of the study: Determine the dose limiting toxicity of BP1001 in combination with Das

Secondary Outcome Measures

Measure:Safety of BP1001 in combination with Das using non-hematologic and hematologic parameters per NCI CTCAE criteria
Time Frame:30 days
Safety Issue:
Description:Evaluate Safety of BP1001 in combination with Das
Measure:Efficacy of the combination of BP1001 and Das using hematologic response by bone marrow aspirate or biopsy and complete blood counts versus Das alone by historical outcome comparison
Time Frame:180 days
Safety Issue:
Description:Determine whether the combination of BP1001 and Das provides greater efficacy (Hematologic Response) than Das alone (by historical comparison)
Measure:Efficacy of the combination of BP1001 and Das using cytogenetic response (karyotyping) by bone marrow aspirate or biopsy versus Das alone by historical outcome comparison
Time Frame:180 days
Safety Issue:
Description:Determine whether the combination of BP1001 and Das provides greater efficacy (Cytogenetic Response) than Das alone (by historical comparison)
Measure:Efficacy of the combination of BP1001 and Das using molecular response (PCR) by bone marrow aspirate or biopsy versus Das alone by historical outcome comparison
Time Frame:180 days
Safety Issue:
Description:Determine whether the combination of BP1001 and Das provides greater efficacy (Molecular Response) than Das alone (by historical comparison)
Measure:In vivo PK using plasma to compute half life and elimination
Time Frame:30 days
Safety Issue:
Description:Evaluate in vivo PK of BP1001 when given alone and in combination with Das
Measure:Time to Response using hematologic response using bone marrow biopsy or aspirate and complete blood counts
Time Frame:30 days
Safety Issue:
Description:Assess time to response from administration of BP1001 + Das to hematologic response
Measure:Time to Response using cytogenetic response (karyotyping) using bone marrow biopsy or aspirate
Time Frame:30 days
Safety Issue:
Description:Assess time to response from administration of BP1001 + Das to cytogenetic response
Measure:Time to Response using molecular response (PCR) using bone marrow biopsy or aspirate
Time Frame:30 days
Safety Issue:
Description:Assess time to response from administration of BP1001 + Das to molecular response
Measure:Duration of Response using hematologic response using bone marrow biopsy or aspirate and complete blood counts from day of response to day of disease progression
Time Frame:30 days
Safety Issue:
Description:Assess duration of response from day of response to day of disease progression
Measure:Duration of Response using cytogenetic response (karyotyping) using bone marrow biopsy or aspirate from day of response to day of disease progression
Time Frame:30 days
Safety Issue:
Description:Assess duration of response from day of response to day of disease progression
Measure:Duration of Response using molecular response (PCR) using bone marrow biopsy or aspirate from day of response to day of disease progression
Time Frame:30 days
Safety Issue:
Description:Assess duration of response from day of response to day of disease progression
Measure:Overall Survival from date of study entry to study closure
Time Frame:180 days
Safety Issue:
Description:Assess overall survival from date of study entry to study closure

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bio-Path Holdings, Inc.

Trial Keywords

  • Liposomal Grb-2 treatment of Ph+ CML
  • Liposomal Grb-2 with Das for Ph+ CML

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