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

NCT02081378 | Completed Phase 1 FDA Drug

• 2 other identifiers: CABL001X21012013-004491-36
• Study Type: interventional
• Target: 326
• Locations: 10 countries
• Sites: 18

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.

Conditions

Chronic Myelogenous Leukemia; Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• 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.

Study Arms (5)

Asciminib in CML patients

EXPERIMENTAL

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+Nilotinib in CML patients

EXPERIMENTAL

Dose escalation study estimated the MTD and/or RDE of asciminib in combination with Nilotinib in adult CML patients

Drug: Asciminib (ABL001); Drug: Nilotinib

Asciminib in Ph+ ALL patients

EXPERIMENTAL

Dose escalation study estimated the MTD and/or RDE of asciminib in adult patients with Ph positive ALL patients

Drug: Asciminib (ABL001)

Asciminib+Imatinib in CML patients

EXPERIMENTAL

Dose escalation study to estimate the MTD and/or RDE of asciminib in combination with imatinib in adult CML patients

Drug: Asciminib (ABL001); Drug: Imatinib

Asciminib+dasatinib in CML patients

EXPERIMENTAL

Dose escalation study estimated the MTD and/or RDE of asciminib in combination with dasatinib in adult CML patients

Drug: Asciminib (ABL001); Drug: Dasatinib

Interventions

Asciminib (ABL001) DRUG

Asciminib was be administered orally in a dose escalation schedule.

Also known as: ABL001

Asciminib in CML patients; Asciminib in Ph+ ALL patients; Asciminib+Imatinib in CML patients; Asciminib+Nilotinib in CML patients; Asciminib+dasatinib in CML patients

Nilotinib DRUG

Asciminib and Nilotinib was administered orally in CML patients

Asciminib+Nilotinib in CML patients

Imatinib DRUG

Asciminib and imatinib was administered orally in CML patients

Asciminib+Imatinib in CML patients

Dasatinib DRUG

Asciminib and dasatinib was administered orally in CML patients

Asciminib+dasatinib in CML patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (18)

Dana Farber Cancer Institute Hematology / Oncology

Boston, Massachusetts, 02215, United States

Location

University of Michigan Comprehensive Cancer Center SC

Ann Arbor, Michigan, 48109, United States

Location

Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering

New York, New York, 10065, United States

Location

Oregon Health Sciences University SC-6

Portland, Oregon, 97239, United States

Location

University of Texas/MD Anderson Cancer Center UT MD Anderson

Houston, Texas, 77030-4009, United States

Location

Huntsman Cancer Institute SC

Salt Lake City, Utah, 84112, United States

Location

Novartis Investigative Site

Adelaide, South Australia, 5000, Australia

Location

Novartis Investigative Site

Paris, Cedex 10, 75475, France

Location

Novartis Investigative Site

Bordeaux, 33076, France

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Frankfurt, 60590, Germany

Location

Novartis Investigative Site

Jena, 07740, Germany

Location

Novartis Investigative Site

Roma, RM, 00161, Italy

Location

Novartis Investigative Site

Kobe, Hyōgo, 650-0017, Japan

Location

Novartis Investigative Site

Amsterdam, 1081 HV, Netherlands

Location

Novartis Investigative Site

Singapore, 169608, Singapore

Location

Novartis Investigative Site

Seoul, Seocho Gu, 06591, South Korea

Location

Novartis Investigative Site

Madrid, 28006, Spain

Location

Related Publications (3)

• Luskin MR, Murakami MA, Keating J, Flamand Y, Winer ES, Garcia JS, Stahl M, Stone RM, Wadleigh M, Jaeckle SL, Hagopian E, Weinstock DM, Liegel J, McMasters M, Wang ES, Stock W, DeAngelo DJ. Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia. Blood. 2025 Feb 6;145(6):577-589. doi: 10.1182/blood.2024025800.

  PMID: 39374521 DERIVED

• 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.

  PMID: 35764773 DERIVED

• 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.

  PMID: 31826340 DERIVED

Related Links

• Novartis results database

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Recurrence

Interventions

asciminib; nilotinib; Imatinib Mesylate; Dasatinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Thiazoles; Sulfur Compounds; Azoles

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2014
• First Posted: March 7, 2014
• Study Start: April 24, 2014
• Primary Completion: June 3, 2021
• Study Completion: March 14, 2023
• Last Updated: March 18, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (2); NL (1); IT (1); SG (1); US (6); DE (3); ES (1); AU (1); JP (1); KR (1)