An open label, study to evaluate the safety of Cannabidiol (CBD) for the prevention of Acute Graft-Versus-Host Disease (GVHD) after allogeneic hematopoietic cell transplantation.

Cannabidiol (CBD), Olive Oil Solution, 1.5% (15 mg/mL CBD) Cannabidiol (CBD), Olive Oil Solution, 3% (30 mg/mL CBD) Cannabidiol (CBD), Olive Oil Solution, 6% (60 mg/mL CBD) Cannabidiol (CBD), dissolved in tocopherol and pharmaceutical grade olive oil, at concentrations of 1.5, 3 or 6%, will be administered orally at doses of 75, 150, or 300 mg twice a day, respectively, beginning on the day of the initiation of conditioning until Day 98 post-Hematopoietic Stem Cell Transplant (HSCT). The administration volume for all doses will be supplied as 5 mL per vial, wherein one dose is contained in a single vial. 36 subjects are planned to be enrolled into this study, distributed among 3 sequential cohorts. The first cohort of 12 subjects will be administered CBD at a dose of 75 mg orally, twice per day. Upon demonstration of safety for the first cohort (after DSMB examination of the safety data), a second cohort of 12 subjects will be administered CBD at a dose of 150 mg orally twice a day. Upon demonstration of safety for the second cohort, a final cohort of 12 subjects will be administered CBD at a dose of 300 mg orally, twice per day. No crossover will be allowed, and subjects will remain in the same dosing study arm until the end of the study. All subjects will receive standard acute GVHD prophylaxis consisting of a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate (MTX) on days 1, 3, and 6 post-HSCT. All subjects will also receive anti-T cell globulin (ATG, Fresenius, Germany or Grafalon, Switzerland) at a dose of 5 mg/kg daily on Days -3 to -1 (prior to HSCT). During this preconditioning period, CBD will be administered once at the beginning of the PK study day and then discontinued until the next study visit at Day -6 ± 3 (study visit 2). CBD will be administered at doses of 75, 150, or 300 mg orally twice a day from Days -6 to 98 post-HSCT (except for Day +7/study visit 4, the second PK sampling day, in which only the morning dose will be administered 15 minutes prior to first PK sampling of this visit). STUDY RELATED ACTIVITIES PER STUDY VISIT: Visit 0: Day -21 to -7 before HSCT, Baseline/Screening: Informed consent form signed and countersigned, Inclusion/exclusion determination Demographics, Physical examination, Medical history Smoking and alcohol consumption status. NOTE: for alcohol consumption assessment, the following units will be used: number of cups of wine/beer/spirits a subject consumes per week. Lung function testing, Cardiac echocardiography or MUGA, HSCT-CI score evaluation Concomitant medications (every day for 1 month after HSCT) Vital signs will include temperature, peripheral arterial blood pressure, heart rate, and respiratory rate. Urine analysis, Biochemistry Panel, Hematology, Coagulation, Fibrinogen, Reticulocytes & Endocrinology, Serology, including Hepatitis A, B, C Viruses (HAV, HBV, HCV), Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Venereal Disease Research Laboratory test (VDRL), HIV, Human T-Lymphotropic Virus (HTLV), Toxoplasma, Herpes Simplex (I & II). Urine pregnancy test: for all females of childbearing potential Karnofsky scale assessment, Collect serum for cytokines/biomarkers. Visit 1: Day -7 (±3) before HSCT, initial PK: PK sampling day, only a single dose of CBD (i.e. one vial) to be given in the morning will be administered on that Day. Plasma Sampling: Blood samples will be obtained immediately prior to dosing (Time = 0) and at 15, 30, 45, 60, 120, 180, and 240 minutes, and 8, 12 and 24 hours after dosing of CBD Urine Sampling: two urine samples (3 mL each) will be obtained: 1) prior to CBD dosing, and 2) as an aliquot derived from a total urine collection in the first 12 hours after CBD dosing. Visit 2: Day -6, Conditioning and First full CBD Dose: Physical examination, Concomitant medications, Vital signs, 12 lead ECG, Weight Laboratory assessments: Biochemistry Panel: Liver Function Tests, Hematology Panel Safety: AE/SAE assessment and EUPHORIA assessment - Euphoria-related terms to predict potential Abuse-Related Adverse Events in Clinical Studies (the following will be evaluated: euphoric mood, elevated mood, feeling abnormal, feeling drunk, feeling of relaxation, dizziness, thinking abnormal, hallucination) Visit 3: Day 0 HSCT date: Physical examination, Concomitant medications Vital signs, 12 lead ECG, Laboratory assessments, Biochemistry Panel: Liver Function Tests, Hematology Panel, Coagulation, Cyclosporine trough levels, Dispensing and administration AE/SAE and EUPHORIA assessments, Collect serum for cytokines/biomarkers Visit 4: Day 7 post-HSCT: Physical examination, Concomitant medications, Vital signs, Cyclosporine trough levels GVHD evaluation, Dispensing and administration, AE/SAE and EUPHORIA assessments, PK sampling, Urine sampling Visit 5: Day 14 post-HSCT: Physical examination, Concomitant medications, Vital signs Laboratory assessments: Biochemistry, Hematology, CMV testing should start on day 14±3/Visit #5 and be carried out every 14 days, until study visit # 17 inclusively and on study visits 19-21 Cyclosporine trough levels, GVHD evaluation, IMP Dispensing and administration AE/SAE and EUPHORIA assessments Visit 6, 8, 10, 12 and 14: Days 21, 35, 49, 63 and 77) post-HSCT: Physical examination, Concomitant medications, Vital signs, Laboratory assessments Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration AE/SAE and EUPHORIA assessments, CMV reactivation (PCR) Visit 7: Day 28, 1M post-HSCT: Physical examination, Concomitant medications Vital signs, 12 lead ECG, Biochemistry, Hematolog, Cyclosporine trough levels GVHD evaluation, Donor chimerism evaluation, CBD Dispensing and administration Karnofsky scale assessment, AE/SAE and EUPHORIA assessments, CMV reactivation (PCR) Collect serum for cytokines/biomarkers Visit 9 and 13: Days 42 and 70 post-HSCT: Physical examination, Concomitant medications, Vital signs, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration AE/SAE and EUPHORIA assessments, CMV reactivation (PCR) Visit 11: D56, 2M post-HSCT: Physical examination, Concomitant medications, Vital signs 12 lead ECG, Weight, Biochemistry, Hematology, Coagulation, Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration, Karnofsky scale assessment, AE/SAE and EUPHORIA assessments, CMV reactivation (PCR), Collect serum for cytokines/biomarkers Visit 12-14: Days 63, 70 and 77 post-HSCT: Physical examination, Concomitant medications Vital signs, Biochemistry Panel, Hematology Panel, Cyclosporine trough levels GVHD evaluation, CBD Dispensing and administration, AE/SAE and EUPHORIA assessments CMV reactivation (PCR) at Visit 13/Day 77 ONLY Visit 15: D84, 3M post-HSCT: Physical examination, Concomitant medications, Vital signs Weight, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation, CBD Dispensing and administration, AE/SAE and EUPHORIA assessments Visit 16: Day 91, Last CBD administration: Physical examination, Concomitant medications Vital signs, 12 lead ECG, Biochemistry, Hematology, Cyclosporine trough levels GVHD evaluation, CBD Dispensing and administration, AE/SAE and EUPHORIA assessments Visit 17: Day 98/No IMP dosing: Physical examination, Concomitant medications, Vital signs, Biochemistry, Hematology, Coagulation, Cyclosporine trough levels, GVHD evaluation, Donor chimerism evaluation in bone marrow or peripheral blood. Karnofsky scale assessment, AE/SAE and EUPHORIA assessments, CMV reactivation (PCR), Collect serum for cytokines/biomarkers Visit 18: D105, Safety FU: Physical examination, Concomitant medications, Vital signs Weight, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation AE/SAE assessment Visits 19-21: Days 130, 155 and 180, Safety FU: Concomitant medications, Vital signs, Biochemistry, Hematology, Cyclosporine trough levels, GVHD evaluation, Karnofsky scale assessment, AE/SAE assessment