Study to Evaluate the Safety and Effectiveness of Withaferin A as a Treatment to Prevent GvHD in Transplant Patients

GVHD - Graft-Versus-Host Disease, Hematological Malignancy, Hematopoietic Stem Cell Transplant (HSCT)

Standardized Withaferin A, Matched related donor Hematopoietic stem cell transplant

What is acute Graft versus host disease (aGvHD)? GvHD is a complication that can occur after an allogeneic stem cell transplant resulting in damage to some organs. The death rate of GvHD patients is 15-40%. In GvHD, the donated peripheral blood stem cells or bone marrow view the recipient's body as foreign, and the donated cells/bone marrow harm the body. aGvHD usually develops in skin, liver or gastrointestinal tract, and symptoms might appear within few weeks after transplant. Symptoms of acute GvHD are observed as skin rash or reddened areas on the skin, yellow discoloration of the skin and/or eyes, and abnormal blood test results, nausea, vomiting, diarrhea, or abdominal cramping. What is the current prevention used for GvHD? To prevent development of GvHD many standard drugs like cyclosporine (CSA), tacrolimus (TAC), methotrexate (MTX), mycophenolate mofetil (MMF), rapamycin and cyclophosphamide are given. What is standardized Withaferin-A (SWA)? Withaferin-A (WA) is the main active component of Withania somnifera (Ashwagandha). It has been shown in many studies to have properties of healing and immune-modulation (improving the immune system). Studies have been done in our Clinical Pharmacology Laboratory that have shown a significant beneficial effect of this drug, when added to the standard drugs used for prophylaxis of GvHD, on reducing the risk of acute GvHD. The drug has also been tested and proven to be very safe in humans. What is the rationale of this trial? As has been described earlier, GvHD is a difficult complication of allogeneic stem cell transplant which can lead to increased hospital stay and deaths post-transplant. The standard drugs for prevention of GvHD are cyclosporine (CSA), tacrolimus (TAC), methotrexate (MTX), mycophenolate mofetil (MMF), rapamycin and cyclophosphamide. These drugs also have some side effects during the course of transplant. This points out the need for new preventive drugs that are safe and effective. SWA is an oral formulation of WA which seems to be beneficial in the early studies done in the Clinical Pharmacology Laboratory, ACTREC. SWA has also been found to be safe at very high doses. SWA will be given along with the standard drugs given to prevent GvHD. Despite of consuming these drugs, about 40 - 60% patients still develop GvHD. The investigators aim to add SWA to these standard drugs during transplant to reduce significant aGvHD. How will SWA be given? Participants who agree to participate in this trial and are found to be eligible will be given SWA as a capsule at a dose of 500 mg/day (2 capsules of 250 mg) to 3000 mg/day (6 capsules of 250 mg) as per the dose level allotted to the Patient. The drug will be given for a total duration 90 days starting from Day +1 of transplant. All other standard treatments which are part of a transplant procedure will be carried out without any change. Participants will be monitored clinically for any adverse events and followed up as per standard protocols post-transplant. What additional tests will be carried out? Additional blood sampling to study the levels of the drug WA blood samples will be collected at 0, 1, 2, 4, 8 hours on the day of start of SWA (Day +1) and Day +7. Checking immune cell profile and cytokines (which are markers of - immunity levels) will be done at Day+30, Day +90, Day+180, Day+365 from the start of SWA which is also the part of routine care. Blood sample of 5 ml will also be taken at Day 0, Day +14, Day +30, Day +60 and Day +90 after start of drug to see level of some special protein called JAK2 STAT3 protein. What are the risks involved in participation? According to available literature and information, SWA is a safe and well tolerated drug. In a phase 1 study, Standardized Withaferin-A was administered to Patients with advanced stage osteosarcoma. The drug was well tolerated by Patient up to a dose of 4800 mg. No severe side effects were observed. Increase in liver enzymes and skin rash were the most common side effects. Other side effects included fatigue, fever, swelling, and diarrhea. What is the possible impact of this trial? If indeed SWA works and prevents GvHD effectively then this could be a breakthrough in treatment. It would help many Pateints to prevent GvHD post allogeneic stem cell transplant and would be a safe, easily available, inexpensive and oral drug for the same. This possibly could benefit and help future Patients who undergo bone marrow transplant (BMT) to have better chances of survival and reduce their financial burden.

Background :Acute graft versus host disease (aGvHD) is one of the most serious complications of allogeneic hematopoietic stem cell transplant (AHSCT) leading to high non relapse mortality (NRM). Withaferin A (WA) is the principal active component of Withania somnifera (Ashwagandha) and is known to have anti-inflammatory and immunomodulatory activity. WA use in GvHD prophylaxis may be beneficial, with the evidence from preclinical models. We designed this study to evaluate the efficacy and safety of oral WA in addition to the standard GvHD prophylaxis backbone in MRD transplants. Study design :Prospective, single arm, Phase I/II, non-randomized interventional study. Study population :Patients ≥ 18 years with any hematological malignancy, planned for MRD (10/10 match on high resolution typing) transplant will be enrolled . Treatment: SWA will be started from Day +1 to Day +90 in addition to the standard GvHD prophylaxis backbone of calcineurin inhibitor and methotrexate. Following standard dose escalation design, patients will be enrolled at 4 dose levels (500 mg OD, 1000 mg OD, 1500 mg OD and 1500 mg BD). Based on the toxicity, pharmacokinetic data and acute GvHD rates the dose will be fixed for the rest of the patients enrolled in the Phase 2 arm Note: Dose escalation: The dose escalation to the next dose level will be made after completion of Day + 30 of all three patients. The 30 days is the safety evaluation period for the determination of MTD which is standard for phase 1 trials Study assessments:1. Baseline CBC, biochemistry, PFT, 2D ECHO/MUGA, GFR and NCCT thorax will be done pre transplant 2. Till Day +100 - Twice weekly OPD follow up with CBC, biochemistry, CMV PCR, clinical evaluation for aGvHD features and toxicity features, engraftment details and chimerism assessment 3. Post-transplant Day 100-Day 365 - Weekly OPD follow up with CBC, biochemistry, CMV PCR, clinical evaluation for GvHD features and chimerism assessment on D+180, D+360 and then yearly basis. 4\. Disease status assessment by Bone marrow assessment / PET Scan on Day+90 and then at 1 year.

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