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

Sirolimus and Mycophenolate Mofetil as GvHD Prophylaxis in Myeloablative, Matched Related Donor Hematopoietic Cell Transplantation

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)

Study Overview

• Status: Terminated
• Conditions: Hematologic Diseases; Leukemia; Hodgkin Lymphoma; Acute-graft-versus-host Disease; Non-Hodgkin Lymphoma (NHL)
• Intervention / Treatment: Drug: Sirolimus; Drug: Mycophenolate mofetil (MMF); Drug: Carmustine; Drug: Etoposide; Drug: Cyclophosphamide (Cyclo, CY); Drug: FTBI

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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 Names: 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: Endoxan; Cytophosphane
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 Names: 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: Endoxan; Cytophosphane; Drug: FTBI; For FTBI + Cyclophosphamide cohort, administered as 1320 cGy delivered in 11 120 cGy fractions over 4 days starting on Day -7.; Other Names: total body irradiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	100 days post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	100 days post-transplant
Disease-free Survival (DFS)	Assessed as survival without recurrence of disease	2 years
Overall Survival	Overall survival is defined as time from enrollment to time of death or last follow-up, within 2 years.	2 years
Veno-occlusive Disease (VoD)	Assessed as the incidence of veno-occlusive disease (VoD) at 100 days post-transplant.	100 days post-transplant

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Laura Johnston, Stanford University

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: November 24, 2009
• First Submitted That Met QC Criteria: October 11, 2010
• First Posted (Estimate): October 13, 2010

Study Record Updates

• Last Update Posted (Actual): June 5, 2017
• Last Update Submitted That Met QC Criteria: May 31, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Hematologic Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Cyclophosphamide; Etoposide; Etoposide phosphate; Mycophenolic Acid; Sirolimus; Carmustine
• Other Study ID Numbers: IRB-14913; SU-09092009-3841 (Other Identifier: Stanford University); BMT209 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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