Acalabrutinib and Anti-CD19 CAR T-cell Therapy for the Treatment of B-cell Lymphoma

Acalabrutinib in Combination With Anti-CD19 Chimeric Antigen Receptor T-Cells (CART) in B-Cell Lymphoma

This phase I/II trial studies the safety of acalabrutinib and axicabtagene ciloleucel in treating patients with B-cell lymphoma. Acalabrutinib may stop the growth of tumor cells by blocking key pathways needed for cell growth. Immunotherapy with axicabtagene ciloleucel is engineered to target a specific surface antigen on lymphoma cells. Acalabrutinib may enhance the efficacy of axicabtagene ciloleucel in treating patients with B-cell lymphoma.

Study Overview

• Status: Recruiting
• Conditions: B-Cell Non-Hodgkin Lymphoma; Primary Mediastinal (Thymic) Large B-Cell Lymphoma; High Grade B-Cell Lymphoma; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3a Follicular Lymphoma; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: Acalabrutinib; Biological: Axicabtagene Ciloleucel

Detailed Description

OUTLINE:

Beginning up to 3 weeks and at least 24 hours prior to leukapheresis, patients receive acalabrutinib orally (PO) every 12 hours. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also receive axicabtagene ciloleucel intravenously (IV) at 36-96 hours after completion of lymphodepleting chemotherapy.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ajay Gopal; Phone Number: 206-606-2307; Email: agopal@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Ajay Gopal; Phone Number: 206-606-2307; Email: agopal@uw.edu
      • Principal Investigator: Ajay Gopal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, and indolent (grade 1-3a) FL
• Criteria must be met for receiving commercial axi-cel per Food and Drug Administration (FDA) label
• >= 18 years of age
• Patients must be capable of understanding and providing a written informed consent
• Negative serum pregnancy test within 2 days of initiating acalabrutinib for women of childbearing potential (WOCBP), defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year
• Fertile male and WOCBP patients must be willing to use highly effective contraceptive methods before, during, and for at least 4 months after the CAR T-cell infusion or within 2 days of acalabrutinib, whichever is longer
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Creatine clearance (CrCl) > 50 mL/min or serum creatinine =< 2.5
• Total bilirubin =< 1.5x the upper limit of normal
• Adequate pulmonary function, defined as =< grade 1 dyspnea and oxygen saturation (SaO2) >= 92% on room air
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3x the upper limit of normal
• Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) of >= 50% and without evidence for pericardial effusion
• At least 1 measurable lesion >= 15 mm according to the International Working Group consensus response evaluation criteria in lymphoma (Younes 2017)
• HIV POSITIVE COHORT: Human immunodeficiency virus (HIV)-1 or HIV-2 infection, as documented by any federally approved, licensed HIV test
• HIV POSITIVE COHORT: HIV plasma HIV-1 ribonucleic acid (RNA) below detected limit obtained by Food and Drug Administration (FDA)-approved assays within 4 weeks prior to registration
• HIV POSITIVE COHORT: CD4 cell count greater than 200 cells/mm3 obtained within 2 weeks prior to enrollment at any U.S. laboratory that has a clinical laboratory improvement amendments (CLIA) certification or its equivalent
• HIV POSITIVE COHORT: Anti-retroviral treatment (ART) should be initiated > 4 weeks prior to study drug so that toxicity assessment of ART is separated from study drug. If patient is on an ART regimen that contains a strong CYP3A inhibitor (e.g ritonavir and cobicistat) or CYP3A inducer (e.g. efavirenz), changes in ART therapy should be considered in collaboration with HIV provider
• HIV POSITIVE COHORT: No acute active HIV-associated opportunistic infection requiring antibiotic treatment
• HIV POSITIVE COHORT: No uncontrolled systemic fungal, bacterial, viral, or other infection
• HIV POSITIVE COHORT: Hemoglobin > 8.0 g/dl
• HIV POSITIVE COHORT: Serum creatinine < 1.5 mg/dL OR creatinine clearance > 60 mL/min AST and ALT < 2.5 x ULN

Exclusion Criteria:

• Active and uncontrolled systemic or clinically significant infection that would contraindicate myelosuppressive therapy or CART infusion
• Patients intolerant of acalabrutinib
• Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study
• Patients with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases
• History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement
• Use of a strong CYP3A inhibitor OR inducer within 7 days of starting study drugs or requirement of use of strong CYP3A inhibitor OR inducer at the time of enrollment
• Disease that is known to be refractory to BTK inhibition
• Absolute neutrophil count (ANC) < 1000/ul
• Platelets < 50K/ul
• Another active malignancy requiring systemic treatment, unless approved by principal investigator (PI)
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study
• Inability to swallow whole pills, malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass
• Active bleeding, history of bleeding diathesis (eg, hemophilia or von Willebrand disease)
• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
• Receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug
• Prothrombin time/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of Lupus anticoagulant) > 2 x upper limit of normal (ULN)
• History of significant cerebrovascular disease or event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug
• Major surgical procedure within 7 days of 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
• Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded
• Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded
• Pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (acalabrutinib, axicabtagene ciloleucel); Beginning up to 3 weeks and at least 24 hours prior to leukapheresis, patients receive acalabrutinib PO every 12 hours. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also receive axicabtagene ciloleucel IV at 36-96 hours after completion of lymphodepleting chemotherapy.	Drug: Acalabrutinib; Given PO; Other Names: ACP-196; Bruton Tyrosine Kinase Inhibitor ACP-196; 1420477-60-6; Biological: Axicabtagene Ciloleucel; Given IV; Other Names: Yescarta; KTE C19; KTE-C19; KTE-C19 CAR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Toxicity as defined by the following: grade >= 3 cytokine release syndrome, grade >= 3 neurotoxicity within 30 days of infusion of axicabtagene ciloleucel. Grading will be done in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for neurotoxicity and the Lee Criteria for cytokine release syndrome, unless otherwise specified.	Up to 30 days post axicabtagene ciloleucel infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate following chimeric antigen receptor T-cells therapy (CART)	Will be assessed per Lugano criteria.	Up to 5 years post treatment
Overall survival		Up to 5 years post treatment
Progression-free survival		Up to 5 years post treatment
Response rate	Will assess response rate (complete response + partial response + stable response) following bridging prior to CART.	Up to 3 weeks

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Ajay Gopal, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2020
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2030

Study Registration Dates

• First Submitted: January 28, 2020
• First Submitted That Met QC Criteria: February 3, 2020
• First Posted (Actual): February 6, 2020

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Non-Hodgkin Lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Acalabrutinib; Axicabtagene ciloleucel; Tyrosine Kinase Inhibitors
• Other Study ID Numbers: RG1006269; 10418 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2020-00238 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No