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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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 Leukemi

Brief 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.

Detailed Summary:

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.


Sponsor: Novartis Pharmaceuticals

Current Primary Outcome: Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment [ Time Frame: First Cycle is 28 days ]

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


Original Primary Outcome: Incidence of dose limiting toxicities (DLTs) during the first cycle of ABL001 treatment [ Time Frame: First Cycle is 28 days ]

Determine the MTD and/or RDE of ABL001 in CML and Ph+ ALL


Current Secondary Outcome:

  • Hematologic Response [ Time Frame: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards ]
  • Cytogenetic response [ Time Frame: at screening or when a patient's BCR-ABL ratio has risen to >1% ]
  • BCR-ABL transcript level [ Time Frame: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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. ]
  • Adverse events [ Time Frame: Collected from screening visit through post-treatment follow-up period ]


Original Secondary Outcome:

  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Baseline, until disease progression or an unacceptable toxicity, 30 days after stopping ABL001 treatment ]
    Adverse events, serious adverse events, changes in laboratory values, vital signs, and electrocardiograms. Patients will be followed during their ABL001 treatment until progressive disease or an unacceptable toxicity. The patient will be followed for an additional 30 days after stopping ABL001 treatment to collect any additional adverse events
  • Preliminary anti-CML and anti Ph+ALL activity associated with ABL001 [ Time Frame: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards ]
    Molecular response (BCR-ABL transcript level)
  • Preliminary anti-CML and anti Ph+ALL activity associated with ABL001 [ Time Frame: at screening or when a patient's BCR-ABL ratio has risen to >1% ]
    Hematologic, cytogenetic response. [Major Cytogenetic Response (MCyR), Complete Cytogenetic Response (CCyR), Partial Cytogenetic Response (PCyR), etc.)
  • PK profile of oral ABL001 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. ]
    Assess the PK profile: Plasma concentration- of ABL001 and PK parameters including but not limited to Cmax, Cmin, AUCinf, AUClast, AUCtau and T1/2
  • PD response of ABL001 [ Time Frame: At screening, cycle 1 day 1, 2, and 15, cycle 2 day 1 and cycle 3 day 1. ]
    Changes between pre- and post-treatment levels of pSTAT5 and pCRKL, in leukemic progenitors in peripheral blood for all patients.


Information By: Novartis

Dates:
Date Received: February 28, 2014
Date Started: April 24, 2014
Date Completion: August 22, 2018
Last Updated: May 12, 2017
Last Verified: May 2017