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

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ClinicalTrials.gov Identifier: NCT02081378
Recruitment Status : Recruiting
First Posted : March 7, 2014
Last Update Posted : July 17, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Chronic Myelogenous Leukemia Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Drug: ABL001 Drug: ABL001 + Nilotinib Drug: ABL001+imatinib Drug: ABL001+dasatinib Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 290 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : April 24, 2014
Estimated Primary Completion Date : December 20, 2022
Estimated Study Completion Date : December 20, 2022


Arm Intervention/treatment
Experimental: ABL001 in CML patients
Dose escalation study to estimate the MTD and/or RDE of ABL001 in adult patients with CML
Drug: ABL001
ABL001 will be administered orally in a dose escalation schedule.

Experimental: ABL001+Nilotinib in CML patients
Dose escalation study to estimate the MTD and/or RDE of ABL001 in combination with Nilotinib in adult CML patients
Drug: ABL001 + Nilotinib
ABL001 and Nilotinib will be administered orally in CML patients

Experimental: ABL001 in Ph+ ALL patients
Dose escalation study to estimate the MTD and/or RDE of ABL001 in adult patients with Ph positive ALL patients
Drug: ABL001
ABL001 will be administered orally in Ph+ ALL patients

Experimental: ABL001+Imatinib in CML patients
Dose escalation study to estimate the MTD and/or RDE of ABL001 in combination with imatinib in adult CML patients
Drug: ABL001+imatinib
ABL001 and imatinib will be administered orally in CML patients

Experimental: ABL001+dasatinib in CML patients
Dose escalation study to estimate the MTD and/or RDE of ABL001 in combination with dasatinib in adult CML patients
Drug: ABL001+dasatinib
ABL001+dasatinib will be administered orally in CML patients




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Hematologic Response [ Time Frame: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards ]
  2. Cytogenetic response [ Time Frame: at screening or when a patient's BCR-ABL ratio has risen to >1% ]
  3. BCR-ABL transcript level [ Time Frame: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards ]
  4. 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. ]
  5. 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. ]
  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. ]
  7. 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. ]
  8. 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. ]
  9. 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. ]
  10. Adverse events [ Time Frame: Collected from screening visit through post-treatment follow-up period ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02081378


Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com

Locations
United States, Massachusetts
Dana Farber Cancer Institute Hematology / Oncology Recruiting
Boston, Massachusetts, United States, 02215
Contact: Shannon Milillo    617-632-6840    shannon_milillo@dfci.harvard.edu   
Principal Investigator: Daniel J. DeAngelo         
United States, Michigan
University of Michigan Comprehensive Cancer Center SC Recruiting
Ann Arbor, Michigan, United States, +1 48109 0944
Contact: Shelagh L. Elliott    734-232-0759    shelagh@med.umich.edu   
Principal Investigator: Moshe Talpaz         
United States, New York
Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering Recruiting
New York, New York, United States, 10065
Contact: Michael Mauro J. Mauro, MD    212-639-3107    maurom@mskcc.org   
Principal Investigator: Michael J. Mauro         
United States, Oregon
Oregon Health and Science University SC-6 Recruiting
Portland, Oregon, United States, 97239
Contact: Bianca Gille    503-494-4603    gille@ohsu.edu   
Principal Investigator: Michael J. Heinrich         
United States, Texas
University of Texas/MD Anderson Cancer Center UT MD Anderson Recruiting
Houston, Texas, United States, 77030-4009
Contact: Jorge E Cortes, MD    713-794-5783    Jcortes@mdanderson.org   
Principal Investigator: Jorge E. Cortes         
United States, Utah
Huntsman Cancer Institute SC Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Aaron Ernst       aaron.ernst@hci.utah.edu   
Principal Investigator: Michael W. Deininger         
Australia, South Australia
Novartis Investigative Site Recruiting
Adelaide, South Australia, Australia, 5000
France
Novartis Investigative Site Recruiting
Paris Cedex 10, Cedex 10, France, 75475
Novartis Investigative Site Recruiting
Bordeaux, France, 33076
Germany
Novartis Investigative Site Recruiting
Berlin, Germany, 13353
Novartis Investigative Site Recruiting
Frankfurt, Germany, 60590
Novartis Investigative Site Recruiting
Jena, Germany, 07740
Italy
Novartis Investigative Site Recruiting
Roma, RM, Italy, 00161
Japan
Novartis Investigative Site Recruiting
Kobe-shi, Hyogo, Japan, 650-0017
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Seocho-gu, Korea, Republic of, 06591
Netherlands
Novartis Investigative Site Recruiting
Amsterdam, Netherlands, 1081 HV
Singapore
Novartis Investigative Site Recruiting
Singapore, Singapore, 169608
Spain
Novartis Investigative Site Recruiting
Madrid, Spain, 28006
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02081378     History of Changes
Other Study ID Numbers: CABL001X2101
First Posted: March 7, 2014    Key Record Dates
Last Update Posted: July 17, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
CML
Ph+ ALL

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Imatinib Mesylate
Dasatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action