Gemcitabine/Clofarabine/Busulfan and Allogeneic Transplantation for Aggressive Lymphomas
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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: Methotrexate |
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 |
- Maximum Tolerated Dose (MTD) of Infusional Gemcitabine [ 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.
- 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:
Drug: Clofarabine
Phase I and Phase II dose of Clofarabine: 40 mg/m2 by vein on Days -6 to -3.
Other Names:
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 -8 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:
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:
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:
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: Methotrexate
5 mg/m2 by vein on Days +1, +3, +6 and +11.
|
Show Detailed Description Eligibility| Ages Eligible for Study: | 12 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age 12 to 65 years of age.
- 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 HLA matched (high resolution typing at A, B, C, DRB1) sibling or unrelated donor.
- Left ventricular EF >/= 45%.
- FEV1, FVC and corrected DLCO >/= 50%.
- Adequate renal function, as defined by estimated serum creatinine clearance >/=50 ml/min (using the Cockroft-Gault formula: creatinine clearance = [(140-age)*kg/(72*serum creatinine)] * 0.85 if female) and/or serum creatinine </=1.6 mg/dL.
- Serum bilirubin </= 2x upper limit of normal.
- SGPT </= 2x upper limit of normal.
- 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.
- 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 CNS disease.
- 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.
- Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV 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.
- HIV infection.
- Active uncontrolled bacterial, viral or fungal infections.
- Exposure to other investigational drugs within 4 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 SCT in the prior 12 months.
Contacts and Locations| Contact: Yago Nieto, MD,PHD | 713-792-8750 |
| United States, Texas | |
| UT MD Anderson Cancer Center | Recruiting |
| Houston, Texas, United States, 77030 | |
| 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 |
| Study First Received: | October 3, 2012 |
| Last Updated: | April 9, 2013 |
| 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 Methotrexate |
Additional relevant MeSH terms:
|
Aggression Lymphoma Behavioral Symptoms Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Antilymphocyte Serum Busulfan Methotrexate Gemcitabine Tacrolimus Lenograstim |
Rituximab Clofarabine Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Therapeutic Uses Myeloablative Agonists Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents |
ClinicalTrials.gov processed this record on May 23, 2013