An Open Label Study of Multiple Doses of Cannabidiol in the Prevention of Acute Graft-Versus-Host Disease (GVHD)

Study Overview
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Brief Summary
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A prospective, open-label, phase 2a study, to evaluate the pharmacokinetic (PK) profile, safety, and efficacy of multiple doses of Cannabidiol (CBD) in participants Graft-Versus-Host Disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)

Detailed Description
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The study contains 3 cohorts of 12 participants each: All participants will be orally administered for 105 days with CBD at doses of 75, 150 or 300 mg (PO) BID for the prevention of acute GVHD (aGVHD) following allogeneic HSCT. In addition to the study drug, all participants will receive standard aGVHD prophylaxis consisting of a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate (MTX). After completion of 105 treatment days, the participant will be followed-up until day 180.

Official Title
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A Phase 2a, Open-label, Multicenter, Study to Evaluate the Pharmacokinetic (PK), Safety and Efficacy of Multiple Doses of Cannabidiol for the Prevention of aGVHD After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Conditions
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Prevention aGVHD

Intervention / Treatment
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* Drug: CBD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any malignant hematological disease in CR or Myelodysplastic Syndrome (MDS) Age ≥ 18 years Karnofsky Score (KS) ≥ 60% HSCT-Comorbidity Index (HSCT-CI) score ≤ 3 No major organ dysfunction Myeloablative or reduced intensity conditioning regimen Matched (7/8 or 8/8) unrelated donor Peripheral blood stem cell graft Female subjects of childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for the follow-up time period. Acceptable methods of contraception include abstinence, barrier method with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method. Male subjects with partners of childbearing potential must agree to use adequate contraception (barrier method or abstinence) during the study. Subject's written informed consent Exclusion Criteria: Malignant hematological disease other than MDS, not in CR Myelofibrosis Allogeneic transplantation from a matched or mismatched sibling donor Cord blood transplantation Positive serology for HIV Serious psychiatric or psychological disorders Any uncontrolled infection at time of registration Active consumption of illicit drugs (such as: Crack cocaine, Heroin, Methamphetamines, Cocaine, Bath Salts, Amphetamines, Methadone, Benzodiazepine, Ecstasy) Use of Cannabis and/or its derivatives fourteen days prior to HSCT and for the duration of study participation Uncontrolled hepatitis B or active hepatitis C infection. QTc>450ms per Fridericia's correction and Impaired cardiac function or clinically significant cardiac diseases Inadequate renal function defined as measured creatinine clearance > 2.0 mg/dl Liver enzymes: ALT and AST > 3x upper limit of normal Pregnancy or breastfeeding ((positive serum β-HCG 7 days before first dose) Treatment with another investigational drug, biological agent, or device within 30 days of first dose, or investigational cell therapy within 6 months of first dose

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: Prevention
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral CBD 75 BID<br> | Drug: CBD<br>* CBD + Standard aGVHD prophylaxis calcineurin inhibitor (cyclosporine or tacrolimus) + methotrexate (MTX). Subjects transplanted from unrelated donors or from mismatched siblings will also receive anti-T cell globulin.<br>|
| Experimental: Oral CBD 150 BID<br> | Drug: CBD<br>* CBD + Standard aGVHD prophylaxis calcineurin inhibitor (cyclosporine or tacrolimus) + methotrexate (MTX). Subjects transplanted from unrelated donors or from mismatched siblings will also receive anti-T cell globulin.<br>|
| Experimental: Oral CBD 300 BID<br> | Drug: CBD<br>* CBD + Standard aGVHD prophylaxis calcineurin inhibitor (cyclosporine or tacrolimus) + methotrexate (MTX). Subjects transplanted from unrelated donors or from mismatched siblings will also receive anti-T cell globulin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) and serious adverse events (SAEs) Reporting | All AEs will be recorded, whether considered minor or serious, drug-related or not | Up to day 180 | 
| Cumulative incidence of aGVHD at day 100 post-transplant | Cumulative Incidence of Grade B-D aGvHD | First 100 days after transplant | 
| Pharmacokinetic parameters of Cannabidiol (CBD) - Cmax | Pharmacokinetic (PK) profile - Cmax - Maximum Plasma Concentration | Blood samples will be obtained on Day 7 before HSCT and Day 7 post HSCT. Sampling times: immediately after CBD dosing and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD | 
| Pharmacokinetic parameters of Cannabidiol (CBD) - Tmax | Pharmacokinetic (PK) profile - Tmax - time to reach maximum plasma concentration | Blood samples will be obtained on Day 7 before HSCT and Day 7 post HSCT. Sampling times: immediately after CBD dosing and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD | 
| Pharmacokinetic parameters of Cannabidiol (CBD) - Tlag | Pharmacokinetic (PK) profile - Tlag - Absorption lag-time defined as the time of the first concentration ≥ Limit of Quantitation (LOQ) | Blood samples will be obtained on Day 7 before HSCT and Day 7 post HSCT. Sampling times: immediately after CBD dosing and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD | 
| Pharmacokinetic parameters of Cannabidiol (CBD) - AUC0-t | Pharmacokinetic (PK) profile - AUC0-t - area under the plasma concentration-time curve (AUC0-t) up to the last quantifiable concentration (LOQ) from time of administration (t=0) up to the selected | Blood samples will be obtained on Day 7 before HSCT and Day 7 post HSCT. Sampling times: immediately after CBD dosing and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD | 
| Pharmacokinetic parameters of Cannabidiol (CBD) - λz | Pharmacokinetic (PK) profile: λz - Elimination rate constant determined by linear regression of the terminal points of the ln-linear plasma concentration-time curve | Blood samples will be obtained on Day 7 before HSCT and Day 7 post HSCT. Sampling times: immediately after CBD dosing and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD | 
| Pharmacokinetic parameters of Cannabidiol (CBD) - T1/2 | Pharmacokinetic (PK) profile: T1/2 - Terminal elimination half-life | Blood samples will be obtained on Day 7 before HSCT and Day 7 post HSCT. Sampling times: immediately after CBD dosing and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD | 
| Pharmacokinetic parameters of Cannabidiol (CBD) - AUC0-∞ | Pharmacokinetic (PK) profile: AUC0-∞ - area under the plasma concentration-time curve extrapolated to infinity | Blood samples will be obtained on Day 7 before HSCT and Day 7 post HSCT. Sampling times: immediately after CBD dosing and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD | 
| Cumulative incidence of aGVHD at day 180 post-transplant | Cumulative Incidence of Grade 2-4 aGvHD | Day 180 post-transplant |