Allogeneic Stem Cell Transplant for CLL

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

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Richter Syndrome; Allogeneic Hematopoietic Stem Cell Transplantation Recipient
• Intervention / Treatment: Drug: Gemcitabine; Drug: Methotrexate; Biological: Filgrastim; Drug: Clofarabine; Biological: Anti-Thymocyte Globulin; Drug: Busulfan; Drug: Tacrolimus; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (combination chemotherapy, stem cell transplant); 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.

Drug: Gemcitabine; Given IV; Other Names: dFdCyd; dFdC; Difluorodeoxycytidine; Drug: Methotrexate; Given IV; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; FILGRASTIM, LICENSE HOLDER UNSPECIFIED; Drug: Clofarabine; Given IV; Other Names: Clofarex; Clolar; Biological: Anti-Thymocyte Globulin; Given IV; Other Names: ATGAM; ATG; Antithymocyte Globulin; Antithymocyte Serum; ATS; Thymoglobulin; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Drug: Tacrolimus; Given PO; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo stem cell transplant; Other Names: Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	Number of patients without any relapse post treatment completion	Up to 1 year post transplant
Time-to-engraftment	The number of days until participants by dose level reach engraftment.	30 days post transplant
Acute and Chronic Graft Verse Host Disease (GvHD)	GvHD (Graft versus Host Disease) occurs when immune cells transplanted from a non-identical donor (graft) recognizes the transplant recipient (the host) as foreign, thereby initiating an immune reaction in the transplant recipient. Acute GvHD typically occurs around the time of engraftment and manifests in skin, GI system, and liver abnormalities. Chronic GvHD is defined by manifestations such as ocular, oral, lung, sclerosis skin, failure to thrive, fascia, cholestasis in liver, esophagus strictures.	Up to 1 year post transplant

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2012
• Primary Completion (Actual): April 25, 2018
• Study Completion (Actual): April 25, 2018

Study Registration Dates

• First Submitted: June 25, 2012
• First Submitted That Met QC Criteria: June 26, 2012
• First Posted (Estimate): June 27, 2012

Study Record Updates

• Last Update Posted (Actual): February 24, 2020
• Last Update Submitted That Met QC Criteria: February 10, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Leukemia, Prolymphocytic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Adjuvants, Immunologic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Gemcitabine; Clofarabine; Lenograstim; Methotrexate; Tacrolimus; Busulfan; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: 2012-0249 (Other Identifier: M D Anderson Cancer Center); P30CA016672 (U.S. NIH Grant/Contract); NCI-2018-01798 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No