Allogeneic Stem Cell Transplant for CLL

Study Overview
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Brief Summary
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This phase I/II trial studies the best dose and side effects of gemcitabine and how well it works with clofarabine and busulfan and donor stem cell transplant in treating participants with chronic lymphocytic leukemia. Drugs used in chemotherapy, such as gemcitabine, clofarabine, and busulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer 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. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of gemcitabine when administered with busulfan and clofarabine. II. To estimate the day 100 treatment-related mortality (TRM) for the preparative regimen busulfan, clofarabine, and gemcitabine followed by allogeneic hematopoietic cell transplantation (HCT) for patients with chronic lymphocytic leukemia (CLL). SECONDARY OBJECTIVES: I. To determine the rate of progression-free survival (PFS), graft versus host disease (GVHD), engraftment, and overall survival (OS) for this treatment regimen at one year post treatment completion. OUTLINE: This is a dose-escalation study of gemcitabine. Participants receive gemcitabine intravenously (IV) over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus orally (PO) daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim subcutaneously (SC) once daily (QD) beginning 1 week after transplant until blood cell levels return to normal. After completion of study treatment, participants are followed up at 3, 6 and 12 months, then every 6 months for 1 year.

Official Title
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Clofarabine, Gemcitabine, and Busulfan Followed by Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia (CLL)

Conditions
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Allogeneic Hematopoietic Stem Cell Transplantation Recipient, Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Richter Syndrome

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Biological: Anti-Thymocyte Globulin
* Drug: Busulfan
* Drug: Clofarabine
* Biological: Filgrastim
* Drug: Gemcitabine
* Drug: Methotrexate
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic lymphocytic leukemia, prolymphocytic leukemia, or Richter's transformation who are eligible for allogeneic transplantation and are not eligible for protocols of higher priority A 10/10 HLA matched (high resolution typing at A, B, C, DRB1, DQ1) sibling or unrelated donor Left ventricular ejection fraction (EF) > 40% Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and corrected diffusion capacity of the lung for carbon monoxide (DLCO) > 40% Serum creatinine < 1.6 mg/dL Serum bilirubin < 2 X upper limit of normal serum glutamate pyruvate transaminase (SGPT) < 2X upper limit of normal Voluntary signed, written Institutional Review Board (IRB)-approved informed consent 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 Pregnant (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 Known infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV)-I, hepatitis B, or hepatitis C Active uncontrolled bacterial, viral or fungal infections Patient has received other investigational drugs within 1 week before enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy, stem cell transplant)<br>Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo stem cell transplant<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;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Drug: Gemcitabine<br>* Given IV<br>* Other names: Difluorodeoxycytidine;Drug: Methotrexate<br>* Given IV<br>* Other names: WR-19039;Drug: Tacrolimus<br>* Given PO<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 100 Day Treatment Related Mortality (TRM) | Number of deaths related to treatment by day 100 post allogeneic transplant | 100 days post transplant | 
| Maximum Tolerated Dose (MTD) | To find the maximum tolerated dose (MTD) of Gemcitabine when administered with Busulfan & Clofarabine | Enrollment up to day 30 post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Will be estimated by the method of Kaplan and Meier. Time-to-event distributions as function of patient baseline covariates will be evaluated using Bayesian time-to-event regression modeling. | Up to 1 year post transplant |