Abbreviated Title: LMB-100 plus SEL-110 Version date: 10/01/18 Abbreviated Title: LMB-100 plus SEL-110 CC Protocol #: 18C0057D Version Date: October 1, 2018 NCT Number: NCT03436732 Title: A Phase I Study of the Mesothelin-Targeted Immunotoxin LMB-100 in Combination with SEL-110 in Subjects with Malignant Pleural or Peritoneal Mesothelioma Investigators: NCI Principal Investigator: Raffit Hassan, M.D. A-E Thoracic and GI Malignancies Branch (TGMB), CCR, NCI Building 10, Room 4-5330 9000 Rockville Pike Bethesda, MD 20892 Telephone: 240-760-6232 E-mail: [email protected] NIH Collaborators Ronald Germain, M.D., Ph.D.F, NIAID, NIH Roles A. Obtain information by intervening or interacting with living individuals for research purposes B. Obtaining identifiable private information about living individuals C. Obtaining the voluntary informed consent of individuals to be subjects D. Makes decisions about subject eligibility E. Studying, interpreting, or analyzing identifiable private information or data/specimens for research purposes F. Studying, interpreting, or analyzing coded, linked data or specimens for research purposes G. Some/all research activities performed outside NIH Investigational Agents: Drug Name: LMB-100 (formerly SEL-110 RO6927005) IND Number: 136483 136483 Sponsor: Center for Cancer Research, Center for Cancer Research, NCI, NIH NCI, NIH Manufacturer: F. Hoffmann-La Roche Selecta Biosciences, Inc. Commercial Agents: None 1 Abbreviated Title: LMB-100 plus SEL-110 Version date: 10/01/18 PRÉCIS Background: x LMB-100 and a closely related immunotoxin also targeting mesothelin have been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer. x Results from these studies showed that the majority of patients formed anti-drug-antibodies (ADAs) that neutralized subsequent injection of the product making it ineffective. x In a small subset of patients that did not form ADAs to the product, good response and regression of tumors was seen. x In a different application SEL-110, a biodegradable nanoparticle containing rapamycin, has been shown in clinical trials to prevent the formation of ADAs to an immunogenic enzyme when co-administered. Preclinical data show that SEL-110 also prevents the formation of ADAs to LMB-100. x This clinical trial will investigate whether SEL-110 when administered with LMB-100 is able to prevent the formation of ADAs and thus allow patients to receive multiple, effective injections of LMB-100. Objectives: x The primary objective of the study is to assess the safety and tolerability of LMB-100 in combination with SEL-110. Eligibility: Primary Inclusion Criteria x 18 years of age x Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma not amenable to potentially curative surgical resection. x Patients must have measurable disease per RECIST 1.1. x Patients must have had at least one prior chemotherapy regimen that includes pemetrexed and cisplatin or carboplatin. There is no limit to the number of prior chemotherapy regimens received. x Patients for whom no standard curative therapy exists Primary Exclusion Criteria: x Known or clinically suspected CNS primary tumors or metastases including leptomeningeal metastases. x Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results. x Evidence of active or uncontrolled infections. 2 Abbreviated Title: LMB-100 plus SEL-110 Version date: 10/01/18 x Live attenuated vaccinations 14 days prior to treatment x Pregnant women are excluded from this study Design: x This is a Phase I, single center, dose escalation study of LMB-100 in combination with SEL-110 x Patients will receive the combination using a dose escalation scheme in which different doses of LMB100 and SEL-110 will be evaluated. x Patients will receive 4 cycles of LMB-100 with SEL-110. A cycle will consist of i.v. infusion of SEL-110 on Day 1 of the cycle followed immediately by an i.v. infusion of LMB-100, then on Days 3 and 5 of the cycle patients will receive an i.v. infusion of LMB- 100 only. Treatment cycles will be separated by 21 days. 3 Abbreviated Title: LMB-100 plus SEL-110 Version date: 10/01/18 TABLE OF CONTENTS PRÉCIS ........................................................................................................................................... 2 TABLE OF CONTENTS ................................................................................................................ 4 1 INTRODUCTION ............................................................................................................... 10 1.1 Study Objectives ...................................................................................................... 10 1.1.1 Primary Objective .................................................................................................... 10 1.1.2 Secondary Objectives............................................................................................... 10 1.1.3 Exploratory Objectives ............................................................................................ 10 1.2 Background and Rationale ....................................................................................... 10 1.2.1 Background on Mesothelioma ................................................................................. 10 1.2.2 Mesothelin as a target for cancer therapy ................................................................ 11 1.2.3 LMB-100.................................................................................................................. 13 1.2.4 SEL-110 ................................................................................................................... 25 1.2.5 Rationale for the study ............................................................................................. 44 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT ...................................................... 45 2.1 Eligibility Criteria .................................................................................................... 45 2.1.1 Inclusion Criteria ..................................................................................................... 45 2.1.2 Exclusion Criteria .................................................................................................... 46 2.1.3 Recruitment Strategies ............................................................................................. 48 2.2 Screening Evaluation ............................................................................................... 48 2.3 Registration Procedures ........................................................................................... 48 2.4 Treatment Assignment Procedures .......................................................................... 49 3 STUDY IMPLEMENTATION ........................................................................................... 49 3.1 Study Design ............................................................................................................ 49 3.1.1 Dose Limiting Toxicity ............................................................................................ 50 3.1.2 Dose Escalation ........................................................................................................ 51 3.2 Drug Administration ................................................................................................ 52 3.2.1 SEL-110 ................................................................................................................... 52 4 Abbreviated Title: LMB-100 plus SEL-110 Version date: 10/01/18 3.2.2 LMB-100.................................................................................................................. 54 3.2.3 Co-administration of SEL-110 and LMB-100 ......................................................... 57 3.2.4 Premedications for Patients Receiving LMB-100 ................................................... 57 3.3 Dose Modifications .................................................................................................. 58 3.3.1 LMB-100.................................................................................................................. 58 3.3.2 SEL-110 ................................................................................................................... 60 3.4 Study Calendar ......................................................................................................... 65 3.5 Criteria for Removal from Protocol Therapy and Off Study Criteria ...................... 68 3.5.1 Criteria for removal from protocol therapy ............................................................. 68 3.5.2 Off-Study Criteria .................................................................................................... 68 3.5.3 Off Protocol Therapy and Off-Study Procedure ...................................................... 68 4 CONCOMITANT MEDICATIONS/MEASURES ............................................................. 68 4.1.1 Permitted Therapy .................................................................................................... 68 4.1.2 Prohibited Therapy................................................................................................... 69 5 BIOSPECIMEN COLLECTION ......................................................................................... 69 5.1 Correlative Studies for Research/Pharmacokinetic Studies ....................................