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60 Brentuximab Vedotin Administered Concurrently with Multi-Agent Chemotherapy As Frontline Treatment of ALCL and Other CD30-Positive Mature T‑Cell and NΚ‑Cell Lymphomas

Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Lymphoma - Therapy with Biologic Agents, excluding Pre-Clinical Models: Novel Agents and Targeted Therapies
Sunday, December 9, 2012: 1:15 PM
Sidney Marcus Auditorium, Level 4, Building A (Georgia World Congress Center)

Michelle A. Fanale, MD1, Andrei R. Shustov, MD2*, Andres Forero-Torres, MD3, Nancy L. Bartlett, MD4, Ranjana H. Advani, MD5, Barbara Pro, MD6, Robert W. Chen, MD7, Andrew Davies, MD8*, Tim Illidge, PhD9*, Dana A. Kennedy, PharmD10* and Steven M. Horwitz, MD11

1Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX
2University of Washington Medical Center, Seattle, WA
3University of Alabama at Birmingham, Birmingham, AL
4Internal Medicine, Washington University School of Medicine, Saint Louis, MO
5Medicine/Oncology, Stanford University Medical Center, Stanford, CA
6Fox Chase Cancer Center, Philadelphia, PA
7Hematology and HCT, City of Hope National Medical Center, Duarte, CA
8Cancer Sciences Division, Southampton University Hospitals Trust, Southampton, United Kingdom
9Christie Hospital NHS, Manchester, United Kingdom
10Seattle Genetics, Inc., Bothell, WA
11Memorial Sloan-Kettering Cancer Center, New York, NY

Background

Systemic anaplastic large cell lymphoma (sALCL) is a subtype of non-Hodgkin lymphoma that expresses CD30. CD30 expression has also been demonstrated in other mature T- and NK-cell lymphomas. Approximately half of sALCL cases are associated with a chromosomal translocation affecting the anaplastic lymphoma kinase (ALK) gene (ALK-positive disease). In a study of sALCL patients, frontline treatment involving mainly anthracycline-containing regimens demonstrated overall response rates in ALK-negative and ALK-positive patients of 76% and 88%, respectively (Savage 2008). In another study, frontline CHOP demonstrated a response rate of 79% and a complete remission (CR) rate of 39% in patients with various peripheral T-cell lymphomas (Reimer 2009).  Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. A phase 2 study of single-agent brentuximab vedotin in patients with relapsed or refractory sALCL demonstrated an objective response rate of 86% and a 57% CR rate.

Methods

Thirty-nine patients have been enrolled in this phase 1, open-label, multicenter study, designed to assess the safety and activity of sequential and combination brentuximab vedotin and standard-dose CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHP (cyclophosphamide, doxorubicin, prednisone), respectively for the frontline treatment of higher-risk sALCL (ALK-negative or ALK-positive patients with IPI score ≥2) and other CD30+ mature T- and NK-cell lymphomas. The study is composed of 3 arms. Patients randomized to Arm 1 received 2 cycles of 1.8 mg/kg brentuximab vedotin treatment (q3wk) followed by 6 cycles of CHOP chemotherapy. Patients randomized to Arms 2 and 3 received treatment with up to 6 cycles of 1.8 mg/kg brentuximab vedotin in combination with standard-dose CHP chemotherapy (q3wk). Arm 2 was designed to determine the recommended dose of brentuximab vedotin in combination with CHP to be further evaluated in Arm 3. Responders received subsequent single-agent brentuximab vedotin therapy for an additional 8–10 cycles.

Results

Data are presented for 26 patients treated with combination brentuximab vedotin and CHP. Patients had a median age of 55.5 years (range 21 to 82). Fifteen of 26 patients were female.  Nineteen of 26 patients had a diagnosis of sALCL and 7 patients had a diagnosis of another mature T- or NK-cell lymphoma: peripheral T-cell lymphoma-NOS (n=2), angioimmunoblastic T-cell lymphoma (n=2), adult T-cell leukemia/lymphoma (n=2), and enteropathy-associated T-cell lymphoma (n=1). Most sALCL patients were ALK negative (16 of 19). Eighteen of 26 patients had advanced-stage disease and 17 of 26 had IPI scores ≥ 2.

The maximum tolerated dose (MTD) of brentuximab vedotin in combination with CHP was not exceeded at 1.8 mg/kg IV, based on 1 DLT (Grade 3 rash) among 6 patients. Treatment-emergent adverse events (AEs) (incidence >30%) included nausea (58%), fatigue (50%), diarrhea (50%), peripheral sensory neuropathy (38%), and alopecia (38%). AEs with a severity of Grade 3 or higher (incidence >5%) included febrile neutropenia (19%), nausea (8%), neutropenia (8%), and pulmonary embolism (8%). Five patients (19%) discontinued therapy due to an AE. The dose of brentuximab vedotin was reduced to 1.2 mg/kg in 4 of 26 patients (15%).

At the time of analysis, all 26 patients had been assessed for clinical response at the end of 6 cycles of combination therapy or at the latest assessment for 3 patients who had discontinued treatment prior to Cycle 6. All patients (100%) achieved an objective response, with 23 patients (88%) achieving a CR. All 7 non-sALCL patients achieved a CR with combination therapy. Following these assessments, 16 of 26 patients were continuing therapy with single-agent brentuximab vedotin and 2 patients experienced disease progression.

Conclusions

Brentuximab vedotin + CHP exhibited manageable tolerability at a recommended dose of 1.8 mg/kg (q3wk) in the frontline treatment of patients with CD30+ mature T- and NK-cell lymphomas. Clinical activity was observed following combination therapy, with an objective response rate of 100% and a CR rate of 88%. A phase 3 study comparing CHOP to brentuximab vedotin + CHP in the frontline treatment of mature T-cell lymphomas is planned.

Disclosures: Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with brentuximab vedotin.. Shustov: Seattle Genetics, Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Forero-Torres: Seattle Geentics, Inc.: Research Funding, Speakers Bureau. Bartlett: Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Advani: Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Abbott: Research Funding. Pro: Seattle Genetics, Inc.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other. Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Davies: Seattle Genetics, Inc.: Research Funding. Illidge: Millennium/Takeda: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Kennedy: Seattle Genetics, Inc.: Employment, Equity Ownership. Horwitz: Seattle Genetics, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Allos Therapeutics: Consultancy, Research Funding; Merck: Honoraria; Genzyme: Research Funding; Infinity Pharmaceuticals: Research Funding.

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