Idelalisib Post Allogeneic Hematopoietic Stem Cell Transplant (HSCT) in B Cell Derived Malignancies

Study Overview
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Brief Summary
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This is a study to evaluate the safety of idelalisib as post-transplantation maintenance in patients with B cell hematologic malignancies undergoing a allogeneic hematopoietic stem cell transplant (HSCT). Safety will be evaluated through the assessment of cytopenias, effect on donor chimerism, effect on the incidence and severity of acute graft versus host disease, and gastro-intestinal tolerance.

Detailed Description
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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 Philadelphia chromosome positive acute lymphocytic leukemia (ALL) and chronic myeloid leukemia(CML), where patients who had disease progression while on TKI therapy pre-allo BMT enjoy marked improvement in overall survival when TKI is part of a maintenance program; the use of DNA hypomethylation agents after allo BMT for relapsed myeloid malignances; or the use of rituximab after allo BMT in follicular lymphoma. Idelalisib, an orally-administered, selective inhibitor of Phosphoinositide 3 kinase (PI3K), is extremely effective in inducing partial responses to complete responses in many B-cell derived malignancies and should be studied in the post alloHSCT setting. Johns Hopkins Hospital has one of the world's largest experiences with alloHSCT. This study proposes a double blinded randomized phase I placebo trial where all patients who have undergone alloHSCT for a B-cell derived hematologic malignancy be offered either idelalisib 100mg or placebo twice daily for 180 days starting approximately 90 days after their HSCT.

Official Title
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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

Conditions
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B Cells-Tumors, B Cell Chronic Lymphocytic Leukemia, Follicular Lymphoma, Mantle Cell Lymphoma, Large B-Cell Diffuse Lymphoma of Bone (Diagnosis)

Intervention / Treatment
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* Drug: Idelalisib 100 MG
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA >18 years of age Has undergone allo HSCT to treat a B-cell derived hematologic malignancy: accepted alloHSCT regimens include: myeloablative or reduced intensity conditioning from any donor (matched, partially mismatched or cord) and any source (peripheral blood, bone marrow, or cord). T bili ≤ 1.5 mg/dL except for patients with Gilbert's syndrome or hemolysis AST, ALT and alk phos all < 2.5X ULN Karnofsky performance score ≥ 40 ECOG ≤3 For women of childbearing potential, a negative serum or urine pregnancy test with sensitivity less than 50 mIU/m within 72 hours before the start of study medication. Use of two forms of contraception with less than a 5% failure rate or abstinence by all transplanted patients for a minimum of 1 month after the last dose of Idelalisib. For the first 60 days post-transplant, transplant recipients should be encouraged to use non-hormonal contraceptives due to the potential adverse effect of hormones on bone marrow engraftment. Ability to receive oral medication. Ability to understand and provide informed consent. EXCLUSION CRITERIA ECOG >3 (Karnofsky <40%) ALT, AST >2.5 ULN or total bilirubin >1.5 ULN (not attributable to Gilbert's) Women who are pregnant or breastfeeding. Exclude if patient has cirrhosis or is currently being actively treated for hepatitis C. History of positive HIV-1 or HIV-2 serologies or nucleic acid test. Active hepatitis B infection as documented by positive Hepatitis B PCR assay Use of investigational drug, other than the study medications specified by the protocol, within 30 days of transplantation. Receipt of a live vaccine within 30 days of receipt of study therapy. ≥ Grade II aGVHD The presence of any medical condition that the Investigator deems incompatible with participation in the trial Subjects who are required to use a medication classified as a strong CYP3A inducer of inhibitor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Idelalisib 100mg or placebo twice daily, starting day +90 (+-/ 10 days) after transplant until day +270.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idelalisib 100mg<br>Idelalisib is an orally-administered, selective inhibitor of Phosphoinositide 3 kinase (PI3K)-delta which has been shown to be extremely effective in inducing partial to complete responses in many B-cell derived malignancies. intervention: 100mg Idelalisib twice daily beginning +90(+/- 10) days after allo HSCT and continued through Day 270 post transplant | Drug: Idelalisib 100 MG<br>* 100mg BID beginning on day 90 (+/- 10days) and continuing until day 270 post transplant.<br>* Other names: Zydelig;|
| Placebo Comparator: Placebo oral tablet<br>Placebo to be taken twice daily beginning +90(+/- 10) days after allo HSCT and continued through Day 270 post transplant | Drug: Placebo Oral Tablet<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-limiting toxicities will be defined as Idelalisib interruption for >14 days, or other >3 adverse events as defined by CTCAE IV not captured in the protocol for dose de-escalation. | The evaluation of the safety of Idelalisib as post-transplantation maintenance in patients with B cell hematologic malignancies | Day 90 - Day 270 post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival at one year. | Impact of Idelalisib on aGVHD, relapse, and non-relapse mortality | Beginning Day 90 post transplant until Day 360 | 
| Identify potential predictive biomarker candidates based on exploratory gene expression analysis of immune biomarkers in bone marrow aspirates and whole or targeted exome sequencing of lymphoma cells | Search for Biomarkers which could better identify which patients would respond to treatment with Idelalisib in the post-transplant setting. | Beginning Day 90 post transplant until Day 270 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idelalisib, Zydelig, allo transplant, PI3K inhibitor, post transplant maintenance therapy