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

• ClinicalTrials.gov Identifier: NCT01701986
• Recruitment Status: Recruiting
• First Posted: October 5, 2012
• Last Update Posted: January 15, 2021
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Tracking Information

• First Submitted Date: October 3, 2012
• First Posted Date: October 5, 2012
• Last Update Posted Date: January 15, 2021
• Actual Study Start Date: October 25, 2012
• Estimated Primary Completion Date: May 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 7, 2019)

• Optimal dose of gemcitabine hydrochloride determined by dose limiting toxicity (Phase I) [ Time Frame: Within 30 days of transplant ]
  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.
• Success rate (Phase II) [ Time Frame: Up to 100 days post-transplant ]
  Defined as percentage of patients who are alive, engrafted and without grade 3-4 graft versus host disease (GVHD).
• Rate of event-free survival (Phase II) [ Time Frame: Up to 5 years ]
• Overall survival (Phase II) [ Time Frame: Up to 5 years ]
• Response rate (Phase II) [ Time Frame: Up to 5 years ]
• Complete response rate (Phase II) [ Time Frame: Up to 5 years ]
• Incidence of grade 2-4 and grade 3-4 acute GVHD (Phase II) [ Time Frame: Up to 5 years ]
• Incidence of limited and extensive chronic GVHD (Phase II) [ Time Frame: Up to 5 years ]

Original Primary Outcome Measures (submitted: October 4, 2012)

Maximum Tolerated Dose (MTD) of Infusional Gemcitabine [ Time Frame: 30 Days ]

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.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: October 4, 2012)

Success Rate [ Time Frame: 100 Days ]

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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: Gemcitabine/Clofarabine/Busulfan and Allogeneic Transplantation for Aggressive Lymphomas
• Brief Summary: 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.

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hematopoietic Cell Transplantation Recipient
• Refractory B-Cell Non-Hodgkin Lymphoma
• Refractory Hodgkin Lymphoma
• Refractory T-Cell Non-Hodgkin Lymphoma

Intervention

• 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
• Biological: Anti-Thymocyte Globulin
  Given IV
  Other Names:

  • Antithymocyte Globulin
  • Antithymocyte Serum
  • ATG
  • ATGAM
  • ATS
  • Thymoglobulin
• Drug: Busulfan
  Given IV
  Other Names:

  • 1, 4-Bis[methanesulfonoxy]butane
  • BUS
  • Bussulfam
  • Busulfanum
  • Busulfex
  • Busulphan
  • CB 2041
  • CB-2041
  • Glyzophrol
  • GT 41
  • GT-41
  • Joacamine
  • Methanesulfonic Acid Tetramethylene Ester
  • Methanesulfonic acid, tetramethylene ester
  • Mielucin
  • Misulban
  • Misulfan
  • Mitosan
  • Myeleukon
  • Myeloleukon
  • Myelosan
  • Mylecytan
  • Myleran
  • Sulfabutin
  • Tetramethylene Bis(methanesulfonate)
  • Tetramethylene bis[methanesulfonate]
  • WR-19508
• Drug: Clofarabine
  Given IV
  Other Names:

  • Clofarex
  • Clolar
• Drug: Gemcitabine Hydrochloride
  Given IV
  Other Names:

  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011
• Drug: Mycophenolate Mofetil
  Given IV then PO
  Other Names:

  • Cellcept
  • MMF
• Procedure: Peripheral Blood Stem Cell Transplantation
  Undergo allogeneic PBSCT
  Other Names:

  • PBPC transplantation
  • PBSCT
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplant
  • Peripheral Stem Cell Transplantation
• Other: Pharmacological Study
  Correlative studies
• Biological: Rituximab
  Given IV
  Other Names:

  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • 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: Tacrolimus
  Given IV then PO
  Other Names:

  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic

Study Arms

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.

Interventions:

• Procedure: Allogeneic Bone Marrow Transplantation
• Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
• Biological: Anti-Thymocyte Globulin
• Drug: Busulfan
• Drug: Clofarabine
• Drug: Gemcitabine Hydrochloride
• Drug: Mycophenolate Mofetil
• Procedure: Peripheral Blood Stem Cell Transplantation
• Other: Pharmacological Study
• Biological: Rituximab
• Drug: Tacrolimus

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 4, 2012): 80
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 1, 2022
• Estimated Primary Completion Date: May 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Yago Nieto, MD,PHD; 713-792-2466; ynieto@mdanderson.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01701986
• Other Study ID Numbers: 2012-0506; NCI-2012-02055 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2012-0506 ( Other Identifier: M D Anderson Cancer Center ); P30CA016672 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: M.D. Anderson Cancer Center
• Study Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Yago L Nieto, MD,PHD; M.D. Anderson Cancer Center

• PRS Account: M.D. Anderson Cancer Center
• Verification Date: January 2021