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
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|ClinicalTrials.gov Identifier: NCT01555541|
Recruitment Status : Active, not recruiting
First Posted : March 15, 2012
Results First Posted : May 17, 2019
Last Update Posted : June 24, 2019
|Condition or disease||Intervention/treatment||Phase|
|Diffuse Large Cell Lymphoma Relapsed/Refractory||Drug: Ofatumumab Drug: Etoposide Drug: Cytarabine||Phase 2|
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||19 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Experimental: Single-arm study||
1000 mg IV days 0, 7, 14, 21
10 mg/Kg IV over 24 hours daily, days 1-4
2000 mg/m2 IV twice daily, days 1-4
- Number of Patients Achieving Complete Response (CR) to the Treatment Upon Successful Stem Cell Mobilization [ Time Frame: Day 42 ]
- 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 negative.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- Overall Survival (OS) [ Time Frame: Up to 5 years after ASCT ]Defined as the time to death for any reason
- CR/ Partial Response (PR) Proportion [ Time Frame: ~ Month 5 ]
CR: See above
- Post-treatment PET positive in at least one previously involved site
- ≥ 50% decrease in sum of product of the diameters (SPD) of up to 6 of largest dominant nodes/nodal masses
- No increase in size of other nodes, liver, spleen
- 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
- Involvement of other organs assessable; no measurable disease present (except splenic or hepatic nodules)
- 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
- New sites of disease to be observed
- Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) Conversion Rate [ Time Frame: ~ Month 5 ]Number of patients who advance from PR to CR following OVA
- 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)
- 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
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 ClinicalTrials.gov identifier (NCT number): NCT01555541
|United States, California|
|UCSF Helen Diller Family Comprehensive Cancer Center|
|San Francisco, California, United States, 94143|
|Principal Investigator:||Charalambos Andreadis, MD, MSCE||University of California, San Francisco|