A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL
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| ClinicalTrials.gov Identifier: NCT02081378 |
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Recruitment Status :
Completed
First Posted : March 7, 2014
Last Update Posted : May 16, 2023
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| 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 |
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) |
| Actual Enrollment : | 326 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 |
| Actual Primary Completion Date : | June 3, 2021 |
| Actual Study Completion Date : | March 14, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: ABL001 in CML patients
Dose escalation study to estimate the MTD and/or RDE of ABL001 in adult patients with CML
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Drug: ABL001
ABL001 will be administered orally in a dose escalation schedule. |
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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
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Drug: ABL001 + Nilotinib
ABL001 and Nilotinib will be administered orally in CML patients |
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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
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Drug: ABL001
ABL001 will be administered orally in Ph+ ALL patients |
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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
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Drug: ABL001+imatinib
ABL001 and imatinib will be administered orally in CML patients |
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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
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Drug: ABL001+dasatinib
ABL001+dasatinib will be administered orally in CML patients |
- 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
- 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 ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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, 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
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
| United States, Massachusetts | |
| Dana Farber Cancer Institute Hematology / Oncology | |
| Boston, Massachusetts, United States, 02215 | |
| United States, Michigan | |
| University of Michigan Comprehensive Cancer Center SC | |
| Ann Arbor, Michigan, United States, 48109 | |
| United States, New York | |
| Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering | |
| New York, New York, United States, 10065 | |
| United States, Oregon | |
| Oregon Health and Science Univ SC-6 | |
| Portland, Oregon, United States, 97239 | |
| United States, Texas | |
| University of Texas/MD Anderson Cancer Center UT MD Anderson | |
| Houston, Texas, United States, 77030-4009 | |
| United States, Utah | |
| Huntsman Cancer Institute SC | |
| Salt Lake City, Utah, United States, 84112 | |
| Australia, South Australia | |
| Novartis Investigative Site | |
| Adelaide, South Australia, Australia, 5000 | |
| France | |
| Novartis Investigative Site | |
| Paris Cedex 10, Cedex 10, France, 75475 | |
| Novartis Investigative Site | |
| Bordeaux, France, 33076 | |
| Germany | |
| Novartis Investigative Site | |
| Berlin, Germany, 13353 | |
| Novartis Investigative Site | |
| Frankfurt, Germany, 60590 | |
| Novartis Investigative Site | |
| Jena, Germany, 07740 | |
| Italy | |
| Novartis Investigative Site | |
| Roma, RM, Italy, 00161 | |
| Japan | |
| Novartis Investigative Site | |
| Kobe-shi, Hyogo, Japan, 650-0017 | |
| Korea, Republic of | |
| Novartis Investigative Site | |
| Seoul, Seocho Gu, Korea, Republic of, 06591 | |
| Netherlands | |
| Novartis Investigative Site | |
| Amsterdam, Netherlands, 1081 HV | |
| Singapore | |
| Novartis Investigative Site | |
| Singapore, Singapore, 169608 | |
| Spain | |
| Novartis Investigative Site | |
| Madrid, Spain, 28006 | |
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT02081378 |
| Other Study ID Numbers: |
CABL001X2101 |
| First Posted: | March 7, 2014 Key Record Dates |
| Last Update Posted: | May 16, 2023 |
| Last Verified: | May 2023 |
| 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 |
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CML Ph+ ALL |
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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 |
Chronic Disease Disease Attributes Pathologic Processes Translocation, Genetic Chromosome Aberrations Niacinamide Imatinib Mesylate Dasatinib Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Vitamin B Complex Vitamins Micronutrients |