PRIMARY OBJECTIVES:
I. To evaluate the safety of JCAR014 in combination with durvalumab in adult patients with
relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).
II. To determine the maximum tolerated dose (MTD) of durvalumab in combination with JCAR014.
III. To characterize the pharmacokinetic (PK) profile of JCAR014.
SECONDARY OBJECTIVES:
I. To assess the antitumor activity of JCAR014 in combination with durvalumab in R/R B-cell
NHL.
II. To estimate the duration of response (DOR), progression-free survival (PFS), and overall
survival (OS) in patients treated with JCAR014 in combination with durvalumab.
III. To characterize the PK profile of durvalumab. IV. To assess the immunogenicity of
JCAR014 and durvalumab.
EXPLORATORY OBJECTIVE:
I. To assess the pharmacodynamic effects of JCAR014 and durvalumab in blood and within the
tumor.
OUTLINE: This is a dose-escalation study of durvalumab administered with a single fixed dose
of JCAR014. Patients are assigned to 1 of 2 treatment arms, listed as Groups 1 and 2 below.
LYMPHODEPLETING CHEMOTHERAPY: All patients receive cyclophosphamide and fludarabine
intravenously (IV) for 3 days starting approximately on day -5 or day -4.
GROUP I: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60
minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in
the absence of disease progression or unacceptable toxicity.
GROUP II: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30
minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 30 days for 30 months,
every 3 months for 12 months, then periodically for at least 15 years.
Inclusion Criteria:
INCLUSION CRITERIA FOR SCREENING:
- Relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified
(NOS); high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements;
primary mediastinal B-cell lymphoma (PMBCL); or DLBCL transformed from indolent
histology with one of the following:
- Persistent disease after first-line chemo-immunotherapy
- Relapse after first-line chemo-immunotherapy and not eligible for autologous
hematopoietic stem cell transplant (HCT)
- Relapse or persistent disease after at least two lines of therapy or after
autologous HCT
- Ability to understand and provide informed consent
INCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION:
- Screening evaluation appropriate for leukapheresis and T-cell collection
- Evidence of CD19 expression on any prior or current tumor specimen or a high
likelihood of CD19 expression based on disease histology
INCLUSION CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB:
- Successful collection of T cells for JCAR014 manufacturing
- Documentation of CD19 expression on any prior or current tumor biopsy
- Internal review of histology
- Detectable positron emission tomography (PET)-positive disease
- Karnofsky performance status >= 60%
- Assessed by the investigator to have adequate bone marrow function to receive
lymphodepleting conditioning chemotherapy
- Serum creatinine < 1.5 x age-adjusted upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN and
total bilirubin =< 2 x ULN
- Adequate pulmonary function, defined as Common Terminology Criteria for Adverse Events
(CTCAE) grade =< 1 dyspnea and oxygen saturation (SaO2) >= 92% on room air; patients
with clinically significant pulmonary dysfunction, as determined by medical history
and physical exam should undergo pulmonary function testing and must have a forced
expiratory volume in 1 second (FEV1) >= 50% of predicted value or diffusing capacity
of the lung for carbon monoxide (DLCO; corrected) >= 40% of predicted value
- Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) >= 35%
as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA)
- Women of reproductive potential (defined as all women physiologically capable of
becoming pregnant) must agree to use suitable methods of contraception for 90 days
after the last dose of study therapy (durvalumab or JCAR014)
- Males who have partners of reproductive potential must agree to use an effective
barrier contraceptive method for 90 days after the last dose of study therapy
(durvalumab or JCAR014)
Exclusion Criteria:
EXCLUSION CRITERIA FOR SCREENING:
- Subjects with known active central nervous system (CNS) involvement by malignancy;
subjects with prior CNS disease that has been effectively treated will be eligible if
treatment was completed at least 3 months prior to enrollment and there is no evidence
of disease or stable abnormalities on repeat imaging
- Planned use of corticosteroids (> 10 mg/day prednisone or equivalent) or other
systemic immunosuppression within 4 days prior to leukapheresis; topical and/or
inhaled steroids are permitted
- Prior treatment with any CD19 CAR T-cell therapy
- Prior allogeneic HCT
- Known active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection
- Pregnant or breastfeeding women
- Known exclusion criteria for leukapheresis, JCAR014, or durvalumab therapy
EXCLUSION CRITERIA FOR LEUKAPHERESIS AND PRE-THERAPY EVALUATION:
- Subjects with known active central nervous system (CNS) involvement by malignancy;
subjects with prior CNS disease that has been effectively treated will be eligible if
treatment was completed at least 3 months prior to enrollment and there is no evidence
of disease or stable abnormalities on repeat imaging
- Prior treatment with programmed cell death (PD)-1, PD-ligand (L)1, cytotoxic T
lymphocyte-associated protein 4 (CTLA 4) targeted therapy, or tumor necrosis factor
receptor superfamily (TNFRSF) agonists including CD134 (OX40), CD27, CD137 (4-1BB),
and CD357 (glucocorticoid-induced tumor necrosis factor receptor family-related
protein [GITR])
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., ulcerative colitis, Crohn's disease], celiac
disease, or other serious chronic gastrointestinal conditions associated with
diarrhea; autoimmune vasculitis; systemic lupus erythematosus; Wegener syndrome
[granulomatosis with polyangiitis]; myasthenia gravis; Graves' disease; rheumatoid
arthritis, hypophysitis, uveitis, etc.) within 3 years prior to the planned start of
treatment; the following are exceptions to this criterion:
- Vitiligo
- Alopecia
- Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Psoriasis not requiring systemic treatment
- Other conditions considered to be low risk of serious deterioration by the
principal investigator (PI)
- History of any one of the following cardiovascular conditions within the past 6
months: class III or IV heart failure as defined by the New York Heart Association
(NYHA), cardiac angioplasty or stenting, myocardial infarction, or unstable angina;
history of other clinically significant cardiac disease that, in the opinion of the PI
or designee, is a contraindication to lymphodepleting chemotherapy, JCAR014 infusion,
or durvalumab infusion is also excluded
- History or presence of clinically relevant CNS pathology such as epilepsy, seizure,
paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease,
cerebellar disease, or psychosis; history of other organic brain syndrome that in the
opinion of the PI or designee is a contraindication to lymphodepleting chemotherapy,
JCAR014 infusion or durvalumab infusion
- History of solid organ transplantation
EXCLUSION CRITERIA FOR LYMPHODEPLETION CHEMOTHERAPY, JCAR014 AND DURVALUMAB:
- For lymphodepletion chemotherapy, JCAR014 and durvalumab: Subjects with known active
CNS involvement by malignancy; subjects with prior CNS disease that has been
effectively treated will be eligible if treatment was completed at least 3 months
prior to enrollment and there is no evidence of disease or stable abnormalities on
repeat imaging
- Uncontrolled infection
- Receipt of live, attenuated vaccine within 28 days prior to the first dose of
durvalumab (Note: enrolled patients should not receive live vaccine during the study
and for 180 days after the last dose of durvalumab)
- Planned use of corticosteroids (> 10 mg/day prednisone or equivalent) or other
systemic immunosuppression is not permitted within 72 hours prior to JCAR014 infusion;
topical and/or inhaled steroids are permitted.
