JCAR014 and Durvalumab in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma
NCT ID: NCT02706405
Last Updated: 2022-08-24
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE1
30 participants
INTERVENTIONAL
2016-11-15
2021-05-28
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Group I (JCAR014, durvalumab) Early - Dose Level 2
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 1 - early: start durvalumab no earlier than 7 days after JCAR014.
Group 1 Dose Level 2 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Group I (JCAR014, durvalumab) Late- Dose Level 1
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 1 - late: start durvalumab no earlier than 21 days after JCAR014
Group 1 Dose Level 1 is 225 mg Durvalumab, up to 2 x 106/kg CAR T cells
.
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Group I (JCAR014, durvalumab) Late - Dose Level 2
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 1 - late: start durvalumab no earlier than 21 days after JCAR014
Group 1 Dose Level 2 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Group II (durvalumab, JCAR014) - Dose Level 1
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.
Group 2 Dose Level 1 is 7.5 mg Durvalumab, up to 2 x 106/kg CAR T cells
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Group II (durvalumab, JCAR014) - Dose Level 2
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.
Group 2 Dose Level 2 is 22.5 mg Durvalumab, up to 2 x 106/kg CAR T cells
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Group II (durvalumab, JCAR014) - Dose Level 3
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.
Group 2 Dose Level 3 is 75 mg Durvalumab, up to 2 x 106/kg CAR T cells
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Group II (durvalumab, JCAR014) - Dose Level 4
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.
Group 2 Dose Level 4 is 225 mg Durvalumab, up to 2 x 106/kg CAR T cells
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Group II (durvalumab, JCAR014) - Dose Level 5
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.
Group 2 Dose Level 5 is 750 mg Durvalumab, up to 2 x 106/kg CAR T cells
Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Interventions
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Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014
Given IV
Cyclophosphamide
Given IV
Durvalumab
Given IV
Fludarabine
Given IV
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
* 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
* 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
* 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
* 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.
18 Years
ALL
No
Sponsors
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AstraZeneca
INDUSTRY
Juno Therapeutics, Inc., a Bristol-Myers Squibb Company
INDUSTRY
MedImmune LLC
INDUSTRY
National Cancer Institute (NCI)
NIH
Fred Hutchinson Cancer Center
OTHER
Responsible Party
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Alexandre Hirayama
Research Associate
Principal Investigators
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Jordan Gauthier
Role: PRINCIPAL_INVESTIGATOR
Fred Hutch/University of Washington Cancer Consortium
Locations
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Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Countries
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References
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Hirayama AV, Kimble EL, Wright JH, Fiorenza S, Gauthier J, Voutsinas JM, Wu Q, Yeung CCS, Gazeau N, Pender BS, Kirchmeier DR, Torkelson A, Chutnik AN, Cassaday RD, Chapuis AG, Green DJ, Kiem HP, Milano F, Shadman M, Till BG, Riddell SR, Maloney DG, Turtle CJ. Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma. Blood Adv. 2024 Jan 23;8(2):453-467. doi: 10.1182/bloodadvances.2023011287.
Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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NCI-2015-02286
Identifier Type: REGISTRY
Identifier Source: secondary_id
9457
Identifier Type: OTHER
Identifier Source: secondary_id
RG6616001
Identifier Type: OTHER
Identifier Source: secondary_id
9457
Identifier Type: -
Identifier Source: org_study_id
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