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Study of 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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01555541
Recruitment Status : Active, not recruiting
First Posted : March 15, 2012
Results First Posted : May 17, 2019
Last Update Posted : June 24, 2019
University of California, San Francisco
Information provided by (Responsible Party):
C. Babis Andreadis, University of California, San Francisco

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Diffuse Large Cell Lymphoma Relapsed/Refractory Drug: Ofatumumab Drug: Etoposide Drug: Cytarabine Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 17, 2012
Actual Primary Completion Date : July 6, 2017
Estimated Study Completion Date : June 2022

Arm Intervention/treatment
Experimental: Single-arm study Drug: Ofatumumab
1000 mg IV days 0, 7, 14, 21
Other Names:
  • Arzerra
  • GSK1841157
  • HuMax-CD20

Drug: Etoposide
10 mg/Kg IV over 24 hours daily, days 1-4
Other Names:
  • Vespid®
  • VP-16

Drug: Cytarabine
2000 mg/m2 IV twice daily, days 1-4
Other Names:
  • Cytosar-U®
  • Ara-C
  • Cytosine arabinoside

Primary Outcome Measures :
  1. Number of Patients Achieving Complete Response (CR) to the Treatment Upon Successful Stem Cell Mobilization [ Time Frame: Day 42 ]

    CR requires:

    1. Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.
    2. Post-treatment residual mass of any size is permitted as long as it is PET negative.
    3. Spleen and/or liver, if enlarged before therapy based on physical examination or CT scan, should not be palpable on physical examination and should be considered normal size by imaging studies, and nodules related to lymphoma should disappear.
    4. If bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made must be adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow cytometry will be considered a CR.

  2. Number of Patients Achieving Mobilization-adjusted Complete Response (maCR) [ Time Frame: Day 42 ]
    Number of patients achieving complete response 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. Subjects who require use of plerixafor or an autologous bone marrow harvest are considered mobilization failures and will be treated as non- responders.

Secondary Outcome Measures :
  1. Time to Neutrophil Engraftment Following Autologous Stem Cell Transplantation (ASCT) [ Time Frame: Response evaluation will occur at day +90 after ASCT, and at 6, 12 and 24 months thereafter ]
    Neutrophil engraftment is defined as the first day of 3 consecutive days with absolute neutrophil count of >500 cells/microliter (uL).

  2. Time to Platelet Engraftment Following Autologous Stem Cell Transplantation (ASCT) [ Time Frame: Response evaluation will occur at day +90 after ASCT, and at 6, 12 and 24 months thereafter ]
    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.

  3. Progression Free Survival [ Time Frame: Up to 48 months after ASCT ]
    Defined as time from day 0 until lymphoma progression, receipt of anti-lymphoma therapy (except for planned post-ASCT radiotherapy), or death as a result of any cause.

  4. Time to Progression [ Time Frame: Up to 48 months after ASCT ]
    Defined as time from study entry until documented lymphoma progression or receipt of anti-lymphoma therapy (except for planned post-ASCT radiotherapy) or death due to lymphoma.

  5. Event-Free Survival (EFS) [ Time Frame: Up to 48 months after ASCT ]
    Measured from day 0 to any treatment failure including disease progression, discontinuation of treatment for any reason, initiation of new therapy without documented progression, incidence of secondary Acute Myeloid Leukemia (AML) or Myelodysplastic syndromes (MDS), or death related to treatment.

  6. Overall Survival (OS) [ Time Frame: Up to 5 years after ASCT ]
    Defined as the time to death for any reason

  7. CR/ Partial Response (PR) Proportion [ Time Frame: ~ Month 5 ]

    CR: See above

    PR requires:

    1. Post-treatment PET positive in at least one previously involved site
    2. ≥ 50% decrease in sum of product of the diameters (SPD) of up to 6 of largest dominant nodes/nodal masses
    3. No increase in size of other nodes, liver, spleen
    4. Splenic & hepatic nodules must regress ≥ 50% in their sum of the product of the greatest diameters (SPD) or, for single nodules, in the greatest transverse diameter
    5. Involvement of other organs assessable; no measurable disease present (except splenic or hepatic nodules)
    6. Bone marrow assessment irrelevant for PR determination if sample positive before treatment. Patients who achieve CR by above criteria, but with persistent morphologic bone marrow involvement will be considered partial responders. If bone marrow was involved before therapy and clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders
    7. New sites of disease to be observed

  8. Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) Conversion Rate [ Time Frame: ~ Month 5 ]
    Number of patients who advance from PR to CR following OVA

  9. Minimal Residual Disease (MRD) [ Time Frame: ~ Month 26 ]
    Minimal Residual Disease (MRD), based on the number of positive copies assessed by polymerase chain reaction (PCR)

  10. Unanticipated CTCAE Grade 3 or Higher Adverse Events [ Time Frame: ~ Month 26 ]
    NCI CTCAE v 4.0 grade 3 or higher adverse events in the first 24 months NOT anticipated to occur with autologous stem cell transplantation

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01555541

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United States, California
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143
Sponsors and Collaborators
C. Babis Andreadis
University of California, San Francisco
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Principal Investigator: Charalambos Andreadis, MD, MSCE University of California, San Francisco
  Study Documents (Full-Text)

Documents provided by C. Babis Andreadis, University of California, San Francisco:
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Responsible Party: C. Babis Andreadis, Assistant Clinical Professor, Department of Medicine, University of California, San Francisco Identifier: NCT01555541    
Other Study ID Numbers: 112525
First Posted: March 15, 2012    Key Record Dates
Results First Posted: May 17, 2019
Last Update Posted: June 24, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by C. Babis Andreadis, University of California, San Francisco:
Additional relevant MeSH terms:
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Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs