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

Chronic Myelogenous Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02081378
• Other study ID #: CABL001X2101
• Secondary ID: 2013-004491-36
• Status: Completed
• Phase: Phase 1
• Start date: April 24, 2014
• Est. completion date: March 14, 2023

Study information

• Verified date: March 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 326
• Est. completion date: March 14, 2023
• Est. primary completion date: June 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Myelogenous Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Philadelphia Chromosome
• Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Asciminib (ABL001)
Asciminib was be administered orally in a dose escalation schedule.
• Nilotinib
Asciminib and Nilotinib was administered orally in CML patients
• Imatinib
Asciminib and imatinib was administered orally in CML patients
• Dasatinib
Asciminib and dasatinib was administered orally in CML patients

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Adelaide	South Australia
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Paris 10	Cedex 10
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Jena
Italy	Novartis Investigative Site	Roma	RM
Japan	Novartis Investigative Site	Kobe-shi	Hyogo
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Netherlands	Novartis Investigative Site	Amsterdam
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Madrid
United States	University of Michigan Comprehensive Cancer Center SC	Ann Arbor	Michigan
United States	Dana Farber Cancer Institute Hematology / Oncology	Boston	Massachusetts
United States	University of Texas/MD Anderson Cancer Center UT MD Anderson	Houston	Texas
United States	Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering	New York	New York
United States	Oregon Health Sciences University SC-6	Portland	Oregon
United States	Huntsman Cancer Institute SC	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Hematologic Response		At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
Secondary	Cytogenetic response		at screening or when a patient's BCR-ABL ratio has risen to >1%
Secondary	BCR-ABL transcript level		At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Adverse events		Collected from screening visit through post-treatment follow-up period

External Links

•   Novartis results database