Acalabrutinib Maintenance for the Treatment of Patients With Large B-cell Lymphoma

• ClinicalTrials.gov Identifier: NCT05256641
• Recruitment Status: Recruiting
• First Posted: February 25, 2022
• Last Update Posted: March 13, 2023
• Sponsor: Jonsson Comprehensive Cancer Center
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Jonsson Comprehensive Cancer Center

Tracking Information

• First Submitted Date: January 4, 2022
• First Posted Date: February 25, 2022
• Last Update Posted Date: March 13, 2023
• Actual Study Start Date: January 23, 2023
• Estimated Primary Completion Date: January 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 15, 2022)

Permanent discontinuation of acalabrutinib [ Time Frame: Up to 12 months from cellular therapy ]

Tolerability will be determined by the number of patients who permanently discontinue acalabrutinib within 12 months from cellular therapy due to intolerance. The proportion of patients with acalabrutinib discontinuation will be reported along with 95% and 90% confidence intervals.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 15, 2022)

• Progression-free survival (PFS) [ Time Frame: At 12 months from cellular therapy ]
  The 1-year PFS will be evaluated based on progression of disease per Lugano criteria or death, and will be reported based on Kaplan-Meier estimates along with 95% confidence interval.
• PFS [ Time Frame: Up to 5 years ]
  Will be reported based on 95% confidence intervals at annual time points.
• Overall survival [ Time Frame: Up to 5 years ]
  Time from cellular therapy to death due to any cause, assessed at 1 and 5 years based on Kaplan-Meier estimates along with 95% confidence interval
• Rate of conversion from partial response following chimeric antigen receptor (CAR) T-cell therapy to complete response after the addition of acalabrutinib maintenance [ Time Frame: Up to day 365 ]
  Will be reported based on 95% confidence intervals.
• Incidence of dose reductions, interruptions, or discontinuations of acalabrutinib based on the protocol criteria [ Time Frame: Up to day 365 ]
  Will be reported based on 95% confidence intervals.
• Incidence of graft versus host disease (GvHD) >= stage 2 [ Time Frame: Up to day 365 ]
  Based on the Mount Sinai Acute GVHD International Consortium criteria for acute GvHD and the National Institutes of Health consensus criteria for chronic GvHD. Will be reported based on 95% confidence intervals.
• Incidence of hematologic adverse events [ Time Frame: Up to day 365 ]
  Based on Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Will be reported based on 95% confidence intervals.
• Incidence of non-hematologic adverse events [ Time Frame: Up to day 365 ]
  Based on CTCAE v5.0. Will be reported based on 95% confidence intervals.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: February 15, 2022)

• CAR T-cell persistence [ Time Frame: Up to 5 years ]
  CAR T-cell persistence measured by mass cytometry upon enrollment, 90 days after initiation of acalabrutinib, and at time of relapse.
• Immunophenotyping of peripheral blood mononuclear cells [ Time Frame: Up to 5 years ]
  Types and numbers of proteins present on the leukemia cell surface via mass cytometry upon enrollment, 90 days after initiation of acalabrutinib, and at time of relapse
• Intracellular cytokine and phospho-protein profiling of peripheral blood mononuclear cells [ Time Frame: Up to 5 years ]
  Types of proteins involved in cell signaling in leukemia cells via mass cytometry upon enrollment, 90 days after initiation of acalabrutinib, and at time of relapse.
• Acalabrutinib metabolite [ Time Frame: At 1-3 weeks after initiation of acalabrutinib ]
  Acalabrutinib metabolite detected in the cerebral spinal fluid at 1-3 weeks after initiation of acalabrutinib in participants with history of secondary central nervous system lymphoma.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Acalabrutinib Maintenance for the Treatment of Patients With Large B-cell Lymphoma
• Official Title: Acalabrutinib Maintenance Following Cellular Therapy for Large B-Cell Lymphoma Patients at Very High Risk for Relapse
• Brief Summary: This phase Ib/II trial studies the side effects and efficacy of maintenance acalabrutinib following cellular therapy in treating patients with large B-cell lymphoma at very high risk of the cancer coming back. Acalabrutinib is a small molecular inhibitor that may interfere with the ability of cancer cells to grow and spread.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the safety and tolerability of maintenance acalabrutinib following cellular therapy in participants with large B-cell lymphoma at very high risk for relapse.

SECONDARY OBJECTIVES:

I. To estimate the effectiveness of maintenance acalabrutinib following cellular therapy in participants with large B-cell lymphoma at high risk for relapse.

II. To estimate the durability of remission after completion of acalabrutinib maintenance.

III. To estimate survival following completion of acalabrutinib maintenance. IV. To estimate the rate of conversion from partial response (PR) following chimeric antigen receptor (CAR) T-cell therapy to complete response (CR) after the addition of acalabrutinib maintenance.

V. To estimate rates of dose reductions, dose pauses, and permanent discontinuations of acalabrutinib that occur post-cellular therapy.

VI. To estimate the rate of stage >= 2 graft-versus-host disease in participants receiving acalabrutinib post-allogeneic hematopoietic cell transplantation (alloHCT).

VII. To estimate the rates of grade 2, 3, and 4 hematologic toxicity in participants receiving acalabrutinib post-cellular therapy.

VIII. To estimate the rates of grade 2, 3, and 4 non-hematologic toxicity in participants receiving acalabrutinib post-cellular therapy.

EXPLORATORY OBJECTIVES:

I. To evaluate CAR T-cell persistence in the setting of acalabrutinib. II. To evaluate changes in immunophenotype of peripheral blood mononuclear cells before and after initiation of acalabrutinib, and changes at time of relapse.

III. To evaluate changes in circulating tumor deoxyribonucleic acid (ctDNA), intracellular cytokine and phospho-protein profiling of peripheral blood mononuclear cells before and after initiation of acalabrutinib, and changes at time of relapse.

IV. To determine if there are signs of central nervous system (CNS) penetration of acalabrutinib.

OUTLINE: Patients are assigned to 1 of 3 groups.

GROUP I (ALLOHCT GROUP): Beginning day 90, patients receive acalabrutinib orally (PO) once daily (QD) and then( orally, twice daily (PO BID) once no longer on prophylactic antifungal (CYP34A inhibitors) until day 365 in the absence of disease progression or unacceptable toxicity.

GROUP II (AUTOLOGOUS STEM CELL TRANSPLANTATION [ASCT] GROUP): Beginning day 60, patients receive acalabrutinib PO QD and then PO BID from day 74 if there are no dose reductions until day 365 in the absence of disease progression or unacceptable toxicity.

GROUP III (CAR-T CELL THERAPY GROUP): Beginning anytime between days 28-104, patients receive acalabrutinib PO BID until day 365 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Diffuse Large B-Cell Lymphoma
• High-grade B-cell Lymphoma
• Transformed Lymphoma
• Secondary Central Nervous System Lymphoma

Intervention

Drug: Acalabrutinib

Given PO

Other Names:

• ACP-196
• Bruton Tyrosine Kinase Inhibitor ACP-196
• Calquence

Study Arms

• Experimental: Group I (acalabrutinib)
  Beginning day 90, patients receive acalabrutinib PO QD and then PO BID once no longer on prophylactic antifungal (CYP34A inhibitors) until day 365 in the absence of disease progression or unacceptable toxicity.
  Intervention: Drug: Acalabrutinib
• Experimental: Group II (acalabrutinib)
  Beginning day 60, patients receive acalabrutinib PO QD and then PO BID from day 74 if there are no dose reductions until day 365 in the absence of disease progression or unacceptable toxicity.
  Intervention: Drug: Acalabrutinib
• Experimental: Group III (acalabrutinib)
  Beginning anytime between days 28-104, patients receive acalabrutinib PO BID until day 365 in the absence of disease progression or unacceptable toxicity.
  Intervention: Drug: Acalabrutinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 15, 2022): 24
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 30, 2025
• Estimated Primary Completion Date: January 30, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Ages 18-70 years

• One of the following:

  • Patients undergoing autologous stem cell transplantation (ASCT) or any Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T-cell therapy product for:

    • High grade B-cell lymphoma (double or triple hit) with rearrangements in bcl-2 and/or bcl-6, and rearrangement in myc
    • Large B-cell lymphoma with a history of secondary CNS involvement
    • Histologic transformation of indolent lymphoma to large B-cell lymphoma, including marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), lymphoplasmacytic leukemia, or Waldenstrom macroglobulinemia
    • High risk international prognostic index (IPI) score 4 or 5, at diagnosis or prior to CAR T-cell leukapheresis
  • Patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for large B-cell lymphoma
• Eastern Cooperative Oncology Group (ECOG) 0-2

• Requirements for post-ASCT and post-alloHCT participants:

  • Disease status of partial response (PR) or complete response (CR) prior to transplantation
  • Receive reduced-intensity conditioning regimen
  • Enrollment no later than day +90

• Requirements for post-CAR T-cell therapy participants:

  • Disease status of PR or CR after post-CAR T-cell therapy positron emission tomography (PET)-computed tomography (CT) at 1-3 months
  • Enrollment no later than day +104
• Ability to give full informed consent
• Female subjects who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib
• Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules and tablets without difficulty
• Absolute neutrophil count (ANC) > 500/uL (microliters)
• Platelets > 50,000/uL independent of transfusions
• Hemoglobin > 8 g/dL independent of transfusions
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN, unless directly attributable to Gilbert's syndrome
• Creatinine clearance >= 60 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR) and serum creatinine (Cr) =< 1.8 mg/dL

Exclusion Criteria:

• Cord blood as donor source in alloHCT
• New York Heart Association Class III or IV
• Left ventricular ejection fraction < 50%
• Estimated glomerular filtration rate < 30 mL/min
• Concurrent long-term use of posaconazole or other strong CYP3A4 inhibitors and unable to replace with equivalent medication
• Acute or chronic graft-versus-host disease (GvHD) >= stage 3 at time of enrollment
• Received packed red blood cells (pRBC) transfusion within the past 2 weeks
• Received platelet transfusion within the past 1 week
• Active invasive fungal infection
• Active bacterial or viral infection until resolution of the infection
• History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML)
• Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug
• Major surgical procedure within 30 days before the first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
• Refractory nausea and vomiting, inability to swallow the formulated product, or malabsorption syndrome; chronic gastrointestinal disease, gastric restrictions, or bariatric surgery such as gastric bypass; partial or complete bowel obstruction, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment
• Received a live virus vaccination within 28 days of first dose of study drug
• Known history of infection with human immunodeficiency virus (HIV)
• History of bleeding diathesis (e.g., hemophilia, von Willebrand disease)
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
• Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited
• Breastfeeding or pregnant
• Concurrent participation in another therapeutic clinical trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Vlad Kustanovitch; 310-206-5756; VKustanovich@mednet.ucla.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05256641
• Other Study ID Numbers: 21-000979; NCI-2021-12421 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Jonsson Comprehensive Cancer Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Jonsson Comprehensive Cancer Center
• Original Study Sponsor: Same as current
• Collaborators: AstraZeneca

Investigators

• Principal Investigator: Caspian Oliai, MD; UCLA / Jonsson Comprehensive Cancer Center

• PRS Account: Jonsson Comprehensive Cancer Center
• Verification Date: March 2023