JCAR014 and Durvalumab in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

NCT02706405 | Terminated Phase 1 Results DMC FDA Drug

• 5 other identifiers: 9457NCI-2015-02286P30CA015704R01CA136551RG6616001
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib trial studies whether anti-CD19-chimeric antigen receptor (CAR) lentiviral vector-transduced autologous T cells (JCAR014) and durvalumab are safe in combination and can work together in treating patients with non-Hodgkin lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). JCAR014 is made of each patient's immune cells (T cells) that have a new gene added to them in a laboratory, which programs them to kill lymphoma cells. Durvalumab is a type of drug called a monoclonal antibody, targeted to PD-L1 that may help immune cells attack cancer cells more effectively and thus help JCAR014 work better.

Conditions

Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements; Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma

Keywords

PD-L1; immunotherapy; non-Hodgkin lymphoma

Outcome Measures

Primary Outcomes (8)

• Count of Participants Who Experienced Adverse Events

  Toxicity graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

  28 days post last infusion of Durvalumab, up to 1 year

• Dose Limiting Toxicity (DLT) Rates

  Will be summarized based on the dose limiting toxicity evaluable analysis set. The target toxicity rate for the maximum tolerated dose is 30%. Outcome will be reported as a count of patients in each arm that experienced a DLT.

  28 days post first infusion of Durvalumab (for participants in Group 1) or 28 days post infusion of JCAR (for participants in Group 2)

• Highest Treatment Dose Administered on Study

  Reporting outcome as the maximum durvalumab dose that we reached on the study. Patients were monitored for 28 days post infusion for dose limiting toxicities. The DLT rate was used to determine dose escalation. The study was terminated prior to reaching the maximum tolerated dose.

  28 days

• Maximum JCAR014 Cmax by Flow Cytometry

  Absolute CD4+ and CD8+ CAR-T cell counts were determined by multiplying the percentages of CD3+CD4+CD8-EGFRt+ and CD3+CD4-CD8+EGFRt+ events, respectively, in a viable CD45+ lymphocyte forward/side scatter gate by an absolute lymphocyte count performed on the same day. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.

  Up to 12 months

• Area Under the Curve (AUC) of JCAR014 by Flow Cytometry

  Absolute CD4+ and CD8+ CAR-T cell counts were determined by multiplying the percentages of CD3+CD4+CD8-EGFRt+ and CD3+CD4-CD8+EGFRt+ events, respectively, in a viable CD45+ lymphocyte forward/side scatter gate by an absolute lymphocyte count performed on the same day. Subjects had samples analyzed at approximately days 0, 3, 7, 10, 14, 21, and 28 after CAR-T cell infusion to generate the AUC from day 0 to 28. The areas under the curve of CAR T-cell counts by flow cytometry and qPCR between time points were calculated by using a trapezoidal rule computational algorithm. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.

  Up to 28 days

• Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis

  The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.

  Up to 12 months

• AUC of JCAR014 Cells by qPCR Analysis

  The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Subjects had samples analyzed at approximately days 0, 3, 7, 10, 14, 21, and 28 after CAR-T cell infusion to generate the AUC from day 0 to 28.The areas under the curve of CAR T-cell counts by flow cytometry and qPCR between time points were calculated by using a trapezoidal rule computational algorithm. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.

  Up to 28 days

• Time to Loss of JCAR014 Detection in Blood by qPCR Analysis

  The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.

  Up to 12 months, +/- 30 days

Secondary Outcomes (6)

• Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria

  Up to 1 year

• Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria

  Up to 1 year

• Objective Response Rate by Investigator Assessment Using Lugano Criteria

  Up to 1 year

• Duration of Response

  From first response to progressive disease or death, assessed up to 1 year

• Progression Free Survival

  From date of first study treatment to progressive disease or death, assessed up to 1 year

Other Outcomes (9)

• B-cell Depletion in Circulation, Profile of Soluble Circulating Proteins Such as Cytokines and Chemokines, and Changes in the Level of Detectable Soluble PD-L1

  Up to 12 months

• Change in the Phenotype of Tumor Cells (e.g., Expression of PD-L1) and of the Tumor Microenvironment (e.g., Infiltration by Chimeric Antigen Receptor [CAR] T Cells)

  Baseline up to 12 months

• Phenotype and/or Genetic Profile of Endogenous Immune Cells and CAR T Cells

  Up to 12 months

Study Arms (8)

Group I (JCAR014, durvalumab) Early - Dose Level 2

EXPERIMENTAL

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

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Group I (JCAR014, durvalumab) Late- Dose Level 1

EXPERIMENTAL

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 .

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Group I (JCAR014, durvalumab) Late - Dose Level 2

EXPERIMENTAL

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

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Group II (durvalumab, JCAR014) - Dose Level 1

EXPERIMENTAL

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

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Group II (durvalumab, JCAR014) - Dose Level 2

EXPERIMENTAL

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

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Group II (durvalumab, JCAR014) - Dose Level 3

EXPERIMENTAL

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

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Group II (durvalumab, JCAR014) - Dose Level 4

EXPERIMENTAL

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

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Group II (durvalumab, JCAR014) - Dose Level 5

EXPERIMENTAL

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

Biological: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014; Drug: Cyclophosphamide; Biological: Durvalumab; Drug: Fludarabine

Interventions

Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ Central Memory T-lymphocytes JCAR014 BIOLOGICAL

Given IV

Also known as: Autologous Anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ CM T-lymphocytes JCAR014, JCAR014

Group I (JCAR014, durvalumab) Early - Dose Level 2; Group I (JCAR014, durvalumab) Late - Dose Level 2; Group I (JCAR014, durvalumab) Late- Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 2; Group II (durvalumab, JCAR014) - Dose Level 3; Group II (durvalumab, JCAR014) - Dose Level 4; Group II (durvalumab, JCAR014) - Dose Level 5

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Group I (JCAR014, durvalumab) Early - Dose Level 2; Group I (JCAR014, durvalumab) Late - Dose Level 2; Group I (JCAR014, durvalumab) Late- Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 2; Group II (durvalumab, JCAR014) - Dose Level 3; Group II (durvalumab, JCAR014) - Dose Level 4; Group II (durvalumab, JCAR014) - Dose Level 5

Durvalumab BIOLOGICAL

Given IV

Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736

Group I (JCAR014, durvalumab) Early - Dose Level 2; Group I (JCAR014, durvalumab) Late - Dose Level 2; Group I (JCAR014, durvalumab) Late- Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 2; Group II (durvalumab, JCAR014) - Dose Level 3; Group II (durvalumab, JCAR014) - Dose Level 4; Group II (durvalumab, JCAR014) - Dose Level 5

Fludarabine DRUG

Given IV

Also known as: 2-Fluorovidarabine, Fluradosa

Group I (JCAR014, durvalumab) Early - Dose Level 2; Group I (JCAR014, durvalumab) Late - Dose Level 2; Group I (JCAR014, durvalumab) Late- Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 1; Group II (durvalumab, JCAR014) - Dose Level 2; Group II (durvalumab, JCAR014) - Dose Level 3; Group II (durvalumab, JCAR014) - Dose Level 4; Group II (durvalumab, JCAR014) - Dose Level 5

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• AstraZeneca: collaborator
• Juno Therapeutics, Inc., a Bristol-Myers Squibb Company: collaborator
• MedImmune LLC: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Related Publications (2)

• 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.

  PMID: 37903325 DERIVED

• 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.

  PMID: 34515338 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin

Interventions

Cyclophosphamide; durvalumab; Immunoglobulin G; Disulfides; fludarabine; fludarabine phosphate

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds

Results Point of Contact

• Title: Dr. Jordan Gauthier
• Organization: Fred Hutchinson Cancer Center

jgauthier@fredhutch.org

2066672713

Study Officials

• Jordan Gauthier

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Associate

Study Record Dates

• First Submitted: February 24, 2016
• First Posted: March 11, 2016
• Study Start: November 15, 2016
• Primary Completion: May 28, 2021
• Study Completion: May 28, 2021
• Last Updated: August 24, 2022
• Results First Posted: August 24, 2022

Record last verified: 2022-08

Locations

US (1)