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

Sponsor

Stanford University (Other)

Overall Status

Completed

CT.gov ID

NCT00350181

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

GVHD prophylaxis of sirolimus and mycophenolate mofetil for patients undergoing matched related allogeneic transplant for acute and chronic leukemia, MDS, high risk NHL and HL

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma, Non-Hodgkin Hematologic Diseases Acute GVHD	Drug: Sirolimus Drug: MMF Drug: BCNU Drug: VP-16 Drug: CY Drug: FTBI Drug: BU	Phase 2

Detailed Description

To explore the novel combination of sirolimus and mycophenolate mofetil (MMF) as graft versus host disease (GVHD) prevention in HLA matched related donor blood or marrow transplantation (BMT). This study will report the toxicities associated with this drug combination and also explore possible correlations between specific blood cell types and antibody production during this therapy.

Study Design

Study Type:

Interventional

Actual Enrollment :

11 participants

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

Study Start Date :

Aug 1, 2006

Actual Primary Completion Date :

Aug 1, 2007

Actual Study Completion Date :

Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen Treatment 1 For subjects 18-60 years old with lymphoma: (BCNU+ VP-16 +CY) BCNU 15 mg / kg (maximum dose 550 mg/m² actual body weight) on day -6. VP 60 mg / kg on day 4 and CY 100 mg / kg on day -2. Followed by Sirolimus and MMF as prophylaxis	Drug: Sirolimus Immunosuppressant beginning day -3 with 12 mg oral loading dose, 4 mg/day orally for adults Other Names: rapamycin Drug: MMF Immunosuppressant given through IV on day 0 at 15 mg/kg twice daily ≥ 2hr after the completion for the donor cell infusion Other Names: Mycophenolate Mofetil Drug: BCNU 15 mg/kg, IV Other Names: Carmustine BiCNU Drug: VP-16 60 mg/kg, IV Other Names: etoposide Drug: CY For subjects aged 18-60 with lymphoma 100 mg/kg, IV For subjects aged with AML, ALL or CML 18-50 60 mg/kg, IV For subjects aged 51-60 with MDS, AML or ALL or patients age 18-60 with MDS, secondary AML or non-CML myeloproliferative disease 45 mg/kg Other Names: cyclophosphamide cytophosphane Endoxan
Experimental: Regimen Treatment 2 For subjects 18-50 years old with AML, ALL or CML: (VP-16 +CY+ FBI) Patients aged 18-50 years with AML, ALL or CML: FTBI 1320 cGy delivered in 11 120 cGy fractions over 4 days on days -8 through -5. VP 60 mg / kg on day -4 and CY 60 mg / kg on day -2. Followed by Sirolimus and MMF as prophylaxis	Drug: Sirolimus Immunosuppressant beginning day -3 with 12 mg oral loading dose, 4 mg/day orally for adults Other Names: rapamycin Drug: MMF Immunosuppressant given through IV on day 0 at 15 mg/kg twice daily ≥ 2hr after the completion for the donor cell infusion Other Names: Mycophenolate Mofetil Drug: VP-16 60 mg/kg, IV Other Names: etoposide Drug: CY For subjects aged 18-60 with lymphoma 100 mg/kg, IV For subjects aged with AML, ALL or CML 18-50 60 mg/kg, IV For subjects aged 51-60 with MDS, AML or ALL or patients age 18-60 with MDS, secondary AML or non-CML myeloproliferative disease 45 mg/kg Other Names: cyclophosphamide cytophosphane Endoxan Drug: FTBI 1320 cGy delivered in 11 120 cGy fractions over 4 day Other Names: total body irradiation
Experimental: Regimen Treatment 3 For subjects 51-60 years with MDS, AML or ALL or 18-60 with MDS, secondary AML pr non-CML myeloproliferative disease: (BU+ VP-16 +CY) BU 1 mg/kg every 6 hours X 14 doses on days -9 through -6 with target concentration at steady state of X 800 ng / ml based on first dose pharmacokinetics. VP 60 mg / kg on day -5 and CY 45 mg / kg per day -2 days on day -3 and day -2. Followed by Sirolimus and MMF as prophylaxis	Drug: Sirolimus Immunosuppressant beginning day -3 with 12 mg oral loading dose, 4 mg/day orally for adults Other Names: rapamycin Drug: MMF Immunosuppressant given through IV on day 0 at 15 mg/kg twice daily ≥ 2hr after the completion for the donor cell infusion Other Names: Mycophenolate Mofetil Drug: VP-16 60 mg/kg, IV Other Names: etoposide Drug: CY For subjects aged 18-60 with lymphoma 100 mg/kg, IV For subjects aged with AML, ALL or CML 18-50 60 mg/kg, IV For subjects aged 51-60 with MDS, AML or ALL or patients age 18-60 with MDS, secondary AML or non-CML myeloproliferative disease 45 mg/kg Other Names: cyclophosphamide cytophosphane Endoxan Drug: BU BU 1 mg/kg every 6hr x 4 doses, IV Other Names: busulfan

Arm

Intervention/Treatment

Experimental: Regimen Treatment 1

For subjects 18-60 years old with lymphoma: (BCNU+ VP-16 +CY) BCNU 15 mg / kg (maximum dose 550 mg/m² actual body weight) on day -6. VP 60 mg / kg on day 4 and CY 100 mg / kg on day -2. Followed by Sirolimus and MMF as prophylaxis

Drug: Sirolimus

Immunosuppressant beginning day -3 with 12 mg oral loading dose, 4 mg/day orally for adults

Other Names:

rapamycin

Drug: MMF

Immunosuppressant given through IV on day 0 at 15 mg/kg twice daily ≥ 2hr after the completion for the donor cell infusion

Other Names:

Mycophenolate Mofetil

Drug: BCNU

15 mg/kg, IV

Other Names:

Carmustine

BiCNU

Drug: VP-16

60 mg/kg, IV

Other Names:

etoposide

Drug: CY

For subjects aged 18-60 with lymphoma 100 mg/kg, IV For subjects aged with AML, ALL or CML 18-50 60 mg/kg, IV For subjects aged 51-60 with MDS, AML or ALL or patients age 18-60 with MDS, secondary AML or non-CML myeloproliferative disease 45 mg/kg

Other Names:

cyclophosphamide

cytophosphane

Endoxan

Experimental: Regimen Treatment 2

For subjects 18-50 years old with AML, ALL or CML: (VP-16 +CY+ FBI) Patients aged 18-50 years with AML, ALL or CML: FTBI 1320 cGy delivered in 11 120 cGy fractions over 4 days on days -8 through -5. VP 60 mg / kg on day -4 and CY 60 mg / kg on day -2. Followed by Sirolimus and MMF as prophylaxis

Drug: Sirolimus

Immunosuppressant beginning day -3 with 12 mg oral loading dose, 4 mg/day orally for adults

Other Names:

rapamycin

Drug: MMF

Immunosuppressant given through IV on day 0 at 15 mg/kg twice daily ≥ 2hr after the completion for the donor cell infusion

Other Names:

Mycophenolate Mofetil

Drug: VP-16

60 mg/kg, IV

Other Names:

etoposide

Drug: CY

Other Names:

cyclophosphamide

cytophosphane

Endoxan

Drug: FTBI

1320 cGy delivered in 11 120 cGy fractions over 4 day

Other Names:

total body irradiation

Experimental: Regimen Treatment 3

For subjects 51-60 years with MDS, AML or ALL or 18-60 with MDS, secondary AML pr non-CML myeloproliferative disease: (BU+ VP-16 +CY) BU 1 mg/kg every 6 hours X 14 doses on days -9 through -6 with target concentration at steady state of X 800 ng / ml based on first dose pharmacokinetics. VP 60 mg / kg on day -5 and CY 45 mg / kg per day -2 days on day -3 and day -2. Followed by Sirolimus and MMF as prophylaxis

Drug: Sirolimus

Immunosuppressant beginning day -3 with 12 mg oral loading dose, 4 mg/day orally for adults

Other Names:

rapamycin

Drug: MMF

Immunosuppressant given through IV on day 0 at 15 mg/kg twice daily ≥ 2hr after the completion for the donor cell infusion

Other Names:

Mycophenolate Mofetil

Drug: VP-16

60 mg/kg, IV

Other Names:

etoposide

Drug: CY

Other Names:

cyclophosphamide

cytophosphane

Endoxan

Drug: BU

BU 1 mg/kg every 6hr x 4 doses, IV

Other Names:

busulfan

Outcome Measures

Primary Outcome Measures

To evaluate the incidence of grade II-IV acute GVHD with sirolimus and mycophenolate mofetil GVHD prophylaxis. [D+100 post-transplant]

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Disease Categories: (one of the following)
AML, age 2 - 60 years beyond 2nd remission or relapsed/refractory disease
AML, age 51-60 years of age, in first or subsequent remission or relapsed/refractory disease
AML with multilineage dysplasia
ALL, age 2 - 60 years beyond 2nd remission or relapsed/refractory disease
ALL, age 51 - 60 years in first or subsequent remission or relapsed/refractory disease
CML Beyond 2nd chronic phase or in blast crisis
MDS; Includes World Health Organization classifications of refractory anemia with excess blasts-1 (RAEB-1), RAEB-2 and therapy-related MDS
Myeloproliferative disorders; MDS with poor long-term survival including myeloid metaplasia and myelofibrosis
High risk NHL in first remission
Relapsed or refractory NHL
HL beyond first remission
Males and females of any ethnic background 2 - 60 years of age
Karnofsky Performance Status ≥ 70% or Lansky performance status > 70% for patients < 16 years of age.
Matched related donor identified: 6/6 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 HCT
HIV infection
Pregnant
Lactating females
Evidence of uncontrolled active infection
Organ Dysfunction:
Serum creatinine > 1.5 mg/dL or 24 hour creatinine clearance < 50 ml/min
Direct bilirubin, ALT or AST > 2 x ULN
In adults DLCO < 60% predicted and in children room air oxygen saturation < 92%
In adults, left ventricular ejection fraction < 45% and in children, shortening fraction < 26%
Fasting Cholesterol > 300 mg/dL or Triglycerides > 300 mg/dL while on lipid-lowering agents.
Patients receiving investigational drugs unless cleared by the PI.
Patients with prior malignancies except basal cell carcinoma or treated carcinoma in-situ.
Cancer treated with curative intent > 5 years will be allowed.
Cancer treated with curative intent ≤ 5 years will not be allowed with PI approval.