Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT

Phase 1

Terminated

• Conditions: Adult Hodgkin Lymphoma; Adult Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Hodgkin Lymphoma; Childhood Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelofibrosis; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia
• Interventions: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Drug: Sirolimus

• Registration Number: NCT02728700
• Lead Sponsor: Stanford University

Brief Summary

This pilot phase I/II trial studies the side effects and how well sirolimus and mycophenolate mofetil work in preventing graft versus host disease (GvHD) in patients with hematologic malignancies undergoing hematopoietic stem cell transplant (HSCT). Biological therapies, such as sirolimus and mycophenolate mofetil, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Giving sirolimus and mycophenolate mofetil after hematopoietic stem cell transplant may be better in preventing graft-versus-host disease.

Detailed Description

PRIMARY OBJECTIVES:

I. Evaluate the safety and feasibility of administering sirolimus and mycophenolate mofetil (MMF) as prophylaxis of grade III-IV acute graft versus host disease (aGvHD) in patients undergoing mismatched unrelated and related donor hematopoietic stem cell transplant (HSCT).

OUTLINE:

Patients receive sirolimus orally (PO) starting on day -3, 3 times a week during hospitalization and then once a week for up to 6 months. Patients undergo HSCT on day 0. Patients also receive mycophenolate mofetil intravenously (IV) or PO three times a day (TID) on days 1-180. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 30, 60, 100, 180, 270, and 365, and then yearly thereafter.

Study Timeline

• Study Start: 2016-02
• Study First Submitted: 2016-03-30
• Study First Submitted QC: 2016-03-30
• Study First Posted: 2016-04-05
• Primary Completion: 2017-04
• Study Completion: 2018-07
• Status Verified: 2018-08
• Last Update Submitted: 2018-09-10
• Last Update Posted: 2018-09-12

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 1

Inclusion Criteria

• Subjects must have one of the following disease categories:

  • Acute myeloid leukemia (AML) beyond 2nd remission or relapsed/refractory disease
  • Acute lymphoblastic leukemia (ALL) beyond 2nd remission or relapsed/refractory disease
  • Chronic myeloid leukemia (CML) beyond 2nd chronic phase or in blast crises
  • Myelodysplastic syndrome (MDS)
  • Myeloproliferative disorders including myeloid metaplasia and myelofibrosis
  • High risk non-Hodgkin's lymphoma (NHL) in first remission
  • Relapsed or refractory NHL
  • Hodgkin's lymphoma (HL) beyond first remission

• Performance status by Karnofsky of >= 70% or Lansky > 70% for patients < 16 years of age

• Human leukocyte antigen (HLA) mismatched related or unrelated donor identified 8/10 or 9/10

• Willingness to take oral medications during the transplantation period

• Willingness and ability to sign a written informed consent (assent if applicable)

Exclusion Criteria

• Prior myeloablative allogeneic or autologous HSCT
• Human immunodeficiency virus (HIV) infection
• Pregnant or lactating females
• Evidence of uncontrolled active infection
• Down syndrome
• Serum creatinine (CR) < 1.5mg/dl or 24 hour CR clearance < 50 ml/min
• Direct bilirubin > 2 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN
• Carbon monoxide diffusing capability test (DLCO) > 60% predicted and in children- room air oxygen saturation > 92%
• Left ventricular ejection fraction < 45% and in children-shortening fraction < 26%
• Fasting cholesterol > 300 mg/dl or triglycerides > 300 while on lipid lowering agents
• Patients who have received an investigational drug within 30 days of enrollment in study
• Patients with prior malignancies except basal cell carcinoma or treated carcinoma in-situ; cancer treated with curative intent > 5 years will be allowed; cancer treatment with curative intent =< 5 years will not be allowed

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (sirolimus, HSCT, MMF)	Allogeneic Hematopoietic Stem Cell Transplantation	Patients receive sirolimus PO starting on day -3, 3 times a week during hospitalization and then once a week for up to 6 months. Patients undergo HSCT on day 0. Patients also receive mycophenolate mofetil IV or PO TID on days 1-180. Treatment continues in the absence of disease progression or unacceptable toxicity.
Treatment (sirolimus, HSCT, MMF)	Laboratory Biomarker Analysis	Patients receive sirolimus PO starting on day -3, 3 times a week during hospitalization and then once a week for up to 6 months. Patients undergo HSCT on day 0. Patients also receive mycophenolate mofetil IV or PO TID on days 1-180. Treatment continues in the absence of disease progression or unacceptable toxicity.
Treatment (sirolimus, HSCT, MMF)	Mycophenolate Mofetil	Patients receive sirolimus PO starting on day -3, 3 times a week during hospitalization and then once a week for up to 6 months. Patients undergo HSCT on day 0. Patients also receive mycophenolate mofetil IV or PO TID on days 1-180. Treatment continues in the absence of disease progression or unacceptable toxicity.
Treatment (sirolimus, HSCT, MMF)	Sirolimus	Patients receive sirolimus PO starting on day -3, 3 times a week during hospitalization and then once a week for up to 6 months. Patients undergo HSCT on day 0. Patients also receive mycophenolate mofetil IV or PO TID on days 1-180. Treatment continues in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Incidence of acute GvHD grade 3 & 4, according to the Glucksberg staging criteria	Up to 100 days post-transplant	Statistical analysis results will be reported using summary tables, figures, and data listings. Continuous variables will be summarized using the mean, standard deviation, median, minimum, and maximum.

Secondary Outcome Measures

Name	Time	Method
Incidence of thrombotic microangiopathy defined according to the bone marrow transplant clinical trials network toxicity committee	Up to 100 days	Defined as: red blood cell fragmentation and at least two schistocytes per high-power field on peripheral smear; concurrent increased serum lactate dehydrogenase measurement above institutional baseline; concurrent doubling of serum creatinine or 50% increase in creatinine clearance from baseline and/or neurological dysfunction without other explanations; and negative direct and indirect Coombs. Statistical analysis results will be reported using summary tables, figures, and data listings. Continuous variables will be summarized using the mean, standard deviation, median, minimum, and maximum.
Time to neutrophil engraftment defined as first of 3 consecutive days with the absolute neutrophil count is > 500/ul in the peripheral blood	Baseline to up to 100 days	Statistical analysis results will be reported using summary tables, figures, and data listings. Continuous variables will be summarized using the mean, standard deviation, median, minimum, and maximum.
Time to platelet engraftment defined as the first day of a minimum of three consecutive measurements on different days when platelet count > 50,000/mm^3 and patient is transfusion-independent for a minimum of 7 days	Baseline to up to 100 days	Statistical analysis results will be reported using summary tables, figures, and data listings. Continuous variables will be summarized using the mean, standard deviation, median, minimum, and maximum.
Incidence of venous-occlusive disease (VOD) using Modified Seattle Criteria	Up to 100 days	Severe VOD will be considered a dose limiting toxicity. Statistical analysis results will be reported using summary tables, figures, and data listings. Continuous variables will be summarized using the mean, standard deviation, median, minimum, and maximum.
Severity of mucositis determined by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03	Up to 100 days	Grade III and IV will be considered dose limiting toxicities. Statistical analysis results will be reported using summary tables, figures, and data listings. Categorical variables will be summarized by numbers and percentages of subjects in corresponding categories.

Trial Locations

Locations (1)

Stanford University, School of Medicine; 🇺🇸 Palo Alto, California, United States