Intensive Consolidation and Stem Cell Mobilization Therapy Followed by Autologous Stem Cell Transplantation in High-risk Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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The goal of this clinical trial is to show that incorporating ofatumumab instead of rituximab in combination with etoposide and cytarabine (OVA) is successful in collecting autologous stem cells for use in an autologous stem cell transplantation (autoSCT) and to examine its effectiveness in eliminating residual diffuse large B-Cell Lymphoma (DLBCL) in patients.

Detailed Description
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Patients with relapsed Diffuse Large B-cell Lymphoma (DLBCL) who are refractory to or relapse within 12 months of first-line rituximab-based therapy, have poor outcomes with conventional approaches to autologous stem cell transplantation as detailed above. The investigators hypothesize that the intensive mobilization strategy developed can overcome some of the obstacles to successful autologous stem cell transplantation (ASCT) by both eliminating residual disease following salvage therapy and by facilitating stem cell collection. Even though there is clinical experience in the cooperative group setting with intensive pre-ASCT mobilization, it has never been prospectively validated in DLBCL and concerns exist as to its ability to improve outcomes with ASCT in this high-risk, and heavily pretreated group of patients. Furthermore, most patients in the study site's registry treated with intensive mobilization were rituximab-naïve and the findings may not translate in the rituximab-refractory population. The investigators also believe that ofatumumab, a novel monoclonal antibody against a distinct cluster of differentiation antigen 20 (CD20) epitope may in fact overcome rituximab resistance in DLBCL patients and through more effective complement dependent cytotoxicity (CDC) may eliminate minimal residual disease in the patient and contaminating tumor cells in the stem cell graft. General Design This is a single-institution, single-arm, prospective phase II study. Patients with high-risk DLBCL (defined as either achieving less than complete remission (CR) to initial rituximab-containing therapy or relapsing within 12 months of initial therapy) will be enrolled on this study and will undergo staging prior to receiving intensive mobilization with ofatumumab, etoposide, and high-dose ara-C (OVA). Following successful stem cell collection, patients will proceed to standard autologous transplantation with cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and etoposide (CBV) preparative regimen. Response evaluation will occur after salvage therapy, following intensive mobilization therapy (d42), at day +90 after ASCT, and at 6, 12 and 24 months thereafter. Event-free, progression-free, and overall survival will also be assessed until 48 months. The primary study endpoint is mobilization-adjusted complete metabolic response rate (maCR) following OVA. Subjects who are not chemosensitive to salvage therapy (i.e. do not achieve a partial response or complete response) will be re-evaluated after an additional salvage regimen. If they are still not chemosensitive at this point, they will be withdrawn from the study and replaced.

Official Title
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A Phase II Study of Intensive Consolidation and Stem Cell Mobilization Therapy With Ofatumumab, Etoposide, and High-dose Ara-C (OVA), Followed by Autologous Stem Cell Transplantation in High-risk Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Conditions
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Diffuse Large Cell Lymphoma Relapsed/Refractory

Intervention / Treatment
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* Drug: Ofatumumab
* Drug: Etoposide
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of refractory or relapsed biopsy-proven CD20+ diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma. Age 18 years or older Refractory to or relapse following a rituximab/anthracycline first-line regimen High-risk disease as defined by one of the following: First relapse after CR within 12 months of initiation of front-line therapy Less than CR to front-line therapy Second-line age-adjusted International Prognostic Index score (sAAIPI) of 1 or higher at the time of relapse Receipt of no more than three prior chemotherapy regimens. Monoclonal antibody therapy alone and involved field radiotherapy are not included in this number. Prior use of ofatumumab is allowed if there has been no disease progression following that therapy (i.e. ofatumumab-based salvage regimens are allowed) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Eligibility to proceed to OVA Chemosensitive disease as defined by at least a partial response to salvage therapy by positron emission tomography/computed tomography (PET/CT) criteria. Bone marrow with less than 15% lymphoma cells following salvage therapy. No evidence of myelodysplasia. Patients must have adequate organ function with serum creatinine <2.0 mg/dL, total bilirubin ≤2 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) ≤3 times the ULN. Neutrophils >1,000/μL and platelets >100,000/μL prior to day 0 No active uncontrolled infection. Eligibility to proceed to CBV ASCT Patients must be out of the hospital after OVA for a minimum of 4 weeks. Adequate peripheral blood stem cell collection with cluster of differentiation 34 (CD34) cell dose ≥2 X 106 /kg (actual body weight). No evidence of disease progression on day 42 assessment Approved by the University of California, San Francisco (UCSF) Bone Marrow Transplant Committee to proceed with ASCT. Exclusion Criteria Presence of disease transformation from a previously diagnosed low-grade lymphoma Progression following prior ofatumumab-based therapy Active central nervous system or meningeal involvement by lymphoma. Patients with a history of central nervous system (CNS) or meningeal involvement must be in a documented remission by cerebrospinal fluid (CSF) evaluation and contrast MRI imaging for at least 3 months prior to study entry. Evidence of myelodysplasia on any bone marrow biopsy. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half-lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study. Other past or current malignancy. Subjects who have been free of malignancy for at least 3 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C. History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae Known HIV infection Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient. Positive serology for Hepatitis B (HB) defined as a positive test for HbsAg and a detectable hepatitis B virus (HBV) DNA viral load. If negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HBV DNA test will be performed and if positive the subject will be excluded. If HBV DNA is negative, subject may be included but must undergo at least every 2-month HBV DNA polymerase chain reaction (PCR) testing from the start of treatment during the treatment course. Prophylactic antiviral therapy may be initiated at the discretion of the investigator. Positive serology for hepatitis C (HC) defined as a positive test for hepatitis C antibody (HCAb), in which case reflexively perform a hepatitis C virus (HCV) PCR to confirm the result Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy. Subjects who have received live virus vaccination within the 4 weeks prior to planned initiation of study treatment.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-arm study<br> | Drug: Ofatumumab<br>* 1000 mg IV days 0, 7, 14, 21<br>* Other names: HuMax-CD20;Drug: Etoposide<br>* 10 mg/Kg IV over 24 hours daily, days 1-4<br>* Other names: VP-16;Drug: Cytarabine<br>* 2000 mg/m2 IV twice daily, days 1-4<br>* Other names: Cytosine arabinoside;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Complete Response (CR) to the Treatment Upon Successful Stem Cell Mobilization | CR will be calculated based on the PET/CT scan following 2 cycles of salvage therapy using the revised International Working Group (IWG) Criteria for a lymphoma response. This includes: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy, Post-treatment residual mass of any size is permitted as long as it is PET-, Spleen and/or liver, if enlarged before therapy based on physical exam or CT scan, should not be palpable on physical exam and should be considered normal size by imaging studies, and nodules related to lymphoma should disappear, If bone marrow was involved by lymphoma before treatment, infiltrate must have cleared on repeat bone marrow biopsy. Biopsy sample must be adequate (with goal of > 20 mm unilateral core). If sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry but demonstrates small population of clonal l | Day 42 | 
| Number of Patients Achieving Mobilization-adjusted Complete Response (maCR) | Number of patients achieving maCR to the treatment upon successful stem cell mobilization, defined as at least 2 x10^6 cluster of differentiation 34 (CD34)+cells/Kg of actual body weight. Patients who require use of plerixafor or an autologous bone marrow harvest are considered mobilization failures and will be treated as non-responders. | Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Received OVA and Then Met Criteria to Proceed to ASCT and Achieved a CR/Partial Response (PR) Post-ASCT | Determination of CR or PR must meet the revised International Working Group (IWG) Criteria for lymphoma response | Up to 5 months | 
| Number of Patients Who Advance From Partial Response (PR) to Complete (CR) | Fluorodeoxyglucose-positron emission tomography (FDG-PET) conversion rate was used determined the number of participants who improved following OVA Treatment. | Up to 5 months | 
| Number of Participants With Successful Neutrophil Engraftments | Neutrophil engraftment is defined as the first day of 3 consecutive days with absolute neutrophil count of >500 cells/microlitre (uL). Response evaluation will occur at day +90 after ASCT, and at 6, 12 and 24 months thereafter | Up to 24 months after ASCT | 
| Number of Participants With Successful Platelet Engraftments | Platelet engraftment is defined as the first of three consecutive measurements for which the platelet count was > 20,000/uL, and must be at least 24 hours following the last platelet transfusion. Response evaluation will occur at day +90 after ASCT, and at 6, 12 and 24 months after ASCT | Up to 24 months after ASCT | 
| Median Time to Progression | Time to progression (TTP) is defined as the time from treatment after OVA until documented lymphoma progression or receipt of anti-lymphoma therapy (except for planned post-ASCT radiotherapy) or death due to lymphoma. Patients are to be censored at the time of last followup or death due to another cause | Up to 48 months | 
| Progression Free Survival Rate | The percentage of participants in the study still alive at time of censoring. The time frame defined as the time from day 0 of OVA treatment until lymphoma progression, receipt of anti-lymphoma therapy (except for planned post-ASCT radiotherapy), or death as a result of any cause. Patients will be censored at the time of median follow-up. | Up to 24 months | 
| Overall Survival Rate (OS) | The percentage of participants in the study still alive at time of censoring. The time frame is defined as the time from day 0 of OVA treatment until death as a result of any cause. Patients will be censored at the time of last followup | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed, refractory, DLBCL, lymphoma, B-cell, diffuse