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

Gemcitabine/Clofarabine/Busulfan and Allogeneic Transplantation for Aggressive Lymphomas

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Refractory Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory T-Cell Non-Hodgkin Lymphoma; Hematopoietic Cell Transplantation Recipient
• Intervention / Treatment: Other: Pharmacological Study; Drug: Gemcitabine Hydrochloride; Biological: Rituximab; Drug: Clofarabine; Biological: Anti-Thymocyte Globulin; Drug: Busulfan; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Bone Marrow Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Mycophenolate Mofetil; Drug: Tacrolimus

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• 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: 12 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (gemcitabine, clofarabine, busulfan, BMT or PBSCT); 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.

Other: Pharmacological Study; Correlative studies; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; LY-188011; LY188011; Biological: Rituximab; Given IV; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar GB241; Rituximab Biosimilar IBI301; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; RTXM83; 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; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; Procedure: Allogeneic Bone Marrow Transplantation; Undergo allogeneic BMT; Other Names: Allo BMT; Allogeneic BMT; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic BMT or PBSCT; Other Names: Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Drug: Mycophenolate Mofetil; Given IV then PO; Other Names: Cellcept; MMF; Drug: Tacrolimus; Given IV then PO; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Yago L Nieto, MD,PHD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• University of Texas MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2012
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): May 31, 2024

Study Registration Dates

• First Submitted: October 3, 2012
• First Submitted That Met QC Criteria: October 4, 2012
• First Posted (Estimated): October 5, 2012

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

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; Lymphoma; Lymphoma, B-Cell; Hodgkin Disease; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Antibodies; Clofarabine; Immunoglobulins; Rituximab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Tacrolimus; Mycophenolic Acid; Busulfan; Thymoglobulin; Antilymphocyte Serum; Gemcitabine
• Other Study ID Numbers: 2012-0506 (Other Identifier: M D Anderson Cancer Center); P30CA016672 (U.S. NIH Grant/Contract); NCI-2012-02055 (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