Gemcitabine/Clofarabine/Busulfan and Allogeneic Transplantation for Aggressive Lymphomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by M.D. Anderson Cancer Center
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01701986
First received: October 3, 2012
Last updated: August 14, 2014
Last verified: August 2014
  Purpose

The goal of this clinical research study is to find the highest tolerable dose of gemcitabine (out of 6 possible doses) that can be given in combination with busulfan and clofarabine before an allogeneic stem cell transplant. Researchers also want to learn if this combination can help to control lymphoma. The safety of this treatment will also be studied.

Busulfan is designed to bind to DNA (the genetic material of cells), which may cause cancer cells to die. It is commonly used in stem cell transplants.

Clofarabine and gemcitabine are designed to block the growth of cancer cells, which may cause the cancer cells to die.


Condition Intervention Phase
Lymphoma
Drug: Gemcitabine
Drug: Clofarabine
Drug: Busulfan
Procedure: Stem Cell Infusion
Drug: Anti-Thymocyte Globulin
Drug: Rituximab
Drug: Filgrastim
Drug: Tacrolimus
Drug: Mycophenolate Mofetil
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Gemcitabine/Clofarabine/Busulfan and Allogeneic Transplantation for Aggressive Lymphomas

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Infusional Gemcitabine Combined With Fixed Doses of Clofarabine and Busulfan [ Time Frame: 30 Days ] [ Designated as safety issue: Yes ]
    Dose limiting toxicity (DLT) 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, occurring within 30 days from transplant. Patient outcome time of occurrence of DLT or, if DLT has not yet occurred by day 30, outcome will be the patient's follow-up time without DLT.


Secondary Outcome Measures:
  • Success Rate [ Time Frame: 100 Days ] [ Designated as safety issue: No ]
    Success rate defined as percentage of patients who are alive, engrafted and without grade 3-4 graft-vs.-host-disease (GVHD), rate of event-free (EFS), overall survival (OS), response rate (RR), complete response (CR) rate, incidence of grade 2-4 and grade 3-4 acute GVHD, and incidence of limited and extensive chronic GVHD.


Estimated Enrollment: 80
Study Start Date: October 2012
Estimated Primary Completion Date: October 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Gemcitabine + Clofarabine + Busulfan

Phase I Starting dose of Gemcitabine: 950 mg/m2 by vein on Days -6 and -4.

Phase II Starting dose of Gemcitabine: Maximum tolerated dose (MTD) from Phase I.

Phase I and Phase II dose of Clofarabine: 40 mg/m2 by vein on Days -6 to -3.

Phase I and Phase II dose of Busulfan: Busulfan will be administered at the dose calculated to achieve a systemic exposure dose of 4000 µMol-min in normal saline over three hours IV every twenty-four hours for four consecutive days (days -6 to -3), starting immediately after the completion of clofarabine. If not feasible to perform pharmacokinetic monitoring, patients receive fixed dose of 100 mg/m2/day for 4 days, which is expected to yield a median daily AUC of 4,000 µMol.min-1.

Stem cell infusion on Day 0.

Drug: Gemcitabine

Phase I Starting dose of Gemcitabine: 75 mg/m2/ loading dose by vein targeting the desired steady state concentration of 20 µmolar on Day -6 and Day -4. This will be immediately followed by an infusion at a fixed rate of 10 mg/m2/min over varying lengths of time per study cohort.

Phase II Starting dose of Gemcitabine: Maximum tolerated dose (MTD) from Phase I.

Other Names:
  • Gemcitabine Hydrochloride
  • Gemzar
Drug: Clofarabine
Phase I and Phase II dose of Clofarabine: 40 mg/m2 by vein on Days -6 to -3.
Other Names:
  • Clofarex
  • Clolar
Drug: Busulfan

Phase I and Phase II dose of Busulfan: Test dose of 32 mg/m2 by vein as an outpatient between Day -15 and Day -8, or on Day -9 as an inpatient.

Busulfan 4000 µMol-min by vein four consecutive days (Days -6 to -3), starting immediately after the completion of clofarabine. If not feasible to perform pharmacokinetic monitoring, patients receive fixed dose of 100 mg/m2/day for 4 days, which is expected to yield a median daily AUC of 4,000 µMol.min-1.

Other Names:
  • Busulfex
  • Myleran
Procedure: Stem Cell Infusion
Stem cell infusion on Day 0.
Drug: Anti-Thymocyte Globulin
0.5 mg/kg on Day -3, 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1 for patients receiving a graft from a matched unrelated donor.
Other Names:
  • Thymoglobulin
  • ATG
Drug: Rituximab
375 mg/m2 by vein on Day -14 and Day -7 and then on Day +1 and Day +8 for patients with CD20+ disease.
Other Name: Rituxan
Drug: Filgrastim
5 mcg/kg/day subcutaneously starting on Day +7 until blood cell levels return to normal.
Other Names:
  • G-CSF
  • Neupogen
Drug: Tacrolimus
0.015 mg/kg by vein beginning on Day -2, as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml. Tacrolimus is changed to oral dosing when tolerated and can be tapered off after day +90 if no graft versus host disease (GVHD) is present.
Other Name: Prograf
Drug: Mycophenolate Mofetil
1,500 mg by vein twice a day on day 0 after cell infusion and will be changed to oral dosing (1:1 conversion) when tolerated.
Other Names:
  • MMF
  • CellCept

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   12 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 12 to 65 years of age.
  2. Patients with refractory B-cell or T-cell non-Hodgkin's lymphoma or Hodgkin's lymphoma who are eligible for allogeneic transplantation.
  3. An 8/8 HLA matched (high resolution typing at A, B, C, DRB1) sibling or unrelated donor.
  4. Left ventricular EF >/= 45%.
  5. FEV1, FVC and corrected DLCO >/= 50%.
  6. Adequate renal function, as defined by estimated serum creatinine clearance >/=50 ml/min (using the Cockcroft -Gault formula: creatinine clearance = [(140-age)*kg/(72*serum creatinine)] * 0.85 if female) and/or serum creatinine </=1.6 mg/dL.
  7. Serum bilirubin </= 2x upper limit of normal.
  8. SGPT </= 2x upper limit of normal.
  9. Voluntary signed 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.
  10. 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:

  1. Patient with active CNS disease.
  2. Pregnancy (positive Beta 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.
  3. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/=10,000 copies/mL, or >/= 2,000 IU/mL).
  4. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
  5. HIV infection.
  6. Active uncontrolled bacterial, viral or fungal infections.
  7. Exposure to other investigational drugs within 4 weeks before enrollment.
  8. Grade >/= 3 non-hematologic toxicity from previous therapy that has not resolved to </= grade 1.
  9. Radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment.
  10. Prior whole brain irradiation.
  11. Prior autologous SCT in the prior 12 months.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01701986

Contacts
Contact: Yago Nieto, MD,PHD 713-792-8750

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
Principal Investigator: Yago Nieto, MD,PHD UT MD Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01701986     History of Changes
Other Study ID Numbers: 2012-0506, NCI-2012-02055
Study First Received: October 3, 2012
Last Updated: August 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Lymphoma
Aggressive lymphomas
Allogeneic stem-cell transplant
alloSCT
Refractory B-cell
T-cell
Non-Hodgkin's lymphoma
Hodgkin's lymphoma
Gemcitabine
Gemcitabine Hydrochloride
Gemzar
Clofarabine
Clofarex
Clolar
Busulfan
Busulfex
Myleran
Anti-Thymocyte Globulin
ATG
Thymoglobulin
Rituximab
Rituxan
Filgrastim
G-CSF
Neupogen
Tacrolimus
Prograf
Mycophenolate Mofetil
MMF
CellCept

Additional relevant MeSH terms:
Aggression
Lymphoma
Behavioral Symptoms
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Antilymphocyte Serum
Busulfan
Clofarabine
Gemcitabine
Lenograstim
Mycophenolate mofetil
Mycophenolic Acid
Rituximab
Tacrolimus
Adjuvants, Immunologic
Alkylating Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors

ClinicalTrials.gov processed this record on October 23, 2014