This phase II trial studies how well the addition of nemtabrutinib to lisocabtagene maraleucel in treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Nemtabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lisocabtagene maraleucel is a type of treatment called chimeric antigen receptor (CAR) T-cell therapy, in which a patient's T-cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T-cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T-cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T-cells are grown in the laboratory and given to the patient by infusion for treatment. Adding nemtabrutinib to lisocabtagene maraleucel may be an effective treatment for relapsed/refractory CLL/SLL.
OUTLINE: Patients receive nemtabrutinib orally (PO) daily on days 1-28 of each cycle (NOTE: nemtabrutinib is not given during lymphodepleting therapy). Cycles repeat every 28 days for up to 1 year after lisocabtagene maraleucel infusion in the absence of disease progression or unacceptable toxicity. Patients undergo leukapheresis 7 days after start of nemtabrutinib treatment. Patients receive standard of care (SOC) lymphodepleting therapy consisting of cyclophosphamide intravenously (IV) and fludarabine IV on approximately the 5th, 4th, and 3rd day prior to lisocabtagene maraleucel infusion. Patients then receive lisocabtagene maraleucel IV 36-96 hours after completion of SOC lymphodepleting therapy. Patients also undergo transthoracic echocardiogram (TTE) or multigated acquisition scan (MUGA) during screening, and positron emission tomography (PET)/computed tomography (CT) scans, Bone marrow biopsy and aspiration, lymph node biopsy, and blood sample collection throughout the study. After completion of study treatment, patients are followed for 5 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Given PO
Given IV
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
RECRUITINGComplete response (CR)
Will be defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Binary proportions will be estimated along with 95% confidence intervals. Confidence intervals for binary proportions will be estimated using the Wilson Score method.
Time frame: Up to 5 years after completion of study treatment
Overall response rate
Will be defined by the iwCLL criteria. Binary proportions will be estimated along with 95% confidence intervals. Confidence intervals for binary proportions will be estimated using the Wilson Score method.
Time frame: Up to 5 years after completion of study treatment
Overall survival (OS)
The distribution of OS will be estimated using the method of Kaplan-Meier. Confidence intervals around median time will be estimated using the Brookmeyer Crowley method.
Time frame: From first dose of protocol treatment to documentation of the first sign of disease progression or death from any cause, assessed up to 5 years after completion of study treatment
Progression free survival (PFS)
Will be defined by the iwCLL criteria. The distribution of PFS will be estimated using the method of Kaplan-Meier. Confidence intervals around median time will be estimated using the Brookmeyer Crowley method.
Time frame: From first dose of protocol treatment to documentation of the first sign of disease progression or death from any cause, assessed up to 5 years after completion of study treatment
Time to response (TTR)
Will be defined by the iwCLL criteria among responders. The distribution of TTR will be estimated using the method of Kaplan-Meier. Confidence intervals around median time will be estimated using the Brookmeyer Crowley method.
Time frame: From start of protocol treatment to first documentation of response among participants documented to have a response, assessed up to 5 years after completion of study treatment
Time to next treatment (TTNT)
TTNT is only defined for participants who start a new treatment and only for those participants with progressive CLL/SLL. The distribution of TTNT will be estimated using the method of Kaplan-Meier. Confidence intervals around median time will be estimated using the Brookmeyer Crowley method.
Time frame: From start of protocol treatment to the start of a subsequent treatment, assessed up to 5 years after completion of study treatment
Duration of response (DoR)
Will be defined by the iwCLL criteria among responders. The distribution of DoR will be estimated using the method of Kaplan-Meier. Confidence intervals around median time will be estimated using the Brookmeyer Crowley method.
Time frame: From first documentation of response to documentation of the first sign of disease progression or death from any cause, whichever comes first, assessed up to 5 years after completion of study treatment
CR on positron emission tomography/computed tomography by Lugano criteria
Binary proportions will be estimated along with 95%. Confidence intervals. Confidence intervals for binary proportions will be estimated using the Wilson Score method.
Time frame: Up to 5 years after completion of study treatment
Incidence of adverse events
Will be assessed by Common Terminology Criteria for Adverse Events 5.0.
Time frame: Up to 30 days after the last dose of nemtabrutinib
Incidence of dose-limiting toxicity (DLT)
For the purpose of this study, the initial observed DLT will be considered the event which counts toward safety suspension rules.
Time frame: Up to 28 days following the infusion of lisocabtagene maraleucel
Incidence of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity (ICANS)
Grade, day of onset, and duration of CRS or ICANS by American Society of Transplant and Cellular Therapy (ASTCT) Consensus grading.
Time frame: Up to 30 days following the infusion of lisocabtagene maraleucel
Time to CRS or ICANS onset
Grade, day of onset, and duration of CRS or ICANS by ASTCT Consensus grading. The distribution of time to CRS or ICANS onset will be estimated using the method of Kaplan-Meier. Confidence intervals around median time will be estimated using the Brookmeyer Crowley method.
Time frame: Up to 30 days following the infusion of lisocabtagene maraleucel
Time from CRS or ICANS onset to resolution
Grade, day of onset, and duration of CRS or ICANS by ASTCT Consensus grading. The distribution of time from CRS or ICANS onset to resolution will be estimated using the method of Kaplan-Meier. Confidence intervals around median time will be estimated using the Brookmeyer Crowley method.
Time frame: Up to 30 days following the infusion of lisocabtagene maraleucel
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