Bendamustine Bridge to Autologous or Allogeneic Transplant for Relapsed/Refractory Lymphoma

Study Overview
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Brief Summary
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This clinical trial is for men and women with whose lymphoma (non-Hodgkin or Hodgkin) did not respond to treatment or has returned after responding to previous therapy, and who are in need of a stem cell transplant. The purpose of this study is to test the safety and effectiveness of giving the drug Bendamustine, followed by high dose chemotherapy, within two weeks prior to a stem cell transplant for lymphoma that has not achieved a complete response to salvage (treatment used for relapsed disease) chemotherapy.

Detailed Description
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Subjects with Hodgkin's or Non-Hodgkin's lymphoma that did not respond to treatment or have disease that has returned after responding to previous treatment, and are in need of a stem cell transplant will be eligible for this pilot study. Thirty subjects will be enrolled, with 15 subjects assigned to the autologous transplant cohort (according to disease status and eligibility) and 15 subjects to the allogeneic transplant cohort (according to diseases status and eligibility). Subjects will undergo the following a number of screening procedures to determine eligibility. All eligible subjects will receive bendamustine at a dose of 200 mg/ m2/ day for two days on Days - 24 and Day - 23 followed by a short break of 10 - 14 days. Subjects will then receive the conditioning regimen, BEAM (carmustine, etoposide, cytarabine arabinoside, and Melphalan) and alemtuzumab for 6 days (Day -6 to Day -1) followed by an autologous or allogeneic transplant. Subjects with pathological confirmed B-cell malignancies will also receive rituximab 375 mg/m2 on Days + 1 and +8 post-transplant. Subjects with T-cell lymphoma will be enrolled in the study but will not receive rituximab. After the transplantation all subjects will receive medication to prevent graft vs host disease and supportive care to prevent infections. To speed up the recovery of stem cells, subjects will receive post-transplant filgrastim (G-CSF). After discharge from the hospital, subjects will be seen regularly in the clinic for an exam and assessments. All these tests are considered standard of care.

Official Title
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A Pilot Study of a Sequential Regimen of Intensive Chemotherapy Followed by Autologous or Allogeneic Transplantation for Refractory Lymphoma (Non-Hodgkin's and Hodgkin's) and Phase 2 Expansion Cohort

Conditions
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Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Carmustine
* Drug: Etoposide
* Drug: Melphalan
* Drug: Cytarabine
* Drug: Alemtuzumab
* Biological: Autologous Stem Cell Transplantation
* Biological: Allogeneic Stem Cell Transplantation
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: must have histologically or cytologically confirmed relapsed or primary refractory lymphoma (including Hodgkin's Lymphoma) staged with Positron Emission Tomography (PET) scan to have Allogeneic arm: Progressive disease or No response to salvage therapy or Partial response to salvage therapy defined as > 50% reduction in bidirectional area of masses but standardized uptake value (SUV) remains ≥8 in at least some PET avid areas Prior autologous transplant Autologous arm: Partial response of >50% reduction in bidirectional area of masses and SUV reduction to <8 in PET avid areas Subjects must have evaluable disease. Subjects must have received at least one induction therapy and one line of salvage therapy that each incorporate at least two drugs that are standard of care for lymphoma Age >18 years. Karnofsky Performance Score (KPS) ≥ 50% For autologous transplants: Subjects must have an adequate number of CD34+ stem cells collected to allow for transplantation. This number is defined as ≥ 2x106 CD34+ cells / kg body weight. If not previously collected and stored, the subject must be willing to undergo stem cell mobilization and collection as per standard practice. If sufficient cells cannot be collected, subjects will be offered the option to proceed with the allogeneic arm of the study. Male and female subjects must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment. Female subjects of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Known to be positive for HIV Subjects may not be receiving any other investigational agents (defined as non FDA-approved agents) at the time of initiating bendamustine regimen. However, the salvage therapy for lymphoma can be part of an ongoing clinical trial with an investigational agent. Women who are pregnant or breast feeding. Women of childbearing age must use adequate contraception and have a negative pregnancy test. The risks to an unborn fetus or potential risks in nursing infants are unknown. History of allergic reactions attributed to compounds of similar chemical or biologic composition to any medications listed in the protocol. Subject with severely decreased Left Ventricular Ejection Fraction (LVEF) or severely impaired pulmonary function tests (PFT's) Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemo plus Autologous Transplantation<br>Bendamustine 200 mg/ m2/ day on Days - 24 and Day - 23 followed by a short break of 10 - 14 days, followed by Melphalan, Carmustine, Etoposide, Cytarabine (BEAM) and alemtuzumab, plus rituximab for all b-cell malignancies, followed by autologous transplant | Drug: Bendamustine<br>* Days - 24 and Day - 23 followed by a short break of 10 - 14 days.<br>* Other names: Treanda;Drug: Carmustine<br>* 300 mg/m2 on Day -6<br>* Other names: Bicnu;Drug: Etoposide<br>* 100 mg/m2 on days -5 to -2<br>* Other names: Toposar;Drug: Melphalan<br>* 140mg/m2 on Day -1<br>* Other names: Alkeran;Drug: Cytarabine<br>* 200 mg/m2 on days -5 to -2<br>* Other names: Ara-C;Drug: Alemtuzumab<br>* 20 mg/m2 days -6 to -2 for UNRELATED donors, and 20 mg/m2 days -4 to -2 for RELATED donors<br>* Other names: Campath;Biological: Autologous Stem Cell Transplantation<br> <br> Drug: Rituximab<br>* Only to be administered in subjects with B-cell malignancies. Dose is 375 mg/m2 on Days 1 and 8 post-transplant<br>* Other names: Rituxan;|
| Experimental: Chemo plus Allogeneic Transplantation<br>Bendamustine 200 mg/ m2/ day on Days - 24 and Day - 23 followed by a short break of 10 - 14 days, followed by Melphalan, Carmustine, Etoposide, Cytarabine (BEAM) and alemtuzumab, plus rituximab for all b-cell malignancies, followed by allogeneic transplant | Drug: Bendamustine<br>* Days - 24 and Day - 23 followed by a short break of 10 - 14 days.<br>* Other names: Treanda;Drug: Carmustine<br>* 300 mg/m2 on Day -6<br>* Other names: Bicnu;Drug: Etoposide<br>* 100 mg/m2 on days -5 to -2<br>* Other names: Toposar;Drug: Melphalan<br>* 140mg/m2 on Day -1<br>* Other names: Alkeran;Drug: Cytarabine<br>* 200 mg/m2 on days -5 to -2<br>* Other names: Ara-C;Drug: Alemtuzumab<br>* 20 mg/m2 days -6 to -2 for UNRELATED donors, and 20 mg/m2 days -4 to -2 for RELATED donors<br>* Other names: Campath;Biological: Allogeneic Stem Cell Transplantation<br> <br> Drug: Rituximab<br>* Only to be administered in subjects with B-cell malignancies. Dose is 375 mg/m2 on Days 1 and 8 post-transplant<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Able to Proceed to Transplant | Number of patients in each arm able to proceed to stem cell transplantation within 14 days of receiving bendamustine treatment | 14 days after bendamustine treatment | 
| Number of Patients Achieving Neutrophil Engraftment | Proportion of patients who successfully achieve neutrophil engraftment after stem cell transplant, defined as an absolute neutrophil count of 500/mm3 or for three consecutive days. | 35 Days Post-Transplant | 
| Number of Patients Achieving Platelet Engraftment | Proportion of patients who successfully achieve platelet engraftment after stem cell transplant, defined as a platelet count of >20k/microL for three consecutive days without transfusion support for seven consecutive days. | 74 Days Post-Transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at Day 100 Post-Transplant | The time from stem cell infusion (Day 0) to death from any cause. | From Day 0 until time of death, assessed up to 100 days post-transplant | 
| Overall Survival at Day 365 Post-Transplant | The time from stem cell infusion (Day 0) to death from any cause. | From Day 0 until time of death, assessed up to 365 days post-transplant | 
| Transplant-Related Mortality | Death due to any cause other than disease progression within first 100 days post-transplant. | From Day 0 until time of death, up to 100 days post-transplant. | 
| Disease Response Following Salvage Chemotherapy | Proportion of patients achieving a complete remission (CR; disappearance of clinically overt disease with no FDG-avid lesions on PET scan), partial remission (PR; reduction in clinical disease buden and >50% bi-dimensional decrease in tumor size on imaging), stable disease (SD; failure to meet the criteria for CR, PR or PD with no new areas of disease involvement) or progressive disease (PD; the appearance of any new lesion >1.5cm in size or a greater than 50% increase in the diameter of a previously identified node of over 1cm in size), as per Cheson Criteria, following salvage chemotherapy with Bendamustine. | Within 14 days of salvage chemotherapy treatment | 
| Disease Response 30 Days Post-Transplant | Proportion of patients achieving a complete remission (CR; disappearance of clinically overt disease with no FDG-avid lesions on PET scan), partial remission (PR; reduction in clinical disease buden and >50% bi-dimensional decrease in tumor size on imaging), stable disease (SD; failure to meet the criteria for CR, PR or PD with no new areas of disease involvement) or progressive disease (PD; the appearance of any new lesion >1.5cm in size or a greater than 50% increase in the diameter of a previously identified node of over 1cm in size), as per Cheson Criteria, 30 days following autologous or allogeneic stem cell transplant | 30 days after stem cell transplant | 
| Disease Response at 1 Year Post-Transplant | Proportion of patients achieving a complete remission (CR; disappearance of clinically overt disease with no FDG-avid lesions on PET scan), partial remission (PR; reduction in clinical disease buden and >50% bi-dimensional decrease in tumor size on imaging), stable disease (SD; failure to meet the criteria for CR, PR or PD with no new areas of disease involvement) or progressive disease (PD; the appearance of any new lesion >1.5cm in size or a greater than 50% increase in the diameter of a previously identified node of over 1cm in size), as per Cheson Criteria, 1 year following autologous or allogeneic stem cell transplant | 1 year after stem cell transplant | 
| Progression-Free Survival After Stem Cell Transplant | Time elapsed between stem cell transplant (Day 0) and disease progression, as defined by the Cheson Criteria (the appearance of any new lesion >1.5cm in size or a greater than 50% increase in the diameter of a previously identified node of over 1cm in size) | Stem cell transplant (Day 0) up to 2 years post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, Lymphoma, Transplant