A Phase 1 interventional study of busulfan and cyclophosphamide in Chronic Myeloproliferative Disorders, Graft Versus Host Disease and Leukemia, sponsored by Massachusetts General Hospital. Completed at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2017-05-25.
Sponsored by Massachusetts General Hospital · Phase 1, Interventional, and Supportive care
RATIONALE: Rasburicase may be an effective treatment for graft-versus-host disease caused by a donor stem cell transplant.
PURPOSE: This clinical trial is studying how well rasburicase works in preventing graft-versus-host disease in patients with hematologic cancer or other disease undergoing donor stem cell transplant.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a multicenter study.
Patients receive a conventional myeloablative conditioning regimen consisting of high doses of cyclophosphamide, busulfan, and etoposide, with or without total-body irradiation. Depending on the preparative regimen selected, the conditioning of recipients will take a total of 6 to 7 days. On day 0, patients will receive filgrastim (G-CSF)-mobilized HLA-matched, related, or unrelated donor allogeneic peripheral blood stem cells (unmanipulated). Patients will receive standard graft-vs-host disease prophylaxis consisting of cyclosporine or tacrolimus and methotrexate or sirolimus. Patients will receive rasburicase IV over 30 minutes, beginning on the first day of conditioning therapy, for 5 consecutive days. If after 5 days of rasburicase the patient's uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.
Blood is obtained on day 0 and then at 14, 28, and 42 days post-transplant for immunologic studies, including quantitative analysis to follow the recovery of T cells, B cells, natural killer cells, dendritic cells (DC), and monocytes using flow cytometry (FCM); phenotypic analysis of T cells, DC and monocytes by FCM; lymphocyte activation analysis: CD3, CD4, CD8, CD25 2. CD3, CD8, CD71, CD69; DC analysis: CD45, CD14, DR, CD86, CD80 2. CD45, CD14, CD40, CD11c; and in vitro functional studies such as mixed lymphocyte reaction (MLR) and cell-mediated lysis (CML) to assess for the graft-versus-host and host-versus-graft responses. Peripheral blood is collected for chimerism studies on days 28 and 100 post-transplant.
After completion of study treatment, patients are followed periodically.
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DISEASE CHARACTERISTICS:
Patients with hematologic malignancies for whom conventional myeloablative allogeneic stem cell transplantation is deemed clinically appropriate and who are eligible for conventional myeloablative allogeneic stem cell transplantation on treatment plans/protocols, including any of the following:
Must be receiving filgrastim (G-CSF)-mobilized related or unrelated donor allogeneic peripheral blood stem cells
PATIENT CHARACTERISTICS:
Inclusion criteria:
Patients with symptomatic visceral, blood stream or nervous system opportunistic infection are eligible if the infection has been appropriately treated and controlled
Exclusion criteria:
Active congestive heart failure from any cause
PRIOR CONCURRENT THERAPY:
Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator's discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant's uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.
Drug: busulfan · Drug: cyclophosphamide · Drug: cyclosporin-A · Drug: etoposide · Drug: methotrexate · Drug: rasburicase · Drug: sirolimus · Drug: tacrolimus · Procedure: allogeneic hematopoietic stem cell transplantation · Procedure: peripheral blood stem cell transplantation · Radiation: total-body irradiation · Drug: fludarabine
Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.
Drug: busulfan · Drug: cyclophosphamide · Drug: cyclosporin-A · Drug: etoposide · Drug: methotrexate · Drug: sirolimus · Drug: tacrolimus · Procedure: allogeneic hematopoietic stem cell transplantation · Procedure: peripheral blood stem cell transplantation · Radiation: total-body irradiation · Drug: fludarabine · Drug: allopurinol
Busulfan 3.2 mg/kg/day from day -7 to day -4 as standard of care for myeloablative (bone marrow depletion) conditioning at the investigator's discretion
Cyclophosphamide as standard of care for myeloablative conditioning at the investigator's discretion
Cyclosporin-A as standard of care for GVHD prophylaxis at the investigator's discretion
Etoposide as standard of care for myeloablative conditioning at the investigator's discretion
Methotrexate 1.5 mg/kg/day on days -3, -2, and -1 as standard of care for GVHD prophylaxis at the investigator's discretion
Rasburicase 0.20 mg/kg intravenous infusion over 30 minutes for 5 to 7 days
Sirolimus as standard of care for GVHD prophylaxis at the investigator's discretion
Tacrolimus as standard of care for GVHD prophylaxis at the investigator's discretion
Total body irradiation 13.2 Gy over 8 fractions from day -7 to day - 4 for myeloablative conditioning at the investigator's discretion
Fludarabine 40 mg/m\^2/day from day -6 to day -3 as myeloablative conditioning at the investigator's discretion
Allopurinol per institutional guidelines
Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD)
aGVHD severity was determined using International Bone Marrow Transplant Registry (IBMTR) scale stage and grade of the skin, liver and gut. Stage 1: Skin=maculopapular rash \<25% of body surface; Liver=Bilirubin 2-3 mg/dL and Gut=500-999 mL diarrhea/day or peristent nausea with histologic evidence of GvHD. Stage 2: Skin=maculopapular rash 25-50% of body surface; Liver=Bilirubin 3.1-6 mg/dL and Gut=1000-1499 mL diarrhea/day. Stage 3: Skin=maculopapular rash \>50% of body surface; Liver=Bilirubin 6.1-15 mg/dL and Gut=≥1500 mL diarrhea/day. Stage 4: Skin=generalized erythroderma with bulla formation; Liver=Bilirubin \>15 mg/dL and Gut=severe abdominal pain. Grade 1: Stage 1-2 rash; no liver or gut involvement. Grade II: Stage 3 rash, or stage 1 liver involvement, or stage 1 gut involvement. Grade III: None to stage 3 skin rash with stage 2-3 liver, or stage 2-4 gut involvement. Grade IV: Stage 4 skin rash, or stage 4 liver involvement.
Time frame: Up to 71 months
Uric Acid Levels
Blood was collected and analyzed at a laboratory for serum uric acid levels reported in milligrams(mg)/deciliter(dL). Data is presented for those participants who experienced Grade II to IV aGVHD and those participants who did not experience Grade II to IV aGVHD at pre-transplant and post-transplant.
Time frame: Pre-transplant Day -7 to Day -1 and Post-transplant Day 0 to Day 6
Number of Participant With Adverse Events (AE)
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 71 months
Graft-versus-host and Host-versus-graft Immune Responses
Laboratory tests such as limited dilution assay (LDA) were to be performed to assess graft-versus-host and host-versus-graft immune responses.
Time frame: Days -2, 0, and Days 14, 21 and 35 days post-transplant
| Milestone | Rasburicase Group | Control Group |
|---|---|---|
| Started | 25 | 21 |
| Received rasburicase per protocol | 24 | 0 |
| Completed | 18 | 12 |
| Not completed | 7 | 9 |
| Withdrew: Death | 6 | 9 |
| Withdrew: Participant withdrew consent | 1 | 0 |
aGVHD severity was determined using International Bone Marrow Transplant Registry (IBMTR) scale stage and grade of the skin, liver and gut. Stage 1: Skin=maculopapular rash \<25% of body surface; Liver=Bilirubin 2-3 mg/dL and Gut=500-999 mL diarrhea/day or peristent nausea with histologic evidence of GvHD. Stage 2: Skin=maculopapular rash 25-50% of body surface; Liver=Bilirubin 3.1-6 mg/dL and Gut=1000-1499 mL diarrhea/day. Stage 3: Skin=maculopapular rash \>50% of body surface; Liver=Bilirubin 6.1-15 mg/dL and Gut=≥1500 mL diarrhea/day. Stage 4: Skin=generalized erythroderma with bulla formation; Liver=Bilirubin \>15 mg/dL and Gut=severe abdominal pain. Grade 1: Stage 1-2 rash; no liver or gut involvement. Grade II: Stage 3 rash, or stage 1 liver involvement, or stage 1 gut involvement. Grade III: None to stage 3 skin rash with stage 2-3 liver, or stage 2-4 gut involvement. Grade IV: Stage 4 skin rash, or stage 4 liver involvement.
| percentage of participants | Rasburicase Group | Control Group |
|---|---|---|
| Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD) | 24 | 57 |
Blood was collected and analyzed at a laboratory for serum uric acid levels reported in milligrams(mg)/deciliter(dL). Data is presented for those participants who experienced Grade II to IV aGVHD and those participants who did not experience Grade II to IV aGVHD at pre-transplant and post-transplant.
| mg/dL | Rasburicase Group | Control Group |
|---|---|---|
| Day -7 | 0.1 ± 0.209 | 4.157 ± 1.886 |
| Day -6 | 0.075 ± 0.199 | 3.419 ± 1.752 |
| Day -5 | 0.086 ± 0.24 | 2.967 ± 1.437 |
| Day -4 | 0.1 ± 0.324 | 2.579 ± 1.249 |
| Day -3 | 0.067 ± 0.2 | 2.358 ± 1.21 |
| Day -2 | 0.081 ± 0.15 | 1.867 ± 1.097 |
| Day -1 | 0.438 ± 0.611 | 1.71 ± 0.931 |
| Day 0 | 0.938 ± 0.887 | 2.163 ± 1.012 |
| Day 1 | 1.624 ± 1.205 | 2.671 ± 1.056 |
| Day 2 | 2.076 ± 1.37 | 2.778 ± 0.985 |
| Day 3 | 2.271 ± 1.303 | 2.805 ± 1.028 |
| Day 4 | 2.548 ± 1.454 | 2.758 ± 1.161 |
| Day 5 | 2.595 ± 1.729 | 2.579 ± 1.318 |
| Day 6 | 2.705 ± 1.665 | 2.653 ± 1.33 |
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
| Participants | Rasburicase Group | Control Group |
|---|---|---|
| Number of Participant With Adverse Events (AE) | 21 | 21 |
Laboratory tests such as limited dilution assay (LDA) were to be performed to assess graft-versus-host and host-versus-graft immune responses.
No measurements were reported for this outcome.
Collected over Up to 71 months. Non-serious events are listed at a 4% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Rasburicase Group | — | 10/21 (47.6%) | 21/21 (100%) |
| Control Group | — | 9/21 (42.9%) | 21/21 (100%) |
| Event | Rasburicase Group | Control Group |
|---|---|---|
| Relapsed diseaseBlood and lymphatic system disorders | 7/21 | 7/21 |
| SeizureNervous system disorders | 1/21 | 0/21 |
| HypoxiaRespiratory, thoracic and mediastinal disorders | 1/21 | 0/21 |
| Engraftment syndromeImmune system disorders | 1/21 | 0/21 |
| Venoocclusive diseaseVascular disorders | 1/21 | 0/21 |
| Infection from aGVHD flareInfections and infestations | 0/21 | 1/21 |
| Respiratory failureInfections and infestations | 0/21 | 1/21 |
| H1N1 influenzaInfections and infestations | 1/21 | 0/21 |
| MetapneumovirusInfections and infestations | 1/21 | 0/21 |
| Event | Rasburicase Group | Control Group |
|---|---|---|
| MucositisGeneral disorders | 20/21 | 17/21 |
| NauseaGastrointestinal disorders | 19/21 | 19/21 |
| DiarrheaGastrointestinal disorders | 15/21 | 9/21 |
| VomitingGastrointestinal disorders | 13/21 | 11/21 |
| FeverGeneral disorders | 5/21 | 9/21 |
| EdemaMetabolism and nutrition disorders | 5/21 | 2/21 |
| RashSkin and subcutaneous tissue disorders | 1/21 | 2/21 |
| Tongue numbnessGastrointestinal disorders | 1/21 | 0/21 |
| ThrombocytopeniaBlood and lymphatic system disorders | 1/21 | 0/21 |
| Hemolytic anemiaBlood and lymphatic system disorders | 1/21 | 0/21 |
Intent-to-treat participants included in the analyses.
| Age, Continuous(years) | Rasburicase Group | Control Group | Total |
|---|---|---|---|
| Mean | 42.9 (20 to 59) | 45 (21 to 55) | 44 (20 to 59) |
| Sex: Female, Male(Participants) | Rasburicase Group | Control Group | Total |
|---|---|---|---|
| Female | 7 | 12 | 19 |
| Male | 14 | 9 | 23 |
| Graft-Versus-Host Disease (GVHD) Prophylaxis Intervention(Participants) | Rasburicase Group | Control Group | Total |
|---|---|---|---|
| MRD: Cyclsporine + Methotrexate | 14 | 11 | 25 |
| MRD: Tacrolimus + Methotrexate | 2 | 2 | 4 |
| MUD: Tacrolimus + Methotrexate + ATG | 4 | 8 | 12 |
| MUD: Tacrolimus + Methotrexate | 1 | 2 | 3 |
| Conditioning Protocol Interventions(Participants) | Rasburicase Group | Control Group | Total |
|---|---|---|---|
| Busulfan + Cyclophosphamide | 12 | 16 | 28 |
| Busulfan + Fludarabine | 2 | 0 | 2 |
| Total Body Irradiation + Cyclophosphamide | 7 | 5 | 12 |
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Massachusetts General Hospital