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

NCT07724873 | Recruiting Phase 1 DMC

• 1 other identifier: 901067
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

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

Keywords

Standardized Withaferin A; Matched related donor Hematopoietic stem cell transplant

Outcome Measures

Primary Outcomes (5)

• Safety and tolerability of oral SWA

  Incidence of treatment-emergent adverse events (TEAEs), including Grade ≥3 adverse events assessed using CTCAE v5.0 and PRO-CTCAE v1.0

  Day 1 to Day 90

• Peak plasma concentration (Cmax) of Withaferin A

  Maximum observed plasma concentration following oral administration

  During PK sampling (Phase I)

• Area Under the Plasma Concentration-Time Curve (AUC)

  Area under the plasma concentration-time curve of Withaferin A

  During PK sampling (Phase I)

• Recommended Phase II Dose (RP2D)

  RP2D determined based on safety, tolerability and PK findings

  By completion of Phase I (Day 90)

• Cumulative incidence of clinically significant acute GvHD (Grade 2-4)

  Incidence of Grade 2-4 acute GvHD according to standard grading criteria

  Day 100 post-transplant

Secondary Outcomes (7)

• Cumulative incidence of severe acute GvHD (Grade 3-4)

  Day 100 and Day 180

• GvHD-free and relapse-free survival (GRFS

  1 year

• Incidence of chronic GvHD

  1 year

• Time to neutrophil engraftment

  Up to Day 30 post-transplant

• Time to platelet engraftment

  Up to Day 100 post-transplant

Other Outcomes (2)

• JAK2-STAT3 pathway activity

  Baseline, Day +14, Day +30, Day +60, Day +90

• Immune cell phenotyping

  Day +30, Day +90, Day +180, Day +365

Study Arms (1)

SWA (standardized root extract of Withania somnifera)

EXPERIMENTAL

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).

Drug: SWA (standardized root extract of Withania somnifera)

Interventions

SWA (standardized root extract of Withania somnifera) DRUG

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

SWA (standardized root extract of Withania somnifera)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ECOG performance score of 0 or 1
• Adequate liver function (Total serum bilirubin \< twice upper normal limit or Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \< 3-fold higher than laboratory upper normal limits)
• Adequate renal function (creatinine clearance \> 50 ml/min)
• Adequate cardiac function (LVEF\>40%)
• Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration.
• Signed, written informed consent

You may not qualify if:

• Known hypersensitivity or contraindications against Withaferin-A.
• Presence of an active uncontrolled infection defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection.
• Any medical or psychiatric illness which precludes the participant from giving informed consent
• Pregnancy, lactation, or inadequate contraception.

Sponsors & Collaborators

• Tata Memorial Centre: lead
• Indian Council of Medical Research: collaborator

Study Sites (2)

Advanced Centre for Treatment, Research and Education in Cancer

Navi Mumbai, Maharashtra, 410210, India

RECRUITING

Advanced Centre for Treatment, Research and Education in Cancer

Navi Mumbai, Maharashtra, 410210, India

RECRUITING

Related Publications (26)

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• Gambhir L, Checker R, Sharma D, Thoh M, Patil A, Degani M, Gota V, Sandur SK. Thiol dependent NF-kappaB suppression and inhibition of T-cell mediated adaptive immune responses by a naturally occurring steroidal lactone Withaferin A. Toxicol Appl Pharmacol. 2015 Dec 1;289(2):297-312. doi: 10.1016/j.taap.2015.09.014. Epub 2015 Sep 25.

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• Straughn AR, Kakar SS. Withaferin A: a potential therapeutic agent against COVID-19 infection. J Ovarian Res. 2020 Jul 19;13(1):79. doi: 10.1186/s13048-020-00684-x.

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• Mehta M, Gohil D, Khattry N, Kumar R, Sandur S, Sharma D, Checker R, Agarwal B, Jha D, Majumdar A, Gota V. Prevention of acute graft-versus-host-disease by Withaferin a via suppression of AKT/mTOR pathway. Int Immunopharmacol. 2020 Jul;84:106575. doi: 10.1016/j.intimp.2020.106575. Epub 2020 May 13.

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Related Links

• CTRI/2024/12/078211 \[Registered on: 17/12/2024\]

MeSH Terms

Conditions

Graft vs Host Disease; Hematologic Neoplasms

Condition Hierarchy (Ancestors)

Immune System Diseases; Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Central Study Contacts

Dr Akanksha Chichra, FNB, DNB Pediatric oncology

CONTACT

91 22- 68735000; akanksha7@hotmail.com

Dr Sachin Punatar, MBBS MD DM Medical Oncology

CONTACT

91 22- 68735000; drsachin_punatar@yahoo.in

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate professor Pediatric oncology

Model Details: Prospective, single arm, Phase I/II interventional study

Study Record Dates

• First Submitted: July 11, 2026
• First Posted: July 24, 2026
• Study Start: January 28, 2025
• Primary Completion (Estimated): December 3, 2029
• Study Completion (Estimated): December 3, 2029
• Last Updated: July 24, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

IN (2)