Hematologic Diseases, Acute-graft-versus-host Disease, Leukemia, Non-Hodgkin Lymphoma (NHL), Hodgkin Lymphoma
Conditions
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.
Interventions
DRUGSirolimus
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.
DRUGMycophenolate 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.
DRUGCarmustine
For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -6 at the lesser of 15 mg/kg or 550 mg/m².
DRUGEtoposide
For Carmustine + Etoposide + Cyclophosphamide cohort, chemotherapy administered IV on Day -4 at 60 mg/kg
DRUGCyclophosphamide (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
DRUGFTBI
For FTBI + Cyclophosphamide cohort, administered as 1320 cGy delivered in 11 120 cGy fractions over 4 days starting on Day -7.
Sponsors
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 60 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Graft-vs-Host Disease (GvHD) (Grade 2 to 4) | 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
| Measure | Time frame | Description |
|---|---|---|
| Acute GvHD (Grade 3 to 4) | 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) | 2 years | Assessed as survival without recurrence of disease |
| Overall Survival | 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) | 100 days post-transplant | Assessed as the incidence of veno-occlusive disease (VoD) at 100 days post-transplant. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GvHD Prophylaxis of Sirolimus & MMF After BCNU+VP16+Cyclo Graft-vs-host disease (GvHD) prophylaxis of sirolimus & mycophenolate mofetil (MMF) after chemotherapeutic regimen of carmustine (BCNU) + etoposide (VP-16) + cyclophosphamide (Cyclo) | 0 |
| GvHD Prophylaxis of Sirolimus & MMF After FTBI + Cyclo Graft-vs-host disease (GvHD) prophylaxis of sirolimus & mycophenolate mofetil (MMF) after therapeutic regimen of cyclophosphamide (Cyclo) chemotherapy and fractionated total body irradiation (FTBI) | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | GvHD Prophylaxis of Sirolimus & MMF After FTBI + Cyclo | Total | GvHD Prophylaxis of Sirolimus & MMF After BCNU+VP16+Cyclo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | — |
| Disease Characteristics Acute Lymphoblastic Leukemia (ALL) | 1 Participants | 1 Participants | — |
| Disease Characteristics Acute Myeloid Leukemia (AML) | 1 Participants | 1 Participants | — |
| Disease Characteristics Biphenotypic Acute Leukaemia (BAL) | 1 Participants | 1 Participants | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | — |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | — |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | — |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | — |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | — |
| Sex: Female, Male Female | 0 Participants | 0 Participants | — |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 3 / 3 |
| other Total, other adverse events | 0 / 0 | 3 / 3 |
| serious Total, serious adverse events | 0 / 0 | 3 / 3 |
Outcome results
Primary
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
Time frame: 100 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GvHD Prophylaxis of Sirolimus & MMF After BCNU+VP16+Cyclo | Acute Graft-vs-Host Disease (GvHD) (Grade 2 to 4) | 0 Participants |
| GvHD Prophylaxis of Sirolimus & MMF After FTBI + Cyclo | Acute Graft-vs-Host Disease (GvHD) (Grade 2 to 4) | 1 Participants |
Secondary
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
Time frame: 100 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GvHD Prophylaxis of Sirolimus & MMF After BCNU+VP16+Cyclo | Acute GvHD (Grade 3 to 4) | 0 Participants |
| GvHD Prophylaxis of Sirolimus & MMF After FTBI + Cyclo | Acute GvHD (Grade 3 to 4) | 1 Participants |
Secondary
Disease-free Survival (DFS)
Assessed as survival without recurrence of disease
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GvHD Prophylaxis of Sirolimus & MMF After BCNU+VP16+Cyclo | Disease-free Survival (DFS) | 0 Participants |
| GvHD Prophylaxis of Sirolimus & MMF After FTBI + Cyclo | Disease-free Survival (DFS) | 0 Participants |
Secondary
Overall Survival
Overall survival is defined as time from enrollment to time of death or last follow-up, within 2 years.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GvHD Prophylaxis of Sirolimus & MMF After FTBI + Cyclo | Overall Survival | 405 Days |
Secondary
Veno-occlusive Disease (VoD)
Assessed as the incidence of veno-occlusive disease (VoD) at 100 days post-transplant.
Time frame: 100 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GvHD Prophylaxis of Sirolimus & MMF After BCNU+VP16+Cyclo | Veno-occlusive Disease (VoD) | 0 Participants |
| GvHD Prophylaxis of Sirolimus & MMF After FTBI + Cyclo | Veno-occlusive Disease (VoD) | 1 Participants |