Elsevier

The Lancet Oncology

Volume 14, Issue 13, December 2013, Pages 1348-1356
The Lancet Oncology

Articles
Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study

https://doi.org/10.1016/S1470-2045(13)70501-1Get rights and content

Summary

Background

Roughly 70–80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma.

Methods

We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.

Findings

Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).

Interpretation

Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma.

Funding

Seattle Genetics Inc and Takeda Pharmaceuticals International Co.

Introduction

Advances such as radiotherapy and combination chemotherapy in the first-line treatment of Hodgkin's lymphoma have contributed to improved outcomes for these patients in the past decades. More recently, the introduction of more dose-intense chemotherapy regimens for advanced stage Hodgkin's lymphoma has been associated with treatment success.1 For patients with advanced stage Hodgkin's lymphoma multiple first-line and second-line treatments, including the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—internationally, the most widely used regimen in Hodgkin's lymphoma—is expected to cure about 70–80% of patients.2, 3, 4, 5, 6, 7 However, in addition to treatment failures noted for ABVD, the regimen is often associated with unpredictable bleomycin-induced lung-related toxic effects that can be life-threatening.8, 9, 10

Brentuximab vedotin (Seattle Genetics Inc, Bothell, WA, USA) is an antibody–drug conjugate composed of a CD30-targeted chimeric monoclonal antibody covalently linked, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In a phase 2 single-arm study11 of patients with relapsed or refractory Hodgkin's lymphoma treated with brentuximab vedotin after failure of high-dose chemotherapy and postautologous stem-cell transplant, 76 (75%) of 102 patients achieved an objective response, and 35 patients (34%) achieved complete remission. Adverse events were manageable with dose reduction or delay.

Brentuximab vedotin was also tested preclinically in combination with chemotherapy. In the L450cy Hodgkin's lymphoma xenograph model, administration of ABVD plus brentuximab vedotin in tumour-bearing mice showed significantly increased antitumour activity than in mice treated with ABVD or brentuximab vedotin alone, suggesting a potentially synergistic effect.12 We aimed to assess the safety of brentuximab vedotin in combination with standard, or modified standard chemotherapy, for the treatment of patients with advanced, treatment-naive, Hodgkin's lymphoma.

Section snippets

Study design

We did a phase 1, open-label, dose-escalation safety study of brentuximab vedotin in combination with standard therapy (ABVD), or a modified standard that omitted bleomycin (AVD) at four study sites (three in the USA and one in Canada; appendix). Our primary objectives were to assess the safety profile of treatment with brentuximab vedotin plus ABVD or AVD, and to establish the maximum tolerated dose in combination with each. Our secondary objectives were to assess the incidence of

Results

Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. Figure 1 shows the study profile and table 1 lists the patients' baseline characteristics. A greater proportion of patients were men, and most patients were white. Most patients had characteristics indicative of high-risk disease; nearly half the patients treated in the study had stage IV disease, and many patients presented at baseline with bulky disease.

15 (60%) of 26

Discussion

Our findings show that brentuximab vedotin should not be given with bleomycin in general or specifically in newly diagnosed advanced stage Hodgkin's lymphoma; however, when combined with AVD given every 2 weeks, this combination was generally well tolerated and resulted in 96% of evaluable patients who completed first-line therapy achieving complete remission. The maximum tolerated dose did not exceed the maximum planned dose of 1·2 mg/kg brentuximab vedotin, in combination with either ABVD or

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