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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hematologic Diseases, Acute-graft-versus-host Disease, Leukemia, Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Mycophenolate mofetil (MMF)
* Drug: Carmustine
* Drug: Etoposide
* Drug: Cyclophosphamide (Cyclo, CY)
* Drug: FTBI


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carmustine Etoposide Cyclophosphamide<br>Carmustine + Etoposide + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis. | Drug: Sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: Mycophenolate mofetil (MMF)<br>* 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.<br>* Other names: Cellcept;Drug: Carmustine<br>* For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -6 at the lesser of 15 mg/kg or 550 mg/m².<br>* Other names: Bis-chloroethylnitrosourea (BCNU, BiCNU);Drug: Etoposide<br>* For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -4 at 60 mg/kg<br>* Other names: VP16;Drug: Cyclophosphamide (Cyclo, CY)<br>* 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<br>* Other names: Endoxan;|
| Experimental: FTBI + Cyclophosphamide<br>FTBI + Cyclophosphamide followed by Sirolimus and Mycophenolate mofetil (MMF) as prophylaxis. | Drug: Sirolimus<br>* 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.<br>* Other names: Rapamune;Drug: Mycophenolate mofetil (MMF)<br>* 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.<br>* Other names: Cellcept;Drug: Cyclophosphamide (Cyclo, CY)<br>* 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<br>* Other names: Endoxan;Drug: FTBI<br>* For FTBI + Cyclophosphamide cohort, administered as 1320 cGy delivered in 11 120 cGy fractions over 4 days starting on Day -7.<br>* Other names: total body irradiation;|

What is the study measuring?
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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 |