Abbreviated Title: Anti-CD19 CAR PBL Version Date: August 23, 2018 Abbreviated Title: Anti-CD19 CAR PBL CC Protocol Number: 09-C-0082 DD IBC Number: RD-08-VII-10 OSP Number: 0809-940 NCT Number: NCT00924326 Version Date: August 23, 2018 PROTOCOL TITLE An Assessment of the Safety and Feasibility of Administering T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients with B-Cell Lymphoma NIH Principal Investigator: Steven A. Rosenberg, M.D., Ph.D. Chief of Surgery, Surgery Branch, CCR, NCI Building 10, CRC, Room 3-3940 9000 Rockville Pike, Bethesda, MD 20892 Phone: 240-760-6218; Email: [email protected] Investigational Agent: Drug Name: PG13-CD19-H3 (anti-CD19 CAR) retroviral vector- transduced autologous PBL IND Number: 13871 Sponsor: Center for Cancer Research Manufacturer: Surgery Branch Cell Production Facility Commercial Agents: Cyclophosphamide and Fludarabine Abbreviated Title: Anti-CD19 CAR PBL Version Date: August 23, 2018 PRÉCIS Background: • We have constructed a retroviral vector that encodes an anti-CD19 chimeric antigen receptor (CAR) that recognizes the CD19 antigen. This chimeric receptor also contains the signaling domains of CD28 and CD3-zeta. The retroviral vector can be used to mediate genetic transfer of this CAR to T-cells with high efficiency (> 50%) without the need to perform any selection. • In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T-cells secreted significant amounts of IFN-γ and IL-2. • We have developed a process for cryopreserving the cell product which may lead to the ability for this product to be manufactured at a central location and shipped to other institutions for treatment of a broader patient population. Objective: • Primary objective: o With the approval of Amendment S, to determine the safety and feasibility of the administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes with a non-myeloablative conditioning regimen in patients with B-cell lymphomas. Eligibility: • Patients of 18 years of age or older must: o Have a CD19-expressing B-cell lymphoma o Be a non-responder to, or recurred after one or more standard chemotherapy- containing regimens for their malignancy o Currently require treatment due to progressive malignancy o Be deemed to be incurable by standard therapy • Patients may not have: o A history of allogeneic stem cell transplantation o CNS disease Design: • PBMC obtained by leukapheresis (approximately 5.0x109 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell proliferation. • Transduction is initiated by exposure of approximately 1.0x108 to 5.0x108 cells to retroviral vector supernatant containing the anti-CD19 CAR. • With the approval of Amendment S, patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphodepletion, followed by cryopreserved anti-CD19-CAR-transduced T-cells. • Patients will be followed until disease progression. • Patients who have responded to treatment and then progress may receive one retreatment. Abbreviated Title: Anti-CD19 CAR PBL Version Date: August 23, 2018 TABLE OF CONTENTS PRÉCIS .......................................................................................................................................... 2 TABLE OF CONTENTS ............................................................................................................. 3 1 INTRODUCTION ................................................................................................................. 8 1.1 Study Objectives ..................................................................................................................... 8 1.1.1 Prior to Amendment E ................................................................................................ 8 1.1.2 With Approval of Amendments E and F .................................................................... 8 1.1.3 With Approval of Amendment H (this study will no longer include aldesleukin) ..... 8 1.1.4 With Approval of Amendment S (this study will include cryopreserved anti-CD19- CAR PBL) ............................................................................................................................... 9 1.2 Background and Rationale ...................................................................................................... 9 1.2.1 Prior Surgery Branch Trials of Cell Transfer Therapy Using Heterogeneous TIL Plus High-Dose IL-2 Following Non-myeloablative but Lymphodepleting Chemotherapy 10 1.2.2 Surgery Branch Trials of Cell Transfer Therapy Using Transduction of TCR Genes that Encode TCR that Recognize Tumor-Associated Antigens into Non-Reactive PBL ..... 10 1.2.3 Chimeric Antigen Receptors (CARs) ....................................................................... 12 1.2.4 B-Cell Malignancies ................................................................................................. 13 1.2.5 CD19 ......................................................................................................................... 14 1.2.6 Development of an Anti-CD19 CAR for Clinical Adoptive T-Cell Transfer .......... 14 1.2.7 Other Anti-CD19 CAR Clinical Trials ..................................................................... 15 1.2.8 Rationale for Measuring Persistence of Adoptively Transferred T-Cells With or Without Lymphodepleting Chemotherapy Prior to Adoptive Transfer ................................ 16 1.2.9 Safety Considerations ............................................................................................... 16 1.2.10 Cryopreservation of the Anti-CD19 CAR Transduced T-Cell Product ................ 17 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 20 2.1 Eligibility Criteria ................................................................................................................. 20 2.1.1 Inclusion Criteria ...................................................................................................... 20 2.1.2 Exclusion Criteria ..................................................................................................... 21 2.2 Screening Evaluation ............................................................................................................ 22 2.2.1 Within 4 Weeks Prior to Starting the Chemotherapy Regimen ................................ 22 2.2.2 Within 14 Days Prior to Starting the Chemotherapy Regimen................................. 23 2.2.3 Within 7 Days Prior to Starting the Chemotherapy Regimen................................... 23 2.3 Protocol Registration ............................................................................................................ 23 2.3.1 Prior to Registration for this Protocol ....................................................................... 23 2.3.2 Registration Procedure .............................................................................................. 23 3 STUDY IMPLEMENTATION .......................................................................................... 23 3.1 Study Design – Beginning with Amendment S .................................................................... 24 3.1.1 Treatment Phase: Cryopreserved PBL ...................................................................... 24 3.1.2 Definition of Dose-Limiting Toxicity (DLT) ........................................................... 26 Abbreviated Title: Anti-CD19 CAR PBL Version Date: August 23, 2018 3.2 Protocol Stopping Rules ....................................................................................................... 27 3.3 Drug Administration ............................................................................................................. 28 3.3.1 Preparative Regimen with Cyclophosphamide and Fludarabine .............................. 29 3.3.2 Cell Infusion.............................................................................................................. 29 3.3.3 Study Calendar .......................................................................................................... 29 3.4 On-Study Evaluation ............................................................................................................. 30 3.4.1 Prior to Starting the Preparative Regimen ................................................................ 30 3.4.2 During the Preparative Regimen (Daily) .................................................................. 30 3.4.3 After Cell Infusion .................................................................................................... 30 3.4.4 During Hospitalization (Every 1-2 Days as Clinically Indicated) ............................ 31 3.5 Retreatment ........................................................................................................................... 31 3.6 Post-Study Evaluation (Follow-up) ...................................................................................... 32 3.6.1 Time-Period of Evaluations ...................................................................................... 32 3.6.2 Scheduled Evaluations .............................................................................................. 32 3.7 Criteria for Removal from Protocol Therapy and Off-Study Criteria .................................. 33 3.7.1 Criteria for Removal from Protocol Therapy............................................................ 33 3.7.2 Off-Study Criteria ....................................................................................................