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

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)

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myelogenous Leukemia; Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Asciminib (ABL001); Drug: Nilotinib; Drug: Imatinib; Drug: Dasatinib

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 Type: Interventional
• Enrollment (Actual): 326
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
• France
  • Bordeaux, France, 33076
    • Novartis Investigative Site
  • Cedex 10
    • Paris 10, Cedex 10, France, 75475
      • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
• Italy
  • RM
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
• Japan
  • Hyogo
    • Kobe-shi, Hyogo, Japan, 650-0017
      • Novartis Investigative Site
• Korea, Republic of
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28006
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute Hematology / Oncology
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center SC
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University SC-6
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center UT MD Anderson
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: ABL001; Drug: Imatinib; Asciminib and imatinib was administered orally in CML patients
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 Names: 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 Names: 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 Names: ABL001
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 Names: ABL001; Drug: Dasatinib; Asciminib and dasatinib was administered orally in CML patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment	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	First Cycle is 28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Hematologic Response	At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
Cytogenetic response	at screening or when a patient's BCR-ABL ratio has risen to >1%
BCR-ABL transcript level	At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
Cmax of ABL001 as measured in plasma	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	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	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	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	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	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	Collected from screening visit through post-treatment follow-up period

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Helpful Links

• Novartis results database

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2014
• Primary Completion (Actual): June 3, 2021
• Study Completion (Actual): March 14, 2023

Study Registration Dates

• First Submitted: February 28, 2014
• First Submitted That Met QC Criteria: March 5, 2014
• First Posted (Estimated): March 7, 2014

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Nilotinib; CML; Imatinib; relapsed or refractory; ABL001; Dasatinib; asciminib; TKIs; Maximum Tolerated Dose (MTD); Ph+ ALL; Recommended Dose for Expansion (RDE)
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Chronic Disease; Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Imatinib Mesylate; Dasatinib; Nilotinib; Asciminib
• Other Study ID Numbers: CABL001X2101; 2013-004491-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No