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Idelalisib Post Allogeneic Hematopoietic Stem Cell Transplant (Hsct) in B Cell Derived Malignancies: a Phase 1 Double Blinded Randomized Placebo Toxicity Trial

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Idelalisib Post Allogeneic Hematopoietic Stem Cell Transplant (Hsct) in B Cell Derived Malignancies: a Phase 1 Double Blinded Randomized Placebo Toxicity Trial Johns Hopkins Protocol ID: J1633 IND: 131805 IDELALISIB POST ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) IN B CELL DERIVED MALIGNANCIES: A PHASE 1 DOUBLE BLINDED RANDOMIZED PLACEBO TOXICITY TRIAL Principal Investigator: Douglas E. Gladstone, MD Associate Professor of Oncology CRB I, Room 287 1650 Orleans Street Baltimore, MD 21287 [email protected] Co-Investigators: Javier Bolanos Meade, MD Richard Jones, MD Richard Ambinder. MD Lode Swinnen, MD Statisticians: Marianna Zahurak Study Site: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins IRB Number: IRB00157704 IND: 131805 Version Date: February 3, 2020 Version Date: February 3, 2020 Page 1 of 31 Johns Hopkins Protocol ID: J1633 IND: 131805 Version Date: February 3, 2020 Page 2 of 31 Johns Hopkins Protocol ID: J1633 IND: 131805 CONTENTS 1. Introduction................................................................................................................................... 5 1.1. Hypothesis ..................................................................................................................................... 6 2. Objectives ...................................................................................................................................... 6 2.1. Primary Endpoint ........................................................................................................................... 6 2.2. Secondary Endpoint ...................................................................................................................... 6 2.3. Tertiary Endpoints ......................................................................................................................... 6 3. Inclusion/Exclusion Criteria ........................................................................................................... 6 3.1. Inclusion Criteria ........................................................................................................................... 6 3.2. Exclusion Criteria ........................................................................................................................... 7 3.3. Enrollment ..................................................................................................................................... 7 4. Study Procedures .......................................................................................................................... 7 4.1. Premature Discontinuation of Study Therapy ............................................................................... 7 4.2. Premature Termination of a participant from the study .............................................................. 8 4.3. Table 1. Schedule of Assessments ................................................................................................ 9 5. Known Toxicities and Dose Adjustments ...................................................................................... 9 5.1. Known toxicities of idelalisib ......................................................................................................... 9 5.2. Dose adjustment of Idelalisib ...................................................................................................... 11 Pneumonitis .............................................................................................................................................. 11 Hepatotoxicity ........................................................................................................................................... 11 Diarrhea..................................................................................................................................................... 11 Neutropenia and thrombocytopenia ........................................................................................................ 12 Late Onset Neutropenia (LON) .................................................................................................................. 12 6. Study Statistics ............................................................................................................................ 12 7. Correlative Studies ...................................................................................................................... 15 7.1 Rationale and outline of correlative studies ............................................................................... 15 7.2 Analysis of Correlative Endpoints…………………………………………………..…………………………………..…..23 7.3 OPERATING PROCEDURES FOR SPECIMEN COLLECTION.......................................................................... 16 8. Risks ............................................................................................................................................. 19 8.1. IDELALISIB RISKS ............................................................................................................................. 19 8.2. RISK MINIMIZATION ....................................................................................................................... 19 Version Date: February 3, 2020 Page 3 of 31 Johns Hopkins Protocol ID: J1633 IND: 131805 9. Adverse Events….. ................................................................................................................... .. 20 9.1. Overview ..................................................................................................................................... 20 9.2. Definitions ................................................................................................................................... 20 9.3. Collecting and Recording Adverse Events ................................................................................... 21 9.4. Grading and Attribution of Adverse Events ................................................................................ 22 Attribution Definitions .......................................................................................................................... 22 9.5. Reporting Serious Adverse Events .............................................................................................. 23 10. Ethical, regulatory, and administrative considerations .............................................................. 23 10.1. Statement of Compliance ............................................................................................................ 23 10.2. Informed Consent........................................................................................................................ 23 10.3. Privacy and Confidentiality .......................................................................................................... 24 10.4. INSTITUTIONAL REVIEW .............................................................................................................. 24 10.5. Monitoring plan ........................................................................................................................... 24 11. References ................................................................................................................................... 24 12. Appendix 1-4 ............................................................................................................................... 27 12.1. Study Calendar…………………………………………………………………………………………………………………..……28 Version Date: February 3, 2020 Page 4 of 31 Johns Hopkins Protocol ID: J1633 IND: 131805 1. INTRODUCTION For all relapsed B cell derived hematologic malignancies, allogeneic bone marrow transplantation (allo BMT) is often the most definitive curative intent therapy. Historically, there have been four obstacles decreasing overall survival (OS) associated with allo BMT: preparative conditioning toxicity, donor availability, graft-versus- host-disease (GVHD) and disease relapse. Reduced intensity conditioning (RIC) regimens have dramatically reduced alloBMT toxicity and have expanded the use of this therapy to patients up to 75 years of age.(1-3) The use of alternative donors has resulted in an average of 2.7 donors for each patient in Johns Hopkins University.(4) The use of post-transplant cyclophosphamide has reduced the incidence of Grade III-IV GVHD to 6% - 11%.(5-7) However, disease relapse after successful engraftment during allo BMT remains the limiting factor for improving overall survival. (5, 6, 8) Currently, in order to improve OS, the BMT program at JHH has recently focused on the introduction of anti- neoplastic therapy post transplantation. We use the allo HSCT as a platform to allow a new intolerant immune system to interact with a post allo HSCT biologic or therapeutic intervention. Currently, to improve overall survival, the focus of the BMT program at JHH the introduction of anti-neoplastic therapy post transplantation: where the allo BMT serves as a platform to allowing a new intolerant immune system to interact with the post allo BMT intervention. The importance of post BMT therapy has been made evident with tyrosine kinase inhibition (TKI) in Ph+ ALL and Ph+ CML, where patients who had disease progression while on TKI therapy pre- allo BMT enjoy marked improvement in OS when TKI is part of a maintenance program (9-12); the use of DNA hypomethylation agents after allo BMT for relapsed myeloid malignances (13); or the use of rituximab after allo BMT in follicular lymphoma (PMID 26183076). At JHH we are currently, utilizing post allo BMT: TKI in Ph+ leukemia’s, sorafenib and other multi-kinase inhibitors in FLT3-ITD AML, and 5-azacytidine in MDS patients.
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