Abbreviated Title: Pomalidomide for cGvHD Version Date: 9/14/2018 Abbreviated Title: Pomalidomide for cGvHD CC Protocol #: 12-C-0197 J NCT #: NCT01688466 Version Date: 9/14/2018 Title: A Randomized Phase 2 Single-Center Study of Pomalidomide for Chronic GVHD NCI Principal Investigator: Steven Pavletic, M.D, ETIB, NCI 10/CRC, RM 4-3130 Phone: 240-760-6174 Email : [email protected] Drug Name: Pomalidomide IND Number: 115336 Sponsor: Center for Cancer Research Manufacturer: Celgene Protocol tracking number: PO-GvHD-NCI-0046 1 Abbreviated Title: Pomalidomide for cGvHD Version Date: 9/14/2018 PRÉCIS Background: • Chronic graft-versus-host disease (cGvHD) is the leading cause of non-relapse morbidity and mortality in persons after allogeneic hematopoietic cell transplants. • About 50% of persons with cGvHD have disease refractory to systemic corticosteroids and there is no standard second-line therapy. • Thalidomide, a drug with immune-modulating effects, was active in advanced cGvHD but was difficult to use at appropriate doses. • Pomalidomide is related to thalidomide but with higher potency and more favorable toxicity profile. It is active in multiple myeloma and myeloproliferative neoplasm–associated myelofibrosis. Preliminary data in humans with cGvHD are encouraging but data are limited. Objective: • Primary: Determine whether pomalidomide is effective in persons with moderate or severe cGvHD not controlled by corticosteroids. Eligibility: • Inclusion Criteria o Moderate or severe cGvHD per NIH criteria o Age 18 to 75 years old o Karnofsky performance score >60% o Has cGvHD that did not respond to high-dose corticosteroids (average 0.5 mg/kg/d prednisone for >8 weeks) or second-line therapy o Receiving stable or tapering doses of systemic therapy in the preceding 4 weeks o Agree to adhere to methods of contraception and other fertility control measures as prescribed by the protocol • Exclusion Criteria o Acute GvHD (classic and late per NIH criteria) o Absolute neutrophils <1.0x109/L, platelets <75x109/L, estimated creatinine clearance <50 mL/min/1.73m2 o NIH lung score 3 o Pregnant or lactating o Uncontrolled infection Design: Randomized phase 2 trial with the single stage selection design. Patients will receive either a constant low dose of pomalidomide (0.5 mg/day) for six months or a strategy of increasing dose of pomalidomide from 0.5 mg/d up through each individual patients’ maximum tolerated dose, with escalations by 0.5 mg/d every 2 weeks to a maximum of 2.0 mg/d. As an early stopping rule for futility, if after 7 patients have enrolled on either arm, 0 have responded, then no further patients will be accrued to that arm as soon as this can be determined. To protect patient safety, an early stopping rule will be implemented. With two arms, each of which has a maximal accrual 2 Abbreviated Title: Pomalidomide for cGvHD Version Date: 9/14/2018 of 16 patients, up to 32 evaluable patients will be randomized. Response assessments will occur every 3 months with primary efficacy endpoint evaluated at 6 months. Patients with responding disease will continue therapy for another 6 months. 3 Abbreviated Title: Pomalidomide for cGvHD Version Date: 9/14/2018 TABLE OF CONTENTS PRÉCIS ........................................................................................................................................... 2 TABLE OF CONTENTS ................................................................................................................ 4 1 INTRODUCTION .................................................................................................................. 7 1.1 Study Objectives .............................................................................................................. 7 1.2 Background and Rationale ............................................................................................... 7 1.3 Pomalidomide................................................................................................................. 12 1.3.3.1 Pharmacokinetics and Product Metabolism in Humans ............................................... 14 1.4 Study Design and Rationale ........................................................................................... 20 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 21 2.1 Eligibility Criteria .......................................................................................................... 21 2.2 Required Testing and Counseling for FCBP and Partners of FCBP .............................. 23 2.3 Screening Evaluation...................................................................................................... 23 2.4 Registration Procedures.................................................................................................. 24 2.5 Treatment Assignment and Randomization procedures................................................. 24 2.6 Baseline Evaluation ........................................................................................................ 25 3 STUDY IMPLEMENTATION ............................................................................................ 25 3.1 Study Design .................................................................................................................. 25 3.2 Drug Administration ...................................................................................................... 27 3.3 Dose Modifications ........................................................................................................ 28 3.4 Questionnaires ................................................................................................................ 30 3.5 Study Calendar ............................................................................................................... 31 3.6 Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 36 4 CONCOMITANT MEDICATIONS/MEASURES .............................................................. 36 4.1 Concomitant Corticosteroid Therapy and Tapering Guideline ...................................... 36 4.2 Other Treatments for cGvHD ......................................................................................... 37 4.3 Venous Thromboembolism Prophylaxis ........................................................................ 37 4.4 Other Allowed Concomitant Therapy ............................................................................ 37 4.5 Prohibited Concomitant Therapy ................................................................................... 38 5 BIOSPECIMEN COLLECTION .......................................................................................... 38 5.1 Correlative Studies for Research .................................................................................... 38 5.2 Sample Storage, Tracking and Disposition .................................................................... 39 4 Abbreviated Title: Pomalidomide for cGvHD Version Date: 9/14/2018 6 DATA COLLECTION AND EVALUATION ..................................................................... 41 6.1 Data Collection ............................................................................................................... 41 6.2 Response Criteria ........................................................................................................... 43 6.3 Toxicity Criteria ............................................................................................................. 46 7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 47 7.1 Definitions ...................................................................................................................... 47 7.2 NCI-IRB and Clinical Director Reporting ..................................................................... 48 7.3 IND Sponsor Reporting Criteria .................................................................................... 49 7.4 Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 51 7.5 Data and Safety Monitoring Plan ................................................................................... 52 8 STATISTICAL CONSIDERATIONS.................................................................................. 53 9 COLLABORATIVE AGREEMENTS ................................................................................. 54 9.1 Cooperative Research and Development Agreement (CRADA) ................................... 54 10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 54 10.1 Rationale For Subject Selection ................................................................................. 54 10.2 Participation of Children ............................................................................................ 54 10.3 Participation of NIH Subjects Unable to Give Consent ............................................. 54 10.4 Evaluation of Benefits and Risks/Discomforts ........................................................... 55 10.5 Risks/Benefits Analysis .............................................................................................. 55 10.6 Consent Process and Documentation ......................................................................... 55 11 PHARMACEUTICAL INFORMATION ............................................................................. 56 11.1 Pomalidomide ............................................................................................................