A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma

Purpose Obinutuzumab (GA101), a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, was superior to rituximab in human diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) xenograft models. In phase I of our study, obinutuzumab (GA101) exhibited encouraging activity but no clear dose-response relationship, and few patients had aggressive histologies. The efficacy and safety of two doses of obinutuzumab (GA101) were explored in our randomized phase II trial in patients with heavily pretreated DBLCL and MCL. Patients and Methods Patients were randomly assigned to receive eight cycles of obinutuzumab (GA101) either as a flat dose of 400 mg for all infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 to 8) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8. Results Forty patients were enrolled: 21 patients in the 400/400-mg treatment arm (DLBCL, n = 10; MCL, n = 11) and 19 patients in the 1,600/800-mg arm (DLBCL, n = 15; MCL, n = 4). End-of-treatment response was 28% (32% and 24% in the 1,600/800-mg and 400/400-mg study arms, respectively). Best overall response rates were 37% in the 1,600/800-mg arm and 24% in the 400/400-mg study arm (DLBCL, eight [32%] of 25 patients; MCL, four [27%] of 15 patients). Five (20%) of 25 rituximab-refractory patients exhibited treatment response, including four of 12 in the 1,600/800-mg group. The most common adverse events were infusion-related reactions (IRRs), which were manageable. Three patients had grade 3/4 IRRs. Grade 3/4 neutropenia was seen in only one patient. Conclusion Obinutuzumab (GA101) 1,600/800 mg achieves early steady-state concentration and clinical activity with an acceptable safety profile in relapsed/refractory DLBCL and MCL, supporting further exploration.

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Diffuse Aggressive Lymphoma

Hematology ◽

10.1182/asheducation-2004.1.221 ◽

2004 ◽

Vol 2004 (1) ◽

pp. 221-236 ◽

Cited By ~ 53

Author(s):

Richard I. Fisher ◽

Thomas P. Miller ◽

Owen A. O'Connor

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Hodgkin's Lymphomas ◽

Large B Cell

Abstract The aggressive non-Hodgkin’s lymphomas can be cured in more than half of the cases. However, there has been great variation in the results reported from individual clinical Phase II trials. This variation in result can be attributed to unrecognized heterogeneity in this group of diseases. Recent clinical and molecular studies have enabled us to define more homogenous population in which new therapies can be studied. For patients with advanced stages of diffuse large B cell lymphoma, a new standard of therapy exists. For patients with localized aggressive non-Hodgkin’s lymphomas, heterogeneity in patient selection prevents us from defining a new standard of care. Finally, in mantle cell lymphoma, new opportunities in drug discovery may permit advances in the treatment of this uniformly fatal malignancy. In Section I, Dr. Richard Fisher reviews the development of combination chemotherapy for patients with advanced stage diffuse large B cell lymphoma. Because of great heterogeneity in patients enrolled in Phase II studies, large randomized Phase III studies were required in the 1980s to define CHOP has the standard of care. This heterogeneity has now been defined carefully in the international prognostic factor index and more recently by gene array studies. It will now need to be incorporated prospectively into studies or retrospectively analyzed to understand clinical trial results. The addition of rituximab to CHOP has now been demonstrated to improve survival in two large Phase III studies in elderly patients. A recently presented study in younger patients suggests a similar benefit. Thus CHOP/rituximab has become the established standard of care for all patients with advanced stage diffuse large B cell lymphoma. Other concepts being evaluated to further improve on these results include: dose intensification; initial treatment with chemotherapy plus allogeneic stem cell transplantation; and infusional chemotherapy. Finally, the status of the treatment for relapsed patients will be defined. In Section II, Dr. Thomas Miller defines the treatment for limited stage aggressive non-Hodgkin’s lymphoma. Randomized trials have demonstrated the critical importance of initial chemotherapy for treatment of these patients. The amount of chemotherapy given needs to be increased for patients with bulky tumors. In most circumstances radiotherapy after the completion of chemotherapy has been shown to be advantageous. A modification of the international prognostic factor index for patients with early stage disease is presented to permit comparisons among different populations. Recently reported early-stage studies need to be analyzed in terms of the heterogeneity of the patients involved to understand the reported results. The addition of monoclonal antibodies, as well as radioimmunotherapy, are being tested in an effort to improve on the results for the poor prognosis patients. In Section III, Dr. Owen O’Connor describes the pathology immunophenotype and natural history of mantle cell lymphoma. Conventional treatment strategies with combination chemotherapy achieved objective responses in approximately half of the patients but no significant impact on survival. The addition to rituximab to CHOP chemotherapy or other treatment strategies appears to improve the remission rate; however, no major changes in survival have also been reported. Excellent single institution results have been reported with HyperCVAD plus rituximab regimen, which is currently being tested in a national cooperative group trial. The most excitement in this field currently relates to the variety of new agents which appear to have significant activity in relapsed patients with mantle cell lymphoma. This includes the proteosome inhibitor, bortezomib, which is shown to have approximately a 50% response rate with some CRs and reasonable durability in early single institution Phase II studies. Larger national multi-center trials are ongoing. In addition, agents such as thalidomide, flavopiridol, and piroxantrone will be reviewed.

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Faculty Opinions recommendation of Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718028213.793482096 ◽

2013 ◽

Author(s):

Nicolas Mounier

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Large B Cell

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Dose‐intense chemoimmunotherapy plus radioimmunotherapy in high‐risk diffuse large B‐cell lymphoma and mantle cell lymphoma: a phase II study

British Journal of Haematology ◽

10.1111/bjh.15138 ◽

2018 ◽

Vol 184 (4) ◽

pp. 647-650

Author(s):

Kathryn E. Hudson ◽

David Rizzieri ◽

Samantha M. Thomas ◽

Thomas W. LeBlanc ◽

Zachary Powell ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Phase Ii Study ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Large B Cell

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A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.779.779 ◽

2011 ◽

Vol 118 (21) ◽

pp. 779-779 ◽

Cited By ~ 8

Author(s):

Beata Holkova ◽

Edward B. Perkins ◽

Lubomir Sokol ◽

Kristy L. Richards ◽

Samir Parekh ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Hdac Inhibitor ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Response Rates ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Large B Cell

Abstract Abstract 779FN2 Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors which interact to induce cell death in various human tumors, particularly indolent B-cell malignancies such as multiple myeloma. Furthermore, recent phase I studies have shown promising results for proteasome/HDAC inhibitor regimens in myeloma. The primary objective of this phase II study was to estimate the response rates of patients with mantle cell lymphoma (MCL), or relapsed or refractory diffuse large B-cell lymphoma (DLBCL) to the proteasome inhibitor bortezomib administered in conjunction with the pan-HDAC inhibitor vorinostat. Patients were assigned to 1 of 3 cohorts: (A) bortezomib - naïve MCL; (B) bortezomib - exposed MCL; and (C) relapsed or refractory DLBCL. The schedule of administration was vorinostat 400 mg administered orally on days 1–5 and 8–12, and bortezomib 1.3 mg/m2 administered intravenously on days 1, 4, 8, and 11; on a 21 day cycle. Fifty-one patients have been enrolled and 47 treated, 17 in cohort A, 4 in cohort B, and 26 in cohort C. Cohort B was closed due to inadequate accrual. Patient characteristics included male/female n = 33 (70%)/14 (30%), median age = 62 years [range 33–83]. ECOG performance scores ranged from 0–2. The median number of prior therapies was 2 [range 0–8]. Common treatment-related adverse events included fatigue, dizziness, leukopenia, neutropenia, lymphopenia, peripheral sensory neuropathy, nausea, vomiting, anorexia, elevated creatinine, thrombocytopenia, diarrhea, and chills. Common grade 3 and 4 toxicities (CTCAE v4) included anemia, diarrhea, fatigue, thrombocytopenia, lymphopenia, dehydration, hyponatremia, and hypotension. Two deaths have occurred: 1 associated with neutropenic sepsis and felt possibly related to study treatment, and 1 due to disease progression after discontinuation of study treatment. Patients were accrued according to a 2-stage Simon minimax design. Investigator-reported responses (CR + PR) have been achieved in cohort A (8 out of 17, 47%) and cohort C (3 out of 26, 12%). Both of these response rates met the thresholds to proceed from the 1st to the 2nd stage of enrollment.CohortTotalABCResponseComplete Response (CR)2–13Partial Response (PR)6–28Stable Disease (SD)32510Progressive Disease (PD)521522Too Early To Evaluate1––1Not Assessed––33Total1742647 Correlative studies are ongoing and are designed to determine whether the combination of bortezomib and vorinostat is more active in lymphomas in which baseline activation of NF-kappa B can be detected. Sample analysis and results are pending. These findings indicate that combined treatment with vorinostat and bortezomib is active in patients with MCL, or relapsed or refractory DLBCL, particularly for MCL where the 47% response rate greatly exceeds the 29% (8 of 28) needed to proceed to stage 2. Disclosures: Sokol: Medimmune: Honoraria; Celgene: Consultancy, Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Allos: Consultancy. Richards:Celgene: Research Funding; Merck: Consultancy; Millennium: Consultancy.

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