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

Sponsor

University of Washington (Other)

Overall Status

Recruiting

CT.gov ID

NCT04257578

Collaborator

AstraZeneca (Industry)

Enrollment

Location

Arm

98.9

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
B-Cell Non-Hodgkin Lymphoma Diffuse Large B-Cell Lymphoma, Not Otherwise Specified High Grade B-Cell Lymphoma Primary Mediastinal (Thymic) Large B-Cell Lymphoma Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma Grade 1 Follicular Lymphoma Grade 2 Follicular Lymphoma Grade 3a Follicular Lymphoma	Drug: Acalabrutinib Biological: Axicabtagene Ciloleucel	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 2, 2020

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2029

Arms and Interventions

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: 1420477-60-6 ACP-196 Bruton Tyrosine Kinase Inhibitor ACP-196 Calquence Biological: Axicabtagene Ciloleucel Given IV Other Names: KTE C19 KTE-C19 KTE-C19 CAR Yescarta

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:

1420477-60-6

ACP-196

Bruton Tyrosine Kinase Inhibitor ACP-196

Calquence

Biological: Axicabtagene Ciloleucel

Given IV

Other Names:

KTE C19

KTE-C19

KTE-C19 CAR

Yescarta

Outcome Measures

Primary Outcome Measures

Incidence of adverse events [Up to 30 days post axicabtagene ciloleucel infusion]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed large B-cell lymphoma after two or more lines of systemic therapy, 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 after two or more lines of systemic therapy
Criteria must be met for receiving commercial axi-cel per Food and Drug Administration (FDA) label
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
Evidence of CD19 expression on tumor cells by immunohistochemistry or flow cytometry
Creatinine clearance (CrCl) > 50 mL/min or serum creatinine =< 2.5
Total bilirubin =< 1.5 x the upper limit of normal
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x the upper limit of normal
Adequate pulmonary function, defined as =< grade 1 dyspnea and oxygen saturation (SaO2) >= 92% on room air
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)

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
Known human immunodeficiency virus (HIV) positivity
Pregnant or breast feeding