Clinical trial NCT02081378: 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
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-03-07
Enrollment: 326
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs) during the first cycle of study treatment
timeFrame: First Cycle is 28 days
Secondary outcomes:
measure: Hematologic Response
timeFrame: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
measure: Cytogenetic response
timeFrame: at screening or when a patient's BCR-ABL ratio has risen to >1%
measure: BCR-ABL transcript level
timeFrame: At screening and first day of cycle 2 and 3 and every 12 weeks afterwards
measure: Cmax of ABL001 as measured in plasma
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: Collected from screening visit through post-treatment follow-up period
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute Hematology / Oncology
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center SC
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering
state: New York
city: Portland
country: United States
facility: Oregon Health Sciences University SC-6
state: Oregon
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center UT MD Anderson
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute SC
state: Utah
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Paris 10
country: France
facility: Novartis Investigative Site
state: Cedex 10
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Jena
country: Germany
facility: Novartis Investigative Site
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Kobe-shi
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Seocho Gu
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
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.
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.