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

Primary Purpose

Chronic Myelogenous Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Asciminib (ABL001)

Nilotinib

Imatinib

Dasatinib

About this trial

This is an interventional treatment trial for Chronic Myelogenous Leukemia focused on measuring CML, Ph+ ALL

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Dana Farber Cancer Institute Hematology / Oncology
University of Michigan Comprehensive Cancer Center SC
Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering
Oregon Health Sciences University SC-6
University of Texas/MD Anderson Cancer Center UT MD Anderson
Huntsman Cancer Institute SC
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Asciminib in CML patients

Asciminib+Nilotinib in CML patients

Asciminib in Ph+ ALL patients

Asciminib+Imatinib in CML patients

Asciminib+dasatinib in CML patients

Arm Description

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

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

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

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Hematologic Response

Cytogenetic response

BCR-ABL transcript level

Cmax of ABL001 as measured in plasma

Cmin of ABL001 as measured in plasma

AUCinf of ABL001 as measured in plasma

AUClast of ABL001 as measured in plasma

AUCtau of ABL001 as measured in plasma

T1/2 of ABL001 as measured in plasma

Adverse events

Full Information

NCT ID

NCT02081378

First Posted

February 28, 2014

Last Updated

October 17, 2023

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02081378

Brief Title

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

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)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Completed

Study Start Date

April 24, 2014 (Actual)

Primary Completion Date

June 3, 2021 (Actual)

Study Completion Date

March 14, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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 CML and Ph+ ALL patients who are relapsed or refractory to or are intolerant of TKIs, and of ABL001+Nilotinib, ABL001+Imatinib and ABL001+Dasatinib in Ph positive CML patients who are relapsed or refractory to TKIs.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Myelogenous Leukemia, Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Keywords

CML, Ph+ ALL

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

326 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Asciminib in CML patients

Arm Type

Experimental

Arm Description

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

Arm Title

Asciminib+Nilotinib in CML patients

Arm Type

Experimental

Arm Description

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

Arm Title

Asciminib in Ph+ ALL patients

Arm Type

Experimental

Arm Description

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

Arm Title

Asciminib+Imatinib in CML patients

Arm Type

Experimental

Arm Description

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

Arm Title

Asciminib+dasatinib in CML patients

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Asciminib (ABL001)

Other Intervention Name(s)

ABL001

Intervention Description

Asciminib will be administered orally in a dose escalation schedule.

Intervention Type

Drug

Intervention Name(s)

Nilotinib

Intervention Description

Asciminib and Nilotinib will be administered orally in CML patients

Intervention Type

Drug

Intervention Name(s)

Imatinib

Intervention Description

Asciminib and imatinib will be administered orally in CML patients

Intervention Type

Drug

Intervention Name(s)

Dasatinib

Intervention Description

Asciminib and dasatinib will be administered orally in CML patients

Primary Outcome Measure Information:

Title

Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment

Description

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

Time Frame

First Cycle is 28 days

Secondary Outcome Measure Information:

Title

Hematologic Response

Time Frame

At screening and first day of cycle 2 and 3 and every 12 weeks afterwards

Title

Cytogenetic response

Time Frame

at screening or when a patient's BCR-ABL ratio has risen to >1%

Title

BCR-ABL transcript level

Time Frame

At screening and first day of cycle 2 and 3 and every 12 weeks afterwards

Title

Cmax of ABL001 as measured in plasma

Time Frame