NCT02081378 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE1
Status at capture: COMPLETED
Registry last update: 2024-03-18

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

eligibility 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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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).
intervention Names
Drug: Asciminib (ABL001)
label
Asciminib in CML patients
type
EXPERIMENTAL
description
Dose escalation study estimated the MTD and/or RDE of asciminib in combination with Nilotinib in adult CML patients
intervention Names
Drug: Asciminib (ABL001)
Drug: Nilotinib
label
Asciminib+Nilotinib in CML patients
type
EXPERIMENTAL
description
Dose escalation study estimated the MTD and/or RDE of asciminib in adult patients with Ph positive ALL patients
intervention Names
Drug: Asciminib (ABL001)
label
Asciminib in Ph+ ALL patients
type
EXPERIMENTAL
description
Dose escalation study to estimate the MTD and/or RDE of asciminib in combination with imatinib in adult CML patients
intervention Names
Drug: Asciminib (ABL001)
Drug: Imatinib
label
Asciminib+Imatinib in CML patients
type
EXPERIMENTAL
description
Dose escalation study estimated the MTD and/or RDE of asciminib in combination with dasatinib in adult CML patients
intervention Names
Drug: Asciminib (ABL001)
Drug: Dasatinib
label
Asciminib+dasatinib in CML patients
type
EXPERIMENTAL

interventions

arm Group Labels
Asciminib in CML patients
Asciminib in Ph+ ALL patients
Asciminib+Imatinib in CML patients
Asciminib+Nilotinib in CML patients
Asciminib+dasatinib in CML patients
description
Asciminib was be administered orally in a dose escalation schedule.
name
Asciminib (ABL001)
other Names
ABL001
type
DRUG
arm Group Labels
Asciminib+Nilotinib in CML patients
description
Asciminib and Nilotinib was administered orally in CML patients
name
Nilotinib
type
DRUG
arm Group Labels
Asciminib+Imatinib in CML patients
description
Asciminib and imatinib was administered orally in CML patients
name
Imatinib
type
DRUG
arm Group Labels
Asciminib+dasatinib in CML patients
description
Asciminib and dasatinib was administered orally in CML patients
name
Dasatinib
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 326
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

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
measure
Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment
time Frame
First Cycle is 28 days

secondary Outcomes

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

Full 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.
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.

Source references

references

citation
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
type
DERIVED
citation
Cortes JE, Sasaki K, Kim DW, Hughes TP, Etienne G, Mauro MJ, Hochhaus A, Lang F, Heinrich MC, Breccia M, Deininger M, Goh YT, Janssen JJWM, Talpaz M, de Soria VGG, le Coutre P, DeAngelo DJ, Damon A, Cacciatore S, Polydoros F, Agrawal N, Rea D. Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after >/=1 prior tyrosine kinase inhibitor: 2-year follow-up results. Leukemia. 2024 Jul;38(7):1522-1533. doi: 10.1038/s41375-024-02278-8. Epub 2024 May 16.
pmid
38755421
type
DERIVED
citation
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
type
DERIVED
citation
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
type
DERIVED