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

20 juli 2026 bijgewerkt door: Akanksha Chichra, Tata Memorial Centre

A Phase I/II Trial to Assess Safety and Activity of Standardized Withaferin A as GvHD Prophylaxis in Patients Undergoing 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.

Studie Overzicht

Toestand

Werving

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

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.

Studietype

Ingrijpend

Inschrijving (Geschat)

54

Fase

  • Fase 2
  • Fase 1

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

  • Naam: Dr Akanksha Chichra, FNB, DNB Pediatric oncology
  • Telefoonnummer: 8686 91 22- 68735000
  • E-mail: akanksha7@hotmail.com

Studie Contact Back-up

  • Naam: Dr Sachin Punatar, MBBS MD DM Medical Oncology
  • Telefoonnummer: 8686 91 22- 68735000
  • E-mail: drsachin_punatar@yahoo.in

Studie Locaties

  • Indië
    • Maharashtra
      • Navi Mumbai, Maharashtra, Indië, 410210
        • Werving
        • Advanced Centre for Treatment, Research and Education in Cancer
        • Contact:
        • Contact:

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Beschrijving

Inclusion Criteria:

  1. ECOG performance score of 0 or 1
  2. 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)
  3. Adequate renal function (creatinine clearance > 50 ml/min)
  4. Adequate cardiac function (LVEF>40%)
  5. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration.
  6. Signed, written informed consent

Exclusion Criteria: -

  1. Known hypersensitivity or contraindications against Withaferin-A.
  2. 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.
  3. Any medical or psychiatric illness which precludes the participant from giving informed consent
  4. Pregnancy, lactation, or inadequate contraception.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Preventie
  • Toewijzing: NVT
  • Interventioneel model: Opdracht voor een enkele groep
  • Masker: Geen (open label)

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: SWA (standardized root extract of Withania somnifera)
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).
Geneesmiddel: SWA (standardized root extract of Withania somnifera)
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

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Safety and tolerability of oral SWA
Tijdsspanne: Day 1 to Day 90
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
Tijdsspanne: During PK sampling (Phase I)
Maximum observed plasma concentration following oral administration
During PK sampling (Phase I)
Area Under the Plasma Concentration-Time Curve (AUC)
Tijdsspanne: During PK sampling (Phase I)
Area under the plasma concentration-time curve of Withaferin A
During PK sampling (Phase I)
Recommended Phase II Dose (RP2D)
Tijdsspanne: By completion of Phase I (Day 90)
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)
Tijdsspanne: Day 100 post-transplant
Incidence of Grade 2-4 acute GvHD according to standard grading criteria
Day 100 post-transplant

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Cumulative incidence of severe acute GvHD (Grade 3-4)
Tijdsspanne: Day 100 and Day 180
Incidence of Grade 3-4 acute GvHD
Day 100 and Day 180
GvHD-free and relapse-free survival (GRFS
Tijdsspanne: 1 year
Participants alive without Grade III-IV acute GvHD, chronic GvHD requiring systemic therapy, relapse, or death
1 year
Incidence of chronic GvHD
Tijdsspanne: 1 year
Incidence of chronic GvHD according to NIH criteria
1 year
Time to neutrophil engraftment
Tijdsspanne: Up to Day 30 post-transplant
Time to neutrophil engraftment, defined as the first of three consecutive days with an absolute neutrophil count (ANC) >500 cells/mm³ following hematopoietic stem cell transplantation.
Up to Day 30 post-transplant
Time to platelet engraftment
Tijdsspanne: Up to Day 100 post-transplant
Time to platelet engraftment, defined as the first day of a platelet count >20,000 cells/mm³ without platelet transfusion during the preceding 7 days.
Up to Day 100 post-transplant
Non-relapse mortality (NRM)
Tijdsspanne: 1 year
Death without prior disease relapse
1 year
Overall survival (OS)
Tijdsspanne: 1 year
Time from transplant until death from any cause
1 year

Andere uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
JAK2-STAT3 pathway activity
Tijdsspanne: Baseline, Day +14, Day +30, Day +60, Day +90
Changes in JAK2-STAT3 signaling levels following SWA prophylaxis
Baseline, Day +14, Day +30, Day +60, Day +90
Immune cell phenotyping
Tijdsspanne: Day +30, Day +90, Day +180, Day +365
Changes in immune cell subsets after SWA prophylaxis
Day +30, Day +90, Day +180, Day +365

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Tata Memorial Centre

Medewerkers

Indian Council of Medical Research

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Nuttige links

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

28 januari 2025

Primaire voltooiing (Geschat)

3 december 2029

Studie voltooiing (Geschat)

3 december 2029

Studieregistratiedata

Eerst ingediend

11 juli 2026

Eerst ingediend dat voldeed aan de QC-criteria

20 juli 2026

Eerst geplaatst (Werkelijk)

24 juli 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

24 juli 2026

Laatste update ingediend die voldeed aan QC-criteria

20 juli 2026

Laatst geverifieerd

1 juli 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • 901067

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Beschrijving IPD-plan

At this time, we do not plan to share individual participant data (IPD) due to concerns regarding patient privacy, the regulatory requirements for data sharing for maintaining patient confidentiality

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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