Gemcitabine Hydrochloride, Clofarabine, and Busulfan Before Donor Stem Cell Transplant in Treating Patients With Refractory B-Cell or T-Cell Non-Hodgkin Lymphoma or Hodgkin Lymphoma

Study Overview
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Brief Summary
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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
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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.

Official Title
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Gemcitabine/Clofarabine/Busulfan and Allogeneic Transplantation for Aggressive Lymphomas

Conditions
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Hematopoietic Cell Transplantation Recipient, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Hodgkin Lymphoma, Refractory T-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Procedure: Allogeneic Bone Marrow Transplantation
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Biological: Anti-Thymocyte Globulin
* Drug: Busulfan
* Drug: Clofarabine
* Drug: Gemcitabine Hydrochloride
* Drug: Mycophenolate Mofetil
* Procedure: Peripheral Blood Stem Cell Transplantation
* Other: Pharmacological Study
* Biological: Rituximab
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (gemcitabine, clofarabine, busulfan, BMT or PBSCT)<br>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. | Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo allogeneic BMT<br>* Other names: Allogeneic BMT;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic BMT or PBSCT<br>* Other names: HSCT;Biological: Anti-Thymocyte Globulin<br>* Given IV<br>* Other names: Thymoglobulin;Drug: Busulfan<br>* Given IV<br>* Other names: WR-19508;Drug: Clofarabine<br>* Given IV<br>* Other names: Clolar;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Drug: Mycophenolate Mofetil<br>* Given IV then PO<br>* Other names: MMF;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Other: Pharmacological Study<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Tacrolimus<br>* Given IV then PO<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal dose of gemcitabine hydrochloride determined by dose limiting toxicity (Phase I) | Defined as grade 3-4 mucositis lasting for more than 3 days at peak severity or grade 3-4 skin toxicity lasting for more than 3 days at peak severity. The Bayesian Time to Event Continual Reassessment Method will be applied to determine the optimal gemcitabine dose in phase I. | Within 30 days of transplant | 
| Success rate (Phase II) | Defined as percentage of patients who are alive, engrafted and without grade 3-4 graft versus host disease (GVHD). | Up to 100 days post-transplant | 
| Rate of event-free survival (Phase II) |  | Up to 5 years | 
| Overall survival (Phase II) |  | Up to 5 years | 
| Response rate (Phase II) |  | Up to 5 years | 
| Complete response rate (Phase II) |  | Up to 5 years | 
| Incidence of grade 2-4 and grade 3-4 acute GVHD (Phase II) |  | Up to 5 years | 
| Incidence of limited and extensive chronic GVHD (Phase II) |  | Up to 5 years |