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

  • STATUS
    Recruiting
  • End date
    Mar 14, 2024
  • participants needed
    330
  • sponsor
    Novartis Pharmaceuticals
Updated on 30 January 2021
imatinib
tyrosine
dasatinib
nilotinib

Summary

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.

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.

Details
Condition Chronic myeloid leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, chronic myelogenous leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
Treatment ABL001, ABL001 + Nilotinib, ABL001+imatinib, ABL001+dasatinib
Clinical Study IdentifierNCT02081378
SponsorNovartis Pharmaceuticals
Last Modified on30 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia or Chronic myeloid leukemia?
Do you have any of these conditions: Chronic myeloid leukemia or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia or chronic myelogenous leukemia?
Do you have any of these conditions: chronic myelogenous leukemia or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia or Chronic myeloid leukemia?
Do you have any of these conditions: chronic myelogenous leukemia or Chronic myeloid leukemia or Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia?
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, respectively
Radiotherapy 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
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