Modified Immune Cells (CD19 CAR T Cells) and Acalabrutinib for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

Study Overview
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Brief Summary
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This phase II trial investigates the side effects of CD19 chimeric antigen receptor (CAR) T cells and acalabrutinib, and to see how well they work in treating patients with mantle cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). T cells are infection fighting blood cells that can kill cancer cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize CD19, a protein on the surface of the cancer cells. These CD19-specific T cells may help the body's immune system identify and kill CD19 positive cancer cells. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving CD19 CAR T cells together with acalabrutinib may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Evaluate the safety of adding CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes (CD19 CAR T cells) to acalabrutinib treatment. (Safety Lead-in) II. Estimate the complete response (CR) rate within 6 months after adding CD19 CAR T cells to acalabrutinib treatment. (Phase 2) SECONDARY OBJECTIVES: I. Assess best response, time to and duration of CR. II. Estimate the 1-year progression free survival (PFS) rate and overall survival (OS). III. Describe the full toxicity profile. EXPLORATORY OBJECTIVES: I. Assess CD19-CAR T cell persistence. II. Assess CD19-CAR T cell activity as measured by CD19 B cell aplasia. III. Describe the duration of CR from completion of acalabrutinib. IV. Describe immunogenicity of CD19-CAR T cells in the presence of the BTK inhibitor. V. Characterize CD19 expression on tumor cells. VI. Describe cytokine profile after CD19-CAR T cell infusion. VII. Determine BTK and PLCG2 mutational status prior to treatment. OUTLINE: Patients receive acalabrutinib orally (PO) twice daily (BID) on days -5 to 28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive CD19 CAR T cells intravenously (IV) on day 0. Treatment with acalabrutinib repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who have not attained CR after the first disease assessment and tolerated the initial CAR T cell infusion may receive a second CAR T cell infusion in cycle 2. After completion of study treatment, patients are followed up at 3, 6 and 12 months, then yearly for up to 15 years post CAR T cells infusion.

Official Title
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A Phase 2 Study to Evaluate CD19-Specific Chimeric Antigen Receptor (CAR)-T Cells Combined With Acalabrutinib for Patients With Relapsed or Refractory Mantle Cell Lymphoma (MCL)

Conditions
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Recurrent Mantle Cell Lymphoma, Refractory Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Acalabrutinib
* Biological: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants must have the ability to understand and the willingness to sign a written informed consent Participants must agree to allow the use of archival tissue from diagnostic tumor biopsies If unavailable, exceptions may be granted with study principal investigator (PI) approval Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky Performance Status (KPS) >= 70% Documented CD19+ mantle cell lymphoma (MCL) by flow cytometry or immunohistochemistry (IHC) (from biopsy) if prior CD19 directed therapy was previously used Participants must be currently receiving acalabrutinib and have been taking acalabrutinib for between 3 and 7 months prior to initiating screening procedures on the study and: Must have failed at least 1 prior regimen before acalabrutinib (not including single-agent corticosteroids) Best response to acalabrutinib therapy is MRD+ CR, partial response (PR) or stable response (SD) at the time of screening Must have measurable disease by computed tomography (CT) scan (>= 1.5 cm) or evidence of blood or bone marrow involvement No contraindications to leukapheresis, steroids or tocilizumab Total serum bilirubin =< 2.0 mg/dL (performed within 28 days prior to enrollment) Participants with Gilbert syndrome may be included if their total bilirubin is >= 3.0 x upper limit of normal (ULN) and direct bilirubin =< 1.5 x ULN (performed within 28 days prior to enrollment) Aspartate aminotransferase (AST) < 3 x ULN (performed within 28 days prior to enrollment) Alanine aminotransferase (ALT) < 3 x ULN (performed within 28 days prior to enrollment) Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula (performed within 28 days prior to enrollment) International normalized ratio (INR) OR prothrombin (PT) =< 1.5 x ULN (performed within 28 days prior to enrollment) Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (performed within 28 days prior to enrollment) Female of childbearing potential: negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Cardiac function (12 lead-electrocardiogram [ECG]): corrected QT (QTc) must be =< 480 msec Left ventricular ejection fraction > 40% Oxygen saturation 92% or above at room air or diffusion capacity of the lung for carbon monoxide (DLCO) of 40% of best predicted Participants of reproductive potential must agree to use highly effective birth control methods throughout therapy and for 2 months after final CAR T cell infusion and/or 2 days after final acalabrutinib dose, whichever is later Exclusion Criteria: Allogeneic hematopoietic cell transplantation (HCT) within the last 6 months Autologous HCT within the last 3 months Prior failure of any BTK inhibitor therapy. (Participant WILL be allowed if they have switched to acalabrutinib due to intolerance of ibrutinib, and if ibrutinib therapy was =< 3 months) Participants known to have mutations associated with resistance to BTK inhibitors from prior studies Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary. Physiologic replacement of steroids (i.e., prednisone =< 7.5 mg /day, or hydrocortisone =< 20 mg /day) is allowed. During study participation, participants may receive systemic corticosteroids as needed for treatment-emergent comorbid conditions Approved anti-cancer therapies other than acalabrutinib are not allowed after enrollment, with the exception of steroids or involved field radiation to control progressive disease during cell manufacturing, prior to lymphodepletion/start of protocol therapy Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to histamine (H2)-receptor antagonists or antacids are eligible for enrollment to this study Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer Unable to discontinue anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of leukapheresis and remain off through end of study treatment Class III/IV cardiovascular disability according to the New York Heart Association classification. Subjects with controlled, asymptomatic atrial fibrillation can enroll Participants with clinically significant arrhythmia or arrhythmias not stable on medical management Active auto-immune disease requiring systemic immunosuppressive therapy, including uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) Suspected or confirmed progressive multifocal leukoencephalopathy (PML) Requires major surgical procedure within 28 days prior to first dose of study drug. If a subject has major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug Participants with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system Known history of drug-specific hypersensitivity or anaphylaxis to either study agent 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 Known bleeding disorders (e.g., von Willebrand's disease or hemophilia) History of stroke or intracranial hemorrhage within 6 months prior to enrollment History of other malignancies, except for the following: malignancy surgically resected (or treated with other modalities) with curative intent, adequately treated in situ carcinoma of the breast or cervix uteri, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; early stage prostate cancer on expectant management; malignancy treated with curative intent with no known active disease present for >= 3 years Lactating women Active chronic graft-versus-host disease (GVHD) post-allogeneic HCT Uncontrolled active infection: Human immunodeficiency virus (HIV) positive or have active hepatitis B or C infection based on testing performed within 4 weeks of enrollment 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) result. 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 Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (CD19 CAR T cells, acalabrutinib)<br>Patients receive acalabrutinib PO BID on days -5 to 28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive CD19 CAR T cells IV on day 0. Treatment with acalabrutinib repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who have not attained CR after the first disease assessment and tolerated the initial CAR T cell infusion may receive a second CAR T cell infusion in cycle 2. | Drug: Acalabrutinib<br>* Given PO<br>* Other names: Calquence;Biological: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes<br>* Given IV<br>* Other names: CD19R(EQ)28zetaEGFRt+ Tn/mem Cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of dose-limiting toxicities (DLTs) (Safety Lead-in) | Rates and associated 95% Clopper and Pearson exact confidence interval (CI) will be estimated for DLTs at the safe dose. | Day 0 up to 28 days after the first chimeric antigen receptor (CAR) T cell infusion | 
| Complete response (CR) (Phase II) | Response will be assessed based on Lugano classification. CR rate is defined as the proportion of response-evaluable participants who achieve a best response of CR within 6 months of CAR T-cell infusion and concurrent acalabrutinib therapy. Rates and associated 95% Clopper and Pearson exact CI will be estimated for CR within 6 months. | Within 6 months of CAR T-cell infusion and concurrent acalabrutinib therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to CR | Descriptive statistics will be used to summarize the time to CR among those who achieve CR. | From the first achievement of CR after CAR T cell infusion through disease relapse or progression or death, assessed up to 15 years | 
| Duration of CR | Duration of CR will be assessed using Kaplan Meier methods. | From the first achievement of CR after CAR T cell infusion through disease relapse or progression or death, assessed up to 15 years | 
| Best response | Defined as the best response documented at any time after CAR T cell infusion through 1 year after CAR T cell infusion or the start of any non-protocol anti-lymphoma therapy, whichever occurs first. Best response will be presented in tabular format including counts and percentages. | Up to 1 year post CAR T cell infusion | 
| Progression-free survival (PFS) | Progression-free survival will be assessed using Kaplan Meier methods. | From start of protocol treatment (start of lymphodepletion) to the first observation of disease relapse/progression or death due to any cause, whichever occurs first, assessed at 1 year | 
| Overall survival (OS) | OS will be assessed using Kaplan Meier methods. | From start of protocol treatment (start of lymphodepletion) to death due to any cause, assessed at 1 year | 
| Incidence of adverse events | Toxicities will be recorded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. Observed toxicities will be summarized by type, severity, date of onset (per each treatment cycle or follow-up period), and attribution. | Up to 15 year post CAR T cell infusion |