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Sirolimus & Mycophenolate Mofetil as GvHD Prophylaxis in Myeloablative, Matched Related Donor HCT

This study has been terminated.
(Low accrual)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01220297
First Posted: October 13, 2010
Last Update Posted: June 5, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Laura Johnston, Stanford University
  Purpose
A continuation study of sirolimus and mycophenolate mofetil (MMF) for graft-vs-host disease (GvHD) prophylaxis for patients undergoing matched related allogeneic hematopoietic stem cell transplantation (HSCT) for acute and chronic leukemia, myelodysplastic syndrome (MDS), high risk non-Hodgkin lymphoma (NHL), or Hodgkin lymphoma (HL)

Condition Intervention Phase
Hematologic Diseases Acute-graft-versus-host Disease Leukemia Non-Hodgkin Lymphoma (NHL) Hodgkin Lymphoma Drug: Sirolimus Drug: Mycophenolate mofetil (MMF) Drug: Carmustine Drug: Etoposide Drug: Cyclophosphamide (Cyclo, CY) Drug: FTBI Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sirolimus and Mycophenolate Mofetil as GvHD Prophylaxis in Myeloablative, Matched Related Donor Hematopoietic Cell Transplantation

Resource links provided by NLM:


Further study details as provided by Laura Johnston, Stanford University:

Primary Outcome Measures:
  • Acute Graft-vs-Host Disease (GvHD) (Grade 2 to 4) [ Time Frame: 100 days post-transplant ]

    Assessed as the incidence of grade 2 to 4 acute graft-vs-host disease (GvHD) at Day 100 post-transplant.

    Stage of Acute GvHD was assessed as follows.

    • Stage 1: Skin: rash < 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea > 500 mL/day or persistent nausea with positive biopsy for GvHD
    • Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea >1000 mL/day.
    • Stage 3: Skin: rash > 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea > 1500 mL/day.
    • Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin > 15 mg/dL. Gut: severe abdominal pain with or without ileus

    Grade of Acute GvHD was determined as follows.

    • Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage
    • Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut
    • Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut
    • Grade 4: Stage 4 Skin + or Stage 2 to 3 Liver + No Gut stage


Secondary Outcome Measures:
  • Acute GvHD (Grade 3 to 4) [ Time Frame: 100 days post-transplant ]

    Assessed as the incidence of grade 3 to 4 acute GvHD at Day 100 post-transplant.

    Stage of Acute GvHD was assessed as follows.

    • Stage 1: Skin: rash < 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea > 500 mL/day or persistent nausea with positive biopsy for GvHD
    • Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea >1000 mL/day.
    • Stage 3: Skin: rash > 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea > 1500 mL/day.
    • Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin > 15 mg/dL. Gut: severe abdominal pain with or without ileus

    Grade of Acute GvHD was determined as follows.

    • Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage
    • Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut
    • Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut
    • Grade 4: Stage 4 Skin + or Stage 2 to 3 Liver + No Gut stage

  • Disease-free Survival (DFS) [ Time Frame: 2 years ]
    Assessed as survival without recurrence of disease

  • Overall Survival [ Time Frame: 2 years ]
    Overall survival is defined as time from enrollment to time of death or last follow-up, within 2 years.

  • Veno-occlusive Disease (VoD) [ Time Frame: 100 days post-transplant ]
    Assessed as the incidence of veno-occlusive disease (VoD) at 100 days post-transplant.


Enrollment: 3
Study Start Date: August 2006
Study Completion Date: August 2011
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Carmustine Etoposide Cyclophosphamide
Carmustine + Etoposide + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis.
Drug: Sirolimus

Immunosuppressant administered orally to:

  • Adults (age 14 and older), beginning on Day -3 with 12 mg loading dose, followed by 4 mg/day.
  • Children < 13 years or weighing 40 kg, beginning on Day -3 with 3 mg/m² loading dose, followed by 1 mg/ m², rounded to the nearest full milligram.

Daily dosage may be adjusted to maintain a target serum trough level of 3 to 12 ng/ml. Sirolimus dose tapering will begin at Day 100 in the absence of GvHD, with the goal of discontinuation by 6 months.

Other Names:
  • Rapamycin
  • Rapamune
Drug: Mycophenolate mofetil (MMF)
Immunosuppressant given intravenously (IV) at 15 mg/kg 3 times daily, starting on Day 0 ≥ 2 hr after the completion of the HSCT infusion. Dose of MMF will be based on actual body weight, but limited to 15 kg above ideal body weight. MMF dose tapering will begin at Day 100 in the absence of GvHD, with the goal of discontinuation by 6 months.
Other Name: Cellcept
Drug: Carmustine
For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -6 at the lesser of 15 mg/kg or 550 mg/m².
Other Name: Bis-chloroethylnitrosourea (BCNU, BiCNU)
Drug: Etoposide
For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -4 at 60 mg/kg
Other Names:
  • VP-16
  • VP16
Drug: Cyclophosphamide (Cyclo, CY)

Cyclophosphamide is a chemotherapy agent.

For FTBI + Cyclophosphamide cohort, administered IV on Day -3 and -2 at 60 mg/kg.

For Carmustine + Etoposide + Cyclophosphamide cohort, administered IV on Day -2 at 100 mg/kg

Other Names:
  • Cytophosphane
  • Endoxan
Experimental: FTBI + Cyclophosphamide
FTBI + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis.
Drug: Sirolimus

Immunosuppressant administered orally to:

  • Adults (age 14 and older), beginning on Day -3 with 12 mg loading dose, followed by 4 mg/day.
  • Children < 13 years or weighing 40 kg, beginning on Day -3 with 3 mg/m² loading dose, followed by 1 mg/ m², rounded to the nearest full milligram.

Daily dosage may be adjusted to maintain a target serum trough level of 3 to 12 ng/ml. Sirolimus dose tapering will begin at Day 100 in the absence of GvHD, with the goal of discontinuation by 6 months.

Other Names:
  • Rapamycin
  • Rapamune
Drug: Mycophenolate mofetil (MMF)
Immunosuppressant given intravenously (IV) at 15 mg/kg 3 times daily, starting on Day 0 ≥ 2 hr after the completion of the HSCT infusion. Dose of MMF will be based on actual body weight, but limited to 15 kg above ideal body weight. MMF dose tapering will begin at Day 100 in the absence of GvHD, with the goal of discontinuation by 6 months.
Other Name: Cellcept
Drug: Cyclophosphamide (Cyclo, CY)

Cyclophosphamide is a chemotherapy agent.

For FTBI + Cyclophosphamide cohort, administered IV on Day -3 and -2 at 60 mg/kg.

For Carmustine + Etoposide + Cyclophosphamide cohort, administered IV on Day -2 at 100 mg/kg

Other Names:
  • Cytophosphane
  • Endoxan
Drug: FTBI
For FTBI + Cyclophosphamide cohort, administered as 1320 cGy delivered in 11 120 cGy fractions over 4 days starting on Day -7.
Other Name: total body irradiation

Detailed Description:

To explore the novel combination of sirolimus and mycophenolate mofetil (MMF) as graft-vs-host disease (GvHD) prevention in human leukocyte antigen (HLA)-matched related donor peripheral blood stem cell (PBSC) or marrow transplantation (BMT), collectively hematopoietic stem cell transplantation (HSCT). This study will report the toxicities associated with this drug combination.

For all treatments and procedures, Study Day is based on the day of HSCT as Day 0.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   2 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

  • Acute myelogenous leukemia (AML), beyond 2nd remission or relapsed/refractory disease, age 2 to 60 years
  • AML, in first or subsequent remission or relapsed/refractory disease, age 51 to 60 years of age
  • AML with multilineage dysplasia
  • Acute lymphoblastic leukemia (ALL), beyond 2nd remission or relapsed/refractory disease, age 2 to 60 years
  • ALL, age 51 - 60 years in first or subsequent remission or relapsed/refractory disease
  • Chronic myeloid leukemia (CML), beyond 2nd chronic phase or in blast crisis
  • Myelodysplastic syndrome (MDS), including World Health Organization (WHO)classifications of refractory anemia with excess blasts-1 (RAEB-1), RAEB-2 and therapy-related MDS
  • MDS with poor long-term survival including myeloid metaplasia and myelofibrosis
  • Myeloproliferative disorders
  • High-risk non-Hodgkin lymphoma (NHL) in 1st emission
  • Relapsed or refractory NHL
  • Hodgkin lymphoma (HL) beyond first remission
  • Males and females of any ethnic background, 2 to 60 years of age
  • Karnofsky Performance Status (KPS) ≥ 70% or Lansky performance status > 70% for patients < 16 years of age.
  • Related, matched-donor identified [6/6 human leukocyte antigen (HLA)-A, B and DRB1]
  • Willingness to take oral medications during the transplantation period
  • Ability to understand and the willingness to sign a written informed consent document

EXCLUSION CRITERIA

  • Prior myeloablative allogeneic or autologous hematopoietic stem cell transplant (HSCT)
  • HIV infection
  • Pregnant
  • Lactating
  • Evidence of uncontrolled active infection
  • Serum creatinine > 1.5 mg/dL or 24-hour creatinine clearance < 50 mL/min
  • Direct bilirubin, Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 x upper limit of normal (ULN)
  • Carbon monoxide diffusing capacity (DlCO) < 60% predicted (adults) OR and in-room air oxygen saturation < 92% (children)
  • Left ventricular ejection fraction < 45% (adults) OR shortening fraction < 26%(children)
  • Fasting cholesterol > 300 mg/dL or Triglycerides > 300 mg/dL while on lipid-lowering agents.
  • Receiving investigational drugs unless cleared by the Principal Investigator (PI).
  • Prior malignancies except basal cell carcinoma or treated carcinoma in-situ.
  • Cancer treated with curative intent ≤ 5 years (EXCEPTION BY PI DISCRETION) (Cancer treated with curative intent > 5 years will be allowed).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01220297


Locations
United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Stanford University
Investigators
Principal Investigator: Laura Johnston Stanford University
  More Information

Responsible Party: Laura Johnston, Associate Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT01220297     History of Changes
Other Study ID Numbers: IRB-14913
SU-09092009-3841 ( Other Identifier: Stanford University )
BMT209 ( Other Identifier: OnCore )
First Submitted: November 24, 2009
First Posted: October 13, 2010
Results First Submitted: March 13, 2017
Results First Posted: June 5, 2017
Last Update Posted: June 5, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Hodgkin Disease
Graft vs Host Disease
Hematologic Diseases
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Sirolimus
Everolimus
Carmustine
Etoposide phosphate
Etoposide
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors