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.
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)
