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A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL

NCT02081378

Description:

The design of a phase I, open label, dose finding study was chosen in order to establish a safe and tolerated dose of single agent ABL001 in CML and Ph+ ALL patients who are relapsed or refractory to or are intolerant of TKIs, and of ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib in Ph positive CML patients who are relapsed or refractory to TKIs.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL
  • Official Title: A Phase I, Multicenter, Open-label Study of Oral ABL001 in Patients With Chronic Myelogenous Leukemia (CML) or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Clinical Trial IDs

  • ORG STUDY ID: CABL001X2101
  • NCT ID: NCT02081378

Conditions

  • Chronic Myelogenous Leukemia
  • Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
ABL001ABL001 in CML patients
ABL001 + NilotinibABL001+Nilotinib in CML patients
ABL001ABL001 in Ph+ ALL patients
ABL001+imatinibABL001+Imatinib in CML patients
ABL001+dasatinibABL001+dasatinib in CML patients

Purpose

The design of a phase I, open label, dose finding study was chosen in order to establish a safe and tolerated dose of single agent ABL001 in CML and Ph+ ALL patients who are relapsed or refractory to or are intolerant of TKIs, and of ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib in Ph positive CML patients who are relapsed or refractory to TKIs.

Detailed Description

      This first-in-human trial with ABL001 is a dose escalation study whose primary purpose is to
      estimate the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of
      single agent ABL001 in CML or Ph+ ALL patients, and in combination with either Nilotinib or
      Imatinib or Dasatinib in Ph positive CML patients. The safety, tolerability and
      pharmacokinetic (PK) profile of ABL001 and ABL001+Nilotinib, ABL001+Imatinib and
      ABL001+Dasatinib will be assessed together with an evaluation of pharmacodynamic (PD) changes
      in peripheral blood mononuclear cells (PBMC) and bone marrow aspirates and all data may
      contribute to the assessment of the RDE.

      An understanding of the MTD/RDE, safety profile, PK/PD relationship, and preliminary evidence
      of anti-CML and ALL activity will be used to inform future development in adults with CML and
      Ph+ ALL. By virtue of its distinct pharmacological profile and by preclinical pharmacological
      studies demonstrating an additive effect, a combination of ABL001 and a tyrosine-kinase
      inhibitor (TKI) has the potential to achieve a deeper molecular response in a higher
      proportion of CML patients as compared to single agent TKI therapy. Such a combination has
      the added advantage of targeting the ABL kinase domain at two distinct locations,
      theoretically preventing single point mutation-associated treatment resistance. The
      prediction is that a nilotinib+ABL001, imatinib+ABL001 and/or dasatinib+ABL001 combination
      will increase the percentage of patients who achieve a complete molecular response (CMR) and
      decrease the time to CMR, thereby increasing the possibility of achieving sustained
      treatment-free remissions in these patients. In addition, some patients may be intolerant of
      therapy with TKIs or may develop mutations that promote resistance to TKI therapy. In these
      patients, ABL001 may provide a novel therapeutic option.
    

Trial Arms

NameTypeDescriptionInterventions
ABL001 in CML patientsExperimentalDose escalation study to estimate the MTD and/or RDE of ABL001 in adult patients with CML
  • ABL001
ABL001+Nilotinib in CML patientsExperimentalDose escalation study to estimate the MTD and/or RDE of ABL001 in combination with Nilotinib in adult CML patients
  • ABL001 + Nilotinib
ABL001 in Ph+ ALL patientsExperimentalDose escalation study to estimate the MTD and/or RDE of ABL001 in adult patients with Ph positive ALL patients
  • ABL001
ABL001+Imatinib in CML patientsExperimentalDose escalation study to estimate the MTD and/or RDE of ABL001 in combination with imatinib in adult CML patients
  • ABL001+imatinib
ABL001+dasatinib in CML patientsExperimentalDose escalation study to estimate the MTD and/or RDE of ABL001 in combination with dasatinib in adult CML patients
  • ABL001+dasatinib

Eligibility Criteria

        Inclusion Criteria:

        For CML patients either:

          -  a. Patients with Ph+ CML in chronic or accelerated phase who were previously treated
             with at least two different tyrosine kinase inhibitors prior to study entry and are
             relapsed, refractory to or intolerant of TKIs as determined by investigators or

          -  b. Patients with CML in chronic or accelerated phase who exhibit relapsed disease
             associated with the presence of the T315I "gatekeeper mutation" after at least one TKI
             are also eligible provided that no other effective therapy exists

        For ALL and CML-BP patients:

          -  Patients with CML BP or Ph+ ALL who have a cytopathologically confirmed diagnosis and
             are relapsed or refractory to at least one prior TKI or intolerant of TKIs. TKI
             failure for Ph+ ALL and CML-BP patients is defined as at least the loss of Molecular
             Response (MR) 4.5 (BCR-ABL ≤ 0.0032%)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

          -  Willingness and ability to comply with all study procedures

          -  Written informed consent obtained prior to any screening procedures

        Exclusion Criteria:

        Wash-out period:

          -  Systemic antineoplastic therapy (including cytotoxic chemotherapy, alfa-interferon and
             toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives,
             whichever is shorter, before the first dose of study treatment

          -  Therapy with TKIs as single agent within 5 half-lives before the first dose of study
             treatment

          -  Unconjugated monoclonal antibody therapies within 28 days or 5 half-lives, whichever
             is shorter, before the first dose of study treatment

          -  For patients receiving ABL001 in combination with either nilotinib or imatinib or
             dasatinib, intolerance to nilotinib, imatinib or dasatinib, respectivelyRadiotherapy
             with a wide field of radiation within 4 weeks or radiotherapy with a limited field of
             radiation for palliation within 1 week of the first dose of study treatment.

          -  CNS irradiation for meningeal leukemia, except if radiotherapy occurred > 3 months
             previously. At least four weeks must have elapsed since prophylactic CNS irradiation
             given as part of a front-line therapy regimen for ALL

          -  Major surgery within 2 weeks before the first dose of study treatment

        Other protocol-defined inclusion/exclusion criteria may apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment
Time Frame:First Cycle is 28 days
Safety Issue:
Description:Determine the MTD and/or RDE of ABL001 as single agent in CML and Ph+ ALL, and in combination with either nilotinib or imatinib or dasatinib in CML patients

Secondary Outcome Measures

Measure:Hematologic Response
Time Frame:At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
Safety Issue:
Description:
Measure:Cytogenetic response
Time Frame:at screening or when a patient's BCR-ABL ratio has risen to >1%
Safety Issue:
Description:
Measure:BCR-ABL transcript level
Time Frame:At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
Safety Issue:
Description:
Measure:Cmax of ABL001 as measured in plasma
Time Frame:Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.
Safety Issue:
Description:
Measure:Cmin of ABL001 as measured in plasma
Time Frame:Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.
Safety Issue:
Description:
Measure:AUCinf of ABL001 as measured in plasma
Time Frame:Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.
Safety Issue:
Description:
Measure:AUClast of ABL001 as measured in plasma
Time Frame:Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.
Safety Issue:
Description:
Measure:AUCtau of ABL001 as measured in plasma
Time Frame:Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.
Safety Issue:
Description:
Measure:T1/2 of ABL001 as measured in plasma
Time Frame:Cycle 1 days 1,2,8,15,16 and 22. Cycle 2 days 1 and 2, and subsequent cycles at the begining of each cycle up to cycle 6.
Safety Issue:
Description:
Measure:Adverse events
Time Frame:Collected from screening visit through post-treatment follow-up period
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • CML
  • Ph+ ALL

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