Hematopoietic Cell Transplantation Recipient, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Hodgkin Lymphoma, Refractory T-Cell Non-Hodgkin Lymphoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of gemcitabine hydrochloride, clofarabine, and busulfan before donor stem cell transplant and to see how well it works in treating patients with B-cell or T-cell non-Hodgkin lymphoma or Hodgkin lymphoma that does not respond to treatment. Giving chemotherapy before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also 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.
Detailed description
PRIMARY OBJECTIVES: I. To define the maximum tolerated dose (MTD) of infusional gemcitabine (gemcitabine hydrochloride) combined with fixed doses of clofarabine and busulfan in patients with lymphoma receiving an allogeneic stem-cell transplant (alloSCT). II. To estimate the day +100 success rate, defined as percentage of patients who are alive, engrafted and without grade 3-4 graft-versus (vs.)-host-disease (GVHD). SECONDARY OBJECTIVES: I. To estimate the day +100 success rate (defined as percentage of patients who are alive, engrafted and without grade 3-4 graft-vs.-host-disease \[GVHD\]). II. To estimate the rate of event-free (EFS). III. To estimate the rate of overall survival (OS). IV. To estimate the response rate (RR) (defined as # of responses / # of patients with measurable tumors). V. To estimate the complete response (CR) rate (defined as # of complete responses / # of patients with measurable tumors). VI. To estimate the incidence of grade 2-4 and grade 3-4 acute GVHD. VII. To estimate the incidence of limited and extensive chronic GVHD. OUTLINE: This is a phase I, dose-escalation study of gemcitabine hydrochloride followed by a phase II study. PREPARATIVE REGIMEN: Patients receive gemcitabine hydrochloride intravenously (IV) over 40-180 minutes on days -6 and -4, clofarabine IV over 1 hour on days -6 to -3, and busulfan IV over 3 hours on days -6 to -3. Patients with matched unrelated donors also receive antithymocyte globulin IV on days -3 to -1 and patients with cluster of differentiation (CD)20-positive disease also receive rituximab IV on days -14, -7, 1, and 8. TRANSPLANT: Patients undergo allogeneic bone marrow (BMT) or peripheral blood stem cell transplant (PBSCT) on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or orally (PO). Beginning on day 0, patients receive mycophenolate mofetil IV over 2 hours or PO thrice daily (TID). After completion of study treatment, patients are followed up at 3, 6, and 12 months, and then every 6 months for 4 years.
Interventions
PROCEDUREAllogeneic Bone Marrow Transplantation
Undergo allogeneic BMT
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic BMT or PBSCT
BIOLOGICALAnti-Thymocyte Globulin
Given IV
DRUGBusulfan
Given IV
DRUGClofarabine
Given IV
DRUGGemcitabine Hydrochloride
Given IV
DRUGMycophenolate Mofetil
Given IV then PO
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSCT
OTHERPharmacological Study
Correlative studies
BIOLOGICALRituximab
Given IV
DRUGTacrolimus
Given IV then PO
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients with refractory B-cell or T-cell non-Hodgkin's lymphoma or Hodgkin's lymphoma who are eligible for allogeneic transplantation * An 8/8 human leukocyte antigen (HLA) matched (high resolution typing at A, B, C, DRB1) sibling or unrelated donor * Left ventricular ejection fraction (EF) \>= 45% * Forced expiratory volume in one second (FEV1) \>= 50% * Forced vital capacity (FVC) \>= 50% * Diffusing capacity of the lung for carbon monoxide (DLCO) \>= 50% * Estimated serum creatinine clearance \>= 50 ml/min (using the Cockcroft-Gault formula) * Serum creatinine =\< 1.6 mg/dL * Serum bilirubin =\< 2 x upper limit of normal * Serum glutamate pyruvate transaminase (SGPT) =\< 2 x upper limit of normal * Voluntary signed Institutional Review Board (IRB)-approved informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care * Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study; female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study; male subject agrees to use an acceptable method for contraception for the duration of the study
Exclusion criteria
* Patient with active central nervous system (CNS) disease * Pregnancy (positive beta human chorionic gonadotropin \[HCG\] test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding; pregnancy testing is not required for post-menopausal or surgically sterilized women * Active hepatitis B, either active carrier (hepatitis B virus surface antigen \[HBsAg\] +) or viremic (hepatitis B virus \[HBV\] deoxyribonucleic acid \[DNA\] \>= 10,000 copies/mL, or \>= 2,000 IU/mL) * Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology * Human immunodeficiency virus (HIV) infection * Active uncontrolled bacterial, viral or fungal infections * Exposure to other investigational drugs within 2 weeks before enrollment * Grade \>= 3 non-hematologic toxicity from previous therapy that has not resolved to =\< grade 1 * Radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment * Prior whole brain irradiation * Prior autologous stem-cell transplant (SCT) in the prior 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Within 30 days of transplant | Dose limiting toxicity is defined as number of participants experienced grade 3-4 mucositis lasting for more than 3 days at peak severity, grade 3-4 skin toxicity lasting for more than 3 days at peak severity, occurring within 30 days from transplant, or grade 4 nonhematological/noninfectious toxicity. |
| Number of Participants That Had 100 Day Success Rate Post Transplant | 100 days post transplant | Number of participants that are alive, engrafted, without grade 3-4 GVHD within 100 days post transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 5 years | Number of participants that are still alive 5 years post transplant. |
| Treatment Related Mortality | Up to 100 days post-transplant | Number of participants that expired from transplant other than disease relapse within the first 100 days post transplant. |
Countries
United States
Participant flow
Recruitment details
All participants were registered in MD Anderson Cancer Center
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1_475mgm2 PREPARATIVE REGIMEN: Patients receive gemcitabine hydrochloride IV over 40-180 minutes on days -6 and -4, clofarabine IV over 1 hour on days -6 to -3, and busulfan IV over 3 hours on days -6 to -3. Patients with matched unrelated donors also receive antithymocyte globulin IV on days -3 to -1 and patients with CD20-positive disease also receive rituximab IV on days -14, -7, 1, and 8.
TRANSPLANT: Patients undergo allogeneic BMT or PBSCT on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or PO beginning on day -2 for up to 6 months and mycophenolate mofetil IV over 2 hours or PO TID beginning day 0.
Allogeneic Bone Marrow Transplantation: Undergo allogeneic BMT
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic BMT or PBSCT
Anti-Thymocyte Globulin: Given IV
Busulfan: Given IV
Clofarabine: Given IV
Gemcitabine Hydrochloride: Given IV
Mycophenolate Mofetil: Given IV then PO
Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSCT
Pharmacological Study: Correlative studies
Rituximab: Given IV
Tacrolimus: Given IV then PO | 8 |
| Cohort 2_675mgm2 PREPARATIVE REGIMEN: Patients receive gemcitabine hydrochloride IV over 40-180 minutes on days -6 and -4, clofarabine IV over 1 hour on days -6 to -3, and busulfan IV over 3 hours on days -6 to -3. Patients with matched unrelated donors also receive antithymocyte globulin IV on days -3 to -1 and patients with CD20-positive disease also receive rituximab IV on days -14, -7, 1, and 8.
TRANSPLANT: Patients undergo allogeneic BMT or PBSCT on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or PO beginning on day -2 for up to 6 months and mycophenolate mofetil IV over 2 hours or PO TID beginning day 0.
Allogeneic Bone Marrow Transplantation: Undergo allogeneic BMT
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic BMT or PBSCT
Anti-Thymocyte Globulin: Given IV
Busulfan: Given IV
Clofarabine: Given IV
Gemcitabine Hydrochloride: Given IV
Mycophenolate Mofetil: Given IV then PO
Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSCT
Pharmacological Study: Correlative studies
Rituximab: Given IV
Tacrolimus: Given IV then PO | 24 |
| Cohort 3_975mgm2 PREPARATIVE REGIMEN: Patients receive gemcitabine hydrochloride IV over 40-180 minutes on days -6 and -4, clofarabine IV over 1 hour on days -6 to -3, and busulfan IV over 3 hours on days -6 to -3. Patients with matched unrelated donors also receive antithymocyte globulin IV on days -3 to -1 and patients with CD20-positive disease also receive rituximab IV on days -14, -7, 1, and 8.
TRANSPLANT: Patients undergo allogeneic BMT or PBSCT on day 0.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or PO beginning on day -2 for up to 6 months and mycophenolate mofetil IV over 2 hours or PO TID beginning day 0.
Allogeneic Bone Marrow Transplantation: Undergo allogeneic BMT
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic BMT or PBSCT
Anti-Thymocyte Globulin: Given IV
Busulfan: Given IV
Clofarabine: Given IV
Gemcitabine Hydrochloride: Given IV
Mycophenolate Mofetil: Given IV then PO
Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSCT
Pharmacological Study: Correlative studies
Rituximab: Given IV
Tacrolimus: Given IV then PO | 32 |
| Total | 64 |
Baseline characteristics
| Characteristic | Cohort 1_475mgm2 | Cohort 2_675mgm2 | Cohort 3_975mgm2 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 23 Participants | 32 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 9 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 19 Participants | 23 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 8 participants | 24 participants | 32 participants | 64 participants |
| Sex: Female, Male Female | 2 Participants | 10 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 6 Participants | 14 Participants | 23 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 8 | 16 / 24 | 18 / 32 |
| other Total, other adverse events | 8 / 8 | 24 / 24 | 32 / 32 |
| serious Total, serious adverse events | 2 / 8 | 2 / 24 | 9 / 32 |
Outcome results
Primary
Number of Participants That Had 100 Day Success Rate Post Transplant
Number of participants that are alive, engrafted, without grade 3-4 GVHD within 100 days post transplant.
Time frame: 100 days post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1_475mgm2 | Number of Participants That Had 100 Day Success Rate Post Transplant | 6 Participants |
| Cohort 2_675mgm2 | Number of Participants That Had 100 Day Success Rate Post Transplant | 17 Participants |
| Cohort 3_975mgm2 | Number of Participants That Had 100 Day Success Rate Post Transplant | 21 Participants |
Primary
Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity
Dose limiting toxicity is defined as number of participants experienced grade 3-4 mucositis lasting for more than 3 days at peak severity, grade 3-4 skin toxicity lasting for more than 3 days at peak severity, occurring within 30 days from transplant, or grade 4 nonhematological/noninfectious toxicity.
Time frame: Within 30 days of transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1_475mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Skin | 0 Participants |
| Cohort 1_475mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Mucositis | 0 Participants |
| Cohort 1_475mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Nonhematological/noninfectious toxicity | 3 Participants |
| Cohort 2_675mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Skin | 0 Participants |
| Cohort 2_675mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Mucositis | 6 Participants |
| Cohort 2_675mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Nonhematological/noninfectious toxicity | 6 Participants |
| Cohort 3_975mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Mucositis | 20 Participants |
| Cohort 3_975mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Nonhematological/noninfectious toxicity | 10 Participants |
| Cohort 3_975mgm2 | Optimal Dose of Gemcitabine Hydrochloride Determined by Dose Limiting Toxicity | Skin | 0 Participants |
Secondary
Overall Survival
Number of participants that are still alive 5 years post transplant.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1_475mgm2 | Overall Survival | 2 Participants |
| Cohort 2_675mgm2 | Overall Survival | 8 Participants |
| Cohort 3_975mgm2 | Overall Survival | 14 Participants |
Secondary
Treatment Related Mortality
Number of participants that expired from transplant other than disease relapse within the first 100 days post transplant.
Time frame: Up to 100 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1_475mgm2 | Treatment Related Mortality | 2 Participants |
| Cohort 2_675mgm2 | Treatment Related Mortality | 1 Participants |
| Cohort 3_975mgm2 | Treatment Related Mortality | 3 Participants |