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

Primary Purpose

Hematologic Diseases, Acute-graft-versus-host Disease, Leukemia

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Mycophenolate mofetil (MMF)
Carmustine
Etoposide
Cyclophosphamide (Cyclo, CY)
FTBI
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematologic Diseases

Eligibility Criteria

2 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Stanford University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Carmustine Etoposide Cyclophosphamide

FTBI + Cyclophosphamide

Arm Description

Carmustine + Etoposide + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis.

FTBI + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis.

Outcomes

Primary Outcome Measures

Acute Graft-vs-Host Disease (GvHD) (Grade 2 to 4)
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)
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)
Assessed as survival without recurrence of disease
Overall Survival
Overall survival is defined as time from enrollment to time of death or last follow-up, within 2 years.
Veno-occlusive Disease (VoD)
Assessed as the incidence of veno-occlusive disease (VoD) at 100 days post-transplant.

Full Information

First Posted
November 24, 2009
Last Updated
May 31, 2017
Sponsor
Stanford University
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1. Study Identification

Unique Protocol Identification Number
NCT01220297
Brief Title
Sirolimus & Mycophenolate Mofetil as GvHD Prophylaxis in Myeloablative, Matched Related Donor HCT
Official Title
Sirolimus and Mycophenolate Mofetil as GvHD Prophylaxis in Myeloablative, Matched Related Donor Hematopoietic Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Terminated
Why Stopped
Low accrual
Study Start Date
August 2006 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
August 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
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)
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematologic Diseases, Acute-graft-versus-host Disease, Leukemia, Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Carmustine Etoposide Cyclophosphamide
Arm Type
Experimental
Arm Description
Carmustine + Etoposide + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis.
Arm Title
FTBI + Cyclophosphamide
Arm Type
Experimental
Arm Description
FTBI + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin, Rapamune
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Other Intervention Name(s)
Cellcept
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Carmustine
Other Intervention Name(s)
Bis-chloroethylnitrosourea (BCNU, BiCNU)
Intervention Description
For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -6 at the lesser of 15 mg/kg or 550 mg/m².
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
VP-16, VP16
Intervention Description
For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -4 at 60 mg/kg
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide (Cyclo, CY)
Other Intervention Name(s)
Cytophosphane, Endoxan
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
FTBI
Other Intervention Name(s)
total body irradiation
Intervention Description
For FTBI + Cyclophosphamide cohort, administered as 1320 cGy delivered in 11 120 cGy fractions over 4 days starting on Day -7.
Primary Outcome Measure Information:
Title
Acute Graft-vs-Host Disease (GvHD) (Grade 2 to 4)
Description
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
Time Frame
100 days post-transplant
Secondary Outcome Measure Information:
Title
Acute GvHD (Grade 3 to 4)
Description
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
Time Frame
100 days post-transplant
Title
Disease-free Survival (DFS)
Description
Assessed as survival without recurrence of disease
Time Frame
2 years
Title
Overall Survival
Description
Overall survival is defined as time from enrollment to time of death or last follow-up, within 2 years.
Time Frame
2 years
Title
Veno-occlusive Disease (VoD)
Description
Assessed as the incidence of veno-occlusive disease (VoD) at 100 days post-transplant.
Time Frame
100 days post-transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility 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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Laura Johnston
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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