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

• ClinicalTrials.gov Identifier: NCT02081378
• Recruitment Status: Completed
• First Posted: March 7, 2014
• Last Update Posted: March 18, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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 Chronic myeloid leukemia (CML) and Philadelphia chromosome positive Acute lymphoblastic leukemia (Ph+ ALL) patients who are relapsed or refractory to or are intolerant of Tyrosine kinase inhibitors (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: Asciminib (ABL001); Drug: Nilotinib; Drug: Imatinib; Drug: Dasatinib	Phase 1

Detailed Description:

This first-in-human trial with ABL001 was a dose escalation study whose primary purpose was 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 were assessed together with an evaluation of pharmacodynamic (PD) changes in peripheral blood mononuclear cells (PBMC) and bone marrow aspirates and all data could 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 wias 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 could be intolerant of therapy with TKIs or could develop mutations that promote resistance to TKI therapy. In these patients, ABL001 could provide a novel therapeutic option.

Study Design

• 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

Arms and Interventions

Arm	Intervention/treatment
Experimental: Asciminib in CML patients; Dose escalation study estimated the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of asciminib in adult patients with chronic myeloid leukemia (CML).	Drug: Asciminib (ABL001); Asciminib was be administered orally in a dose escalation schedule.; Other Name: ABL001
Experimental: Asciminib+Nilotinib in CML patients; Dose escalation study estimated the MTD and/or RDE of asciminib in combination with Nilotinib in adult CML patients	Drug: Asciminib (ABL001); Asciminib was be administered orally in a dose escalation schedule.; Other Name: ABL001; Drug: Nilotinib; Asciminib and Nilotinib was administered orally in CML patients
Experimental: Asciminib in Ph+ ALL patients; Dose escalation study estimated the MTD and/or RDE of asciminib in adult patients with Ph positive ALL patients	Drug: Asciminib (ABL001); Asciminib was be administered orally in a dose escalation schedule.; Other Name: ABL001
Experimental: Asciminib+Imatinib in CML patients; Dose escalation study to estimate the MTD and/or RDE of asciminib in combination with imatinib in adult CML patients	Drug: Asciminib (ABL001); Asciminib was be administered orally in a dose escalation schedule.; Other Name: ABL001; Drug: Imatinib; Asciminib and imatinib was administered orally in CML patients
Experimental: Asciminib+dasatinib in CML patients; Dose escalation study estimated the MTD and/or RDE of asciminib in combination with dasatinib in adult CML patients	Drug: Asciminib (ABL001); Asciminib was be administered orally in a dose escalation schedule.; Other Name: ABL001; Drug: Dasatinib; Asciminib and dasatinib was administered orally in CML patients

Outcome Measures

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 ]

Eligibility Criteria

• 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, 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

Contacts and Locations

Locations

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 Sciences University 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 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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

Novartis results database 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Li YF, Combes FP, Hoch M, Lorenzo S, Sy SKB, Ho YY. Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases. Clin Pharmacokinet. 2022 Oct;61(10):1393-1403. doi: 10.1007/s40262-022-01148-9. Epub 2022 Jun 28. Erratum In: Clin Pharmacokinet. 2022 Aug 17;:

Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, Breccia M, Goh YT, Talpaz M, Hochhaus A, le Coutre P, Ottmann O, Heinrich MC, Steegmann JL, Deininger MWN, Janssen JJWM, Mahon FX, Minami Y, Yeung D, Ross DM, Tallman MS, Park JH, Druker BJ, Hynds D, Duan Y, Meille C, Hourcade-Potelleret F, Vanasse KG, Lang F, Kim DW. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019 Dec 12;381(24):2315-2326. doi: 10.1056/NEJMoa1902328.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02081378
• Other Study ID Numbers: CABL001X2101; 2013-004491-36 ( EudraCT Number )
• First Posted: March 7, 2014
• Last Update Posted: March 18, 2024
• Last Verified: March 2024

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; asciminib; ABL001; Maximum Tolerated Dose (MTD); Recommended Dose for Expansion (RDE); relapsed or refractory; TKIs; Nilotinib; Imatinib; Dasatinib

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; Hematologic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Translocation, Genetic; Chromosome Aberrations; Imatinib Mesylate; Dasatinib; Nilotinib; Asciminib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents