Abstract
Abstract 798
Hodgkin lymphoma (HL) is a lymphoid neoplasm associated with the presence of CD30-positive Hodgkin Reed-Sternberg cells in a background of inflammatory cells. The regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has become a common standard of care for the frontline treatment of HL. However, although ABVD is curative for the majority of patients with advanced stage HL, up to 30% of patients will require a salvage therapy. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE).
This phase 1, open-label, multicenter study was conducted to evaluate the safety of brentuximab vedotin when administered in combination with standard therapy (ABVD) or a modified standard (AVD) (ClinicalTrials.gov NCT01060904). Patients received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, depending upon cohort assignment. The combination regimens were administered on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Each regimen evaluated a dose limiting toxicity (DLT) period, defined as any Cycle 1 toxicity requiring a delay of ≥ 7 days in standard ABVD or AVD therapy. Determination of antitumor activity was based on investigator assessment of objective response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). FDG-PET interpretation for Cycle 2 was performed by a central review per Deauville criteria with uptake above liver background considered positive.
Data are presented for the 51 patients treated. Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg with ABVD; 26 patients received 1.2 mg/kg with AVD. Overall, 37 patients were male (73%) and the median age of all patients was 33 years (range, 18–59). At baseline, 45% of all patients had Stage IV HL, 25% had an IPS score ≥4, and all patients with available ECOG status had a score of 0 or 1. No DLT was observed up to 1.2 mg/kg in either regimen. Common AEs (≥20 patients overall) noted in the ABVD and AVD cohorts, respectively, were nausea (76%, 77%), neutropenia (80%, 69%), peripheral sensory neuropathy (72%, 65%), vomiting (60%, 38%), fatigue (44%, 46%), and constipation (48%, 31%). Common ≥Grade 3 AEs (>10% of patients overall) observed in the ABVD and AVD cohorts, respectively, were neutropenia (80%, 65%), anemia (20%, 12%), febrile neutropenia (20%, 8%), and pulmonary toxicity (24%, 0%). In the ABVD cohorts, 11/25 (44%) patients had AEs of pulmonary toxicity, interstitial lung disease, or pneumonitis that led to discontinuation of bleomycin; 2 of these events led to death. Of these 11 patients, 7 completed treatment with AVD and brentuximab vedotin. In general, these events occurred between Cycles 3 and 6. No pulmonary toxicity was observed in the AVD cohort. The incidence of neuropathy was similar between the ABVD (72%) and AVD (73%) regimens; none of these events were ≥Grade 4 in severity. Overall, 7 patients discontinued brentuximab vedotin due to an AE (5 ABVD patients and 2 AVD patients).
At Cycle 2, 48 patients were evaluated by FDG-PET by central review; of these, all 22 ABVD and 24/26 AVD patients were PET negative. Of the 51 patients treated, 4 withdrew consent or were lost to follow-up prior to end of treatment (EOT) assessments. The remaining 47 patients had a 96% objective response rate: 21/22 ABVD patients (95%) and 23/25 AVD patients (92%) achieved CR at the end of frontline therapy, 1 AVD patient had PR (with further workup ongoing), 1 ABVD patient died of AEs (hyponatremia and pulmonary toxicity) prior to EOT, and 1 AVD patient had PD.
In patients with newly diagnosed HL, the maximum tolerated dose of brentuximab vedotin combined with ABVD or AVD was not reached; no DLT was observed up to 1.2 mg/kg every 2 weeks, the maximum planned dose. The safety profile observed confirmed that brentuximab vedotin can be safely combined with AVD; however, combination with a bleomycin-containing regimen is not recommended due to the incidence of pulmonary toxicity. The very high CR rate seen in this cohort of advanced-stage HL patients compares favorably with historical controls and warrants comparison with standard therapy. A phase 3 study comparing brentuximab vedotin combined with AVD versus ABVD alone is planned.
Disclosures:
Ansell: Seattle Genetics, Inc.: Research Funding; Celgene Corporation: Consultancy. 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. Connors:Seattle Genetics, Inc.: Research Funding. Park:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Affimed: Research Funding; Gilead: Research Funding.
P101 (0149) PHASE 1/2 STUDY OF BRENTUXIMAB VEDOTIN PLUS AVD IN PEDIATRIC PATIENTS WITH ADVANCED STAGE NEWLY DIAGNOSED CLASSICAL HODGKIN LYMPHOMA
