A Phase 1/2 interventional study of rabbit anti-thymocyte globulin (ATG) and therapeutic allogeneic lymphocytes in Chronic Myeloproliferative Disorders, Leukemia and Lymphoma, sponsored by UNC Lineberger Comprehensive Cancer Center. Completed at 1 site in United States. Open to participants aged 18 Years to 55 Years. Per ClinicalTrials.gov, last updated 2017-07-17.
Sponsored by UNC Lineberger Comprehensive Cancer Center · Phase 1/2, Interventional, and Treatment
RATIONALE: Giving chemotherapy, such as fludarabine and busulfan, before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving a monoclonal antibody, alemtuzumab, before the transplant and tacrolimus after the transplant may stop this from happening.
PURPOSE: The phase I portion of this trial identified the maximum tolerated dose of busulfan after treating 40 patients on a dose-escalation scheme. We are now treating an additional 26 patients on the phase II portion of the trial at a Pharmacokinetic (PK)-directed dose of total area under curve (AUC) 6912 micrometer (uM)-min/24 hours. We transitioned to the Phase II portion of the study in October 2009.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a non-randomized, open-label, parallel group study of busulfan. Patients are stratified according to donor relationship - matched related donor (MRD) vs matched unrelated donor (MUD).
Phase I portion only: Cohorts of 3-6 patients receive escalating doses of busulfan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
After the completion of study treatment, patients are followed periodically for up to 5 years.
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This study's enrollment of 54 is above the median of 40 across 4,508 interventional studies indexed under Lymphoma.
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INCLUSION CRITERIA
Histologically confirmed diagnosis of any of the following:
Chronic lymphocytic leukemia or prolymphocytic leukemia Chemotherapy-refractory or advanced disease after ≥ 3 prior treatments Chronic myelogenous leukemia Diagnosis based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood counts (WBC) in peripheral blood or marrow Patients with progressive disease on imatinib mesylate or other protein tyrosine kinase inhibitors; less than a major cytogenetic or fluorescent in situ hybridization (FISH) complete response (CR) after a minimum of 6 months of targeted therapy; or less than a complete FISH or cytogenetic response after 12 months of targeted therapy are eligible Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible Non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma Any World Health Organization (WHO) classification histologic subtype allowed Must have advanced disease as defined by relapse after initial CR or failure to achieve CR OR deemed to have less than a 30% likelihood of durable response with an autologous stem cell transplant Refractory low-grade NHL histologies or any intermediate or aggressive large cell or mantle cell lymphoma allowed Acute myeloid leukemia (AML) High-risk disease in first CR (CR1) OR evidence of any recurrent disease beyond CR1 High-risk individuals are those requiring more than 1 course of induction therapy to achieve remission; those with extra-medullary disease at presentation; or those with high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3) or > 2 cytogenetic abnormalities
Myelofibrosis/agnogenic myeloid metaplasia
Myeloproliferative disorders with advanced disease (e.g., progressive or spent phase polycythemia vera, myelofibrosis, or essential thrombocythemia)
Human Leucocyte Antigen (HLA)-identical or 1 antigen-mismatched sibling (5/6, 6/6, or 8/10) donor
8/10 matched unrelated donor (MUD)
5/6 MUD
PATIENT CHARACTERISTICS:
EXCLUSION CRITERIA Uncontrolled or severe cardiovascular disease, pulmonary disease, or infection that, in the opinion of the treating physician, would make this study unreasonably hazardous to the patient Other serious illness that would limit survival to \< 2 years Psychiatric condition that would preclude study compliance Uncontrolled diabetes mellitus or active serious infection Active second malignancy except for nonmelanomatous skin cancer Known hypersensitivity to E. coli-derived products HIV positivity
PRIOR CONCURRENT THERAPY:
More than 4 weeks since prior chemotherapy, radiotherapy, or surgery
Subjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine . Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.
Biological: rabbit anti-thymocyte globulin (ATG) · Biological: therapeutic allogeneic lymphocytes · Drug: busulfan · Drug: fludarabine phosphate · Drug: tacrolimus · Procedure: allogeneic hematopoietic stem cell transplantation · Procedure: peripheral blood stem cell transplantation · Drug: methotrexate
.5 mg/kg on day -3 and 2.5 mg/kg on day -2
minimum total cluster of differentiation (CD34+) cells of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on day 0
PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.
30 mg/m\^2/day x 5 days intravenous piggyback (IVPB) over 30 minutes on Days -7 through -3
The suggested starting dose is 0.03 mg/kg po bid starting on day -1
A minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and maximum of 8 x 10\^6 cells/kg will be infused on day 0
minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on day 0
5 mg/m\^2 on days +1, +3 and +6
Three-year Relapse-free Survival (RFS) Rate at the Maximum Tolerated Dose Identified During Phase I of the Trial (Target AUC 6912)
Relapse is defined as new or increased sites of disease or positive one marrow after a complete response (CR). The RFS was calculated as the percentage of patients who were alive and without relapse at 3 years
Time frame: Three years post-transplant
Number of Participants With Dose Limiting Toxicities (DLTs)
Dose limiting toxicity will be defined as any irreversible grade 3 or any grade 4 non-hematologic toxicity that is related to busulfan infusion and not graft vs host disease or late infection after recovery from the initial period of myelosuppression. The maximum tolerated dose (MTD) is defined as the dose with probability of dose limiting toxicity (DLT) of 0.25. The dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine and alemtuzumab plus tacrolimus for GVHD prophylaxis.
Time frame: first 6 weeks or 42 days following stem cell infusion
Capacity of Test Dosing of Busulfan That Would Result in the Desired Area Under the Curve Concentration Exposure of Patients Receiving a Full-dose Busulfan Regimen
Test doses of busulfan were administered and plasma levels were measured to determine a targeted AUC dosing estimate. The capacity is reported as the precision with which these test dose goals predicted the actual 90-hour mean AUC levels.Dose targeting precision was estimated by root mean squared error.
Time frame: Day -15 to Day -11
Incidence of Graft vs Host Disease in Patients Between One Month and Two Years Post Transplant
GVHD can be mild, moderate or severe depending on the differences in tissue type between patient and donor. GVHD can be acute or chronic. Its symptoms can include: * Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body * Blistering, causing the exposed skin surface to flake off in severe cases * Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected * Jaundice, or a yellowing of the skin, which can indicate liver damage * Excessive dryness of the mouth and throat, leading to ulcers * Dryness of the lungs, vagina and other surfaces
Time frame: 100 days post transplant
Incidence of DNA Chimerism in Patients Between One Month Post Transplant
Deoxyribonucleic acid (DNA) chimerism is a measure identifying the genetic profiles of the transplant recipient and of the donor and then evaluating the extent of mixture in the recipient's blood, bone marrow, or other tissue.
Time frame: 30 days post transplant
Overall Survival
Percentage of participants alive at 3 years post transplant
Time frame: Three years post-transplant
Patients with advanced, refractory, or high-risk hematologic cancers who were deemed suitable for myeloablative conditioning were recruited from one institution.
| Milestone | Experimental: GVHD Prophylaxis |
|---|---|
| Started | 54 |
| Completed | 54 |
| Not completed | 0 |
Relapse is defined as new or increased sites of disease or positive one marrow after a complete response (CR). The RFS was calculated as the percentage of patients who were alive and without relapse at 3 years
| percentage of participants | Low Busulfan AUC Tertile | Intermediate Busulfan AUC Tertile | High Busulfan AUC Tertile |
|---|---|---|---|
| Three-year Relapse-free Survival (RFS) Rate at the Maximum Tolerated Dose Identified During Phase I of the Trial (Target AUC 6912) | 22 | 39 | 43 |
Dose limiting toxicity will be defined as any irreversible grade 3 or any grade 4 non-hematologic toxicity that is related to busulfan infusion and not graft vs host disease or late infection after recovery from the initial period of myelosuppression. The maximum tolerated dose (MTD) is defined as the dose with probability of dose limiting toxicity (DLT) of 0.25. The dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine and alemtuzumab plus tacrolimus for GVHD prophylaxis.
| DLTs | Dose Level 1 | Dose Level 2 | Dose Level 3 | Dose Level 4 | Dose Level 5 |
|---|---|---|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | 1 | 1 | 1 | 2 | 2 |
Test doses of busulfan were administered and plasma levels were measured to determine a targeted AUC dosing estimate. The capacity is reported as the precision with which these test dose goals predicted the actual 90-hour mean AUC levels.Dose targeting precision was estimated by root mean squared error.
| percentage of error | Dose Level 1 | Dose Level 2 | Dose Level 3 | Dose Level 4 | Dose Level 5 |
|---|---|---|---|---|---|
| Capacity of Test Dosing of Busulfan That Would Result in the Desired Area Under the Curve Concentration Exposure of Patients Receiving a Full-dose Busulfan Regimen | 11.7 | 4.9 | 10.2 | 11.1 | 15.9 |
GVHD can be mild, moderate or severe depending on the differences in tissue type between patient and donor. GVHD can be acute or chronic. Its symptoms can include: * Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body * Blistering, causing the exposed skin surface to flake off in severe cases * Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected * Jaundice, or a yellowing of the skin, which can indicate liver damage * Excessive dryness of the mouth and throat, leading to ulcers * Dryness of the lungs, vagina and other surfaces
| Participants | Low Busulfan AUC Tertile | Intermediate Busulfan AUC Tertile | High Busulfan AUC Tertile |
|---|---|---|---|
| Acute GVHD grade >=II | 7 | 10 | 11 |
| Acute GVHD grades III and IV | 2 | 4 | 3 |
| Chronic GVHD; intermediate/severe | 4 | 6 | 2 |
Deoxyribonucleic acid (DNA) chimerism is a measure identifying the genetic profiles of the transplant recipient and of the donor and then evaluating the extent of mixture in the recipient's blood, bone marrow, or other tissue.
| Participants | Experimental: GVHD Prophylaxis |
|---|---|
| Whole blood chimerism-Any | 49 |
| Whole blood chimerism->=95% donor | 47 |
| T Cell chimerism-Any | 46 |
| T Cell chimerism>=95% donor | 30 |
Percentage of participants alive at 3 years post transplant
| percentage of participants | Low Busulfan AUC Tertile (5078) | Intermediate Busulfan AUC Tertile (6372) | High Busulfan AUC Tertile (7605) |
|---|---|---|---|
| Overall Survival | 28 | 39 | 55 |
Collected over Mortality was assessed at one year. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Experimental: GVHD Prophylaxis | 15/54 (27.8%) | 26/54 (48.1%) | 54/54 (100%) |
| Event | Experimental: GVHD Prophylaxis |
|---|---|
| Gr 4 mucositisGastrointestinal disorders | 5/54 |
| SepsisInfections and infestations | 4/54 |
| thrombocytopeniaBlood and lymphatic system disorders | 4/54 |
| Veno-occlusive diseaseHepatobiliary disorders | 3/54 |
| Aspergillus pneumoniaInfections and infestations | 2/54 |
| renal FailureRenal and urinary disorders | 2/54 |
| BK cystitisInfections and infestations | 1/54 |
| Liver FailiureHepatobiliary disorders | 1/54 |
| Gr 4 GVHDGastrointestinal disorders | 1/54 |
| CMV pneumonitisInfections and infestations | 1/54 |
| Event | Experimental: GVHD Prophylaxis |
|---|---|
| grade 3 or 4 hematologic toxicities (expected)Blood and lymphatic system disorders | 54/54 |
| AlopeciaSkin and subcutaneous tissue disorders | 54/54 |
| grade 3 GI toxicityGastrointestinal disorders | 21/54 |
| Age, Continuous(years) | Experimental: GVHD Prophylaxis |
|---|---|
| Median | 50 (27 to 66) |
| Sex: Female, Male(Participants) | Experimental: GVHD Prophylaxis |
|---|---|
| Female | 20 |
| Male | 34 |
| Race (NIH/OMB)(Participants) | Experimental: GVHD Prophylaxis |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 1 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 3 |
| White | 48 |
| More than one race | 0 |
| Unknown or Not Reported | 2 |
| Region of Enrollment(participants) | Experimental: GVHD Prophylaxis |
|---|---|
| United States | 54 |
| Donor-recipient sex(Participants) | Experimental: GVHD Prophylaxis |
|---|---|
| Male-Female | 6 |
| Female-Male | 12 |
| Male-Male | 22 |
| Female-Female | 14 |
| Host cytomegalovirus (CMV) status(Participants) | Experimental: GVHD Prophylaxis |
|---|---|
| Negative | 18 |
| Positive | 36 |
| Disease histology(Participants) | Experimental: GVHD Prophylaxis |
|---|---|
| Myelogenous leukemia | 26 |
| Myelodysplasia | 8 |
| Chronic myelogenous leukemia | 1 |
| Acute lymphoblastic leukemia | 7 |
| Non-Hodgkin Lymphoma | 5 |
| Hodgkin lymphoma | 2 |
| Myelofibrosis | 1 |
| Chronic lymphoblastic leukemia | 1 |
| Chronic myelomonocytic leukemia | 1 |
| Plastic cell leukemia | 2 |
| Type of transplant(Participants) | Experimental: GVHD Prophylaxis |
|---|---|
| Matched unrelated donor (MUD) | 34 |
| Matched unrelated donor (MRD) | 20 |
1 further baseline measures are reported on the registry.
Plan to share: No
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