Factors Affecting Post-transplant Cyclophosphamide (PTCy) Efficacy

Study Overview
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Brief Summary
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This study will examine the influence of donor and recipient pharmacogenetics (PG), drug pharmacokinetics (PK), and T cell phenotypes and how it may permit a tailored dosing strategy to improve the therapeutic index of post-transplant cyclophosphamide (PTCy) and optimize the graft versus tumor effect, while minimizing acute and chronic graft versus host disease (GVHD).

Detailed Description
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The primary objective of this single-arm, pilot study is to determine whether pharmacogenetics (PG) of Cy-related candidate genes from the recipients and/or donors (haploidentical and matched related donor HCTs only) germ-line DNA is associated with incidence and severity of acute and chronic GVHD. Secondary objectives include determining whether pharmacogenetics (PG) of Cy-related candidate genes from the recipients and/or donors (haploidentical and matched related donor HCTs only) germ-line DNA is associated with Cy (and metabolites) exposure and toxicities; quantifying Cy (and related metabolites) exposure measured as the area under the concentration time curve (AUC) from zero to 24 hours both before (day -6) and after transplant (day +3), and correlate exposure with incidence of acute and chronic GVHD, and Adverse Events of Special Interest (AESIs); and determining whether immune activation or polarization prior to or following Cy GVHD prophylaxis is associated with grade of acute or chronic GVHD grade and AESIs. Safety objects include evaluating Cy administered, adverse events of special interest (including deaths while on study therapy), selected laboratory parameters (including time to neutrophil recovery), and immunosuppressant concomitant medications administration. Initially, 20 participants (HCT recipients and their respective haploidentical or matched related donors) will be enrolled with a subsequent 100 additional subjects enrolled.

Official Title
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Elucidation of Factors Predicting Efficacy and Toxicity of Post Transplantation Cyclophosphamide (PTCy) as a Strategy for Graft Versus Host Disease Prevention in Haploidentical, Matched Related Donor and Matched Unrelated Donor Peripheral Blood Hematopoietic Cell Transplantation

Conditions
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Leukemia, Not Otherwise Specified, Leukemia, Other

Intervention / Treatment
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* Drug: Cyclophosphamide
* Other: Specimen collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Recipients and donors must meet all of the following applicable inclusion criteria to participate in this study: Informed consent and HIPAA authorization for release of personal health information signed by the subject. Age ≥ 18 years at the time of consent. Subject is scheduled as a recipient or respective donor (Donor consent/participation is not required for subjects undergoing matched unrelated donor HCT) for the following hematopoietic stem cell transplants (HCT) procedures using a non-myeloablative regimen at Levine Cancer Institute (LCI), and has been deemed a qualified candidate by his/her physician, per LCI medical standards: haplo-identical donor HCT, match related donor (MRD) HCT, matched unrelated donor (MUD) HCT. Recipient only: Planned post-transplant cyclophosphamide As determined by the enrolling physician, ability of the subject to understand and comply with study procedures for the entire length of the study Exclusion Criteria Subjects meeting any of the criteria below may not participate in the study: Recipient only (applies only to haplo-identical and MRD HCT recipients; not required for MUD HCT recipients): Does not have a respective donor who is willing to sign informed consent for participation in this study. Recipient only: Treatment with any investigational drug within 30 days prior to day -6 of treatment Donor only (applies only to haplo-identical and MRD HCTs; donor participation is not required for MUD HCTs): Does not have a respective recipient who is willing to sign informed consent for participation in this study.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Recipient<br>Cyclophosphamide | Drug: Cyclophosphamide<br>* Pharmacogenomics of candidate genes and pharmacokinetic analyses of cyclophosphamide administered as part of a reduced intensity conditioning (RIC) regimen and as post-transplant GVHD prophylaxis will be examined.<br>Other: Specimen collection<br>* Buccal swabs will be obtained from donors for pharmacogenomics.<br>|
| Donor<br>Specimen collection | Other: Specimen collection<br>* Buccal swabs will be obtained from donors for pharmacogenomics.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Cy cMax Values | Evaluation and comparison of average Day 3 Cy cMax values between subjects who experience acute GVHD versus subjects who do not experience acute GVHD | Approx. 24 mos | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of chronic GVHD | Calculated for each subject as a binary variable indicating whether or not subject experienced chronic GVHD | Approx. 24 mos | 
| Cy exposure | Cy (and related metabolites) exposure will be calculated using area under the concentration curve (AUC). This will be accomplished using the trapezoidal approximation, and will be calculated over the 24 hour period following first pre-transplant dose of Cy and over the 24 hour period following post-transplant dose of Cy. | Approx. 10 days | 
| Toxicities | The incidence of adverse events of special interests will be collected according to CTCAE version 4.03 | Approx. 180 days | 
| Pharmacogenetics of Cy-related genes | Evaluation of the prognostic value of pharmacogenetics (PG) of Cy-related candidate genes from the recipient's germ-line DNA, using logistic regression, on the incidence and severity of acute and chronic GVHD. PG of Cy-related candidate genes will be performed on 12 genes. Genes encoding CYP enzymes will be classified into metabolizer status and other genes will be classified as either wild type, heterozygous, or homozygous variants. | Approx. 24 mos |