This phase I trial tests the safety, side effects and best dose of asciminib as maintenance treatment for adults with Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) who have undergone cellular therapies such as hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor (CAR) T cell therapy. Maintenance treatment is given to help keep cancer from coming back after it has disappeared following initial therapy. Asciminib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving asciminib may be safe and tolerable as maintenance treatment for adult patients with Philadelphia chromosome positive ALL who have undergone cellular therapies.
PRIMARY OBJECTIVES: I. Evaluate the safety of asciminib maintenance in adults with Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) in morphological complete remission (CR) post hematopoietic stem cell transplantation (HSCT; Arm 1) or chimeric antigen receptor (CAR) T cell therapy (Arm 2). II. Determine the recommended phase 2 dosing (RP2D) of asciminib maintenance post cellular therapies in Ph+ ALL in each arm. SECONDARY OBJECTIVES: I. Evaluate feasibility of asciminib maintenance measured as the number of patients who continue asciminib \> 3 cycles post cellular therapy. II. Duration of response. III. Timing for minimal residual disease (MRD) and full relapse. IV. Relapse free survival at 1 year post cellular therapy. V. Overall survival at 1 year post cellular therapy. VI. Non-relapse mortality at 1 year post cellular therapy. VII. Relapse at 1 year post cellular therapy. VIII. Rates of asciminib discontinuation and interruption due to toxicity at 1 year post cellular therapy. IX. Rate of switching to another tyrosine kinase inhibitor (TKI) at 1 year post cellular therapy X. Rate and grade of acute graft-versus-host disease (GVHD) at 180 days post initiation of asciminib maintenance post HSCT. (Arm 1) XI. Rate and grade of chronic GVHD at 1 year post initiation of asciminib maintenance post HSCT. (Arm 1) XII. GVHD-free, relapse-free survival (GRFS) at 1 year post HSCT. (Arm 1) EXPLORATORY OBJECTIVES: I. For patients who are MRD-negative, evaluate MRD relapse by clonoSEQ during therapy. II. Evaluate immune cell populations and immune reconstitution post-transplant during asciminib therapy. III. Evaluate the impact of prevalent BCR-ABL mutations and treatment emergent BCR-ABL mutations. IV. Evaluate B-cell aplasia and CAR T cell persistence during asciminib therapy. (Arm 2) V. Quality of life assessments using Patient Reported Outcomes Measurement Information System (PROMIS). OUTLINE: This is a dose-escalation study of asciminib followed by a dose-expansion study. Patients receive asciminib orally (PO) once daily (QD) or twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography during screening and as clinically indicated, and bone marrow biopsy, bone marrow aspirate and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 30 days then every 3 months for 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Given PO
Undergo blood sample collection
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Undergo echocardiography
Ancillary studies
City of Hope Medical center
Duarte, California, United States
Incidence of adverse events
Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The toxicity/adverse event information recorded on each subject will include type, severity, duration, attribution/ association with the study agent by arm and cycle. Tables will be constructed to summarize the observed incidence, severity and type of toxicity, including infection. Point estimates and 90% confidence intervals will be provided.
Time frame: From start of treatment on day 1 to the end of cycle 1 on day 28
Number of patients who have completed at least 3 cycles of asciminib and have taken ≥ 70% planned doses in each cycle post cellular therapy
The protocol therapy will be deemed feasible if \> 70% or higher of patients meet this feasibility criteria. Point estimates and 90% confidence intervals will be provided.
Time frame: Up to completion of 3 cycles (cycle length= 28 days)
Duration of remission
Point estimates and 90% confidence intervals will be provided.
Time frame: Up to 1 year after completion of study treatment
Relapse including minimal residual disease (MRD) relapsed
MRD relapse assed by polymerase chain reaction (PCR) and flow cytometry. MRD relapse is defined as detectable leukemic cells at \> 0.01% in morphological remission bone marrow. However, due to rate of false positivity of PCR BCR::ABL1, confirmation is required by either positive MRD flow or/and clonoSEQ \> 0.01%. Will be calculated using the competing risk method. Point estimates and 90% confidence intervals will be provided.
Time frame: Up to 1 year after completion of study treatment
Relapse free survival
Kaplan-Meier curves will be used for survival endpoints. Point estimates and 90% confidence intervals will be provided.
Time frame: From start of protocol therapy to relapse, or death, up to 1 year after completion of study treatment
Overall survival
Kaplan-Meier curves will be used for survival endpoints. Point estimates and 90% confidence intervals will be provided.
Time frame: From start of protocol therapy to death regardless of cause, up to 1 year after completion of study treatment
Non-relapse mortality
Will be calculated using the competing risk method. Point estimates and 90% confidence intervals will be provided.
Time frame: From start of protocol therapy to death without relapse/progression, up to 1 year after completion of study treatment
Switching tyrosine kinase inhibitors (TKI)
Defined as changing treatment to a different TKI due to asciminib toxicity or intolerability per the treating physician judgment. Point estimates and 90% confidence intervals will be provided.
Time frame: Up to 1 year after completion of study treatment
Asciminib discontinuation
Discontinuation is defined as not taking asciminib \> 28 days due to treatment-related toxicity. Point estimates and 90% confidence intervals will be provided.
Time frame: Up to 1 year
Asciminib interruption
Interruption is defined as not taking asciminib for \> 7 days because of treatment-related toxicity. Point estimates and 90% confidence intervals will be provided.
Time frame: Up to 1 year
Rate of acute graft versus host disease (aGVHD) of grades 2-4 (arm 1)
Documented/biopsy proven aGVHD is graded according to Mount Sinai Acute graft versus host disease (GVHD) International Consortium (MAGIC) grading. Point estimates and 90% confidence intervals will be provided.
Time frame: From hematopoietic stem cell transplantation (HSCT) to day 180 post HSCT
Rate of aGVHD of grades 3-4 (Arm 1)
Documented/biopsy proven aGVHD is graded according to MAGIC Grading. Point estimates and 90% confidence intervals will be provided.
Time frame: From HSCT to day 180 post HSCT
GVHD-free, relapse-free survival (Arm 1)
Kaplan-Meier curves will be used for survival endpoints. Point estimates and 90% confidence intervals will be provided.
Time frame: From start of protocol therapy to the first observation of developing grade 3-4 aGVHD, chronic (c) GVHD requiring systemic therapy, relapse/progression, or death, whichever comes first, up to 1 year after completion of study treatment
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