Background

Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Direct cytotoxicity, driven by MMAE, is at the heart of the multifaceted anticancer activity of BV (Sutherland 2006). BV was the first ADC to be approved in multiple cancer types, including treatment-naïve Stage III or IV classical Hodgkin lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) (Connors 2017). Nivolumab is a fully humanized monoclonal antibody that targets programmed cell death protein 1 and is approved for the treatment of adults with relapsed/refractory (R/R) cHL. Both agents have been well tolerated with encouraging activity when combined with multi-agent chemotherapy. BV plus nivolumab was evaluated as a frontline treatment option for patients with cHL who are ≥60 years of age and ineligible for, or declined, conventional combination chemotherapy. The ongoing study reported an objective response rate (ORR) of 82% in 11 evaluable patients, and BV appears to be well tolerated in this population (Friedberg 2018). The combination of BV and nivolumab produced a 67% complete response (CR) rate and an estimated 3-year progression-free survival (PFS) rate of 77% in 93 patients with R/R cHL treated in the first-line salvage setting (Advani 2021). BV plus doxorubicin and dacarbazine (AD) without radiation therapy was evaluated in 34 patients with non-bulky Stage I or II cHL. BV-AD treatment resulted in interim and end of treatment (EOT) CR rates of 94% and 97%, respectively. The 4-year PFS and overall survival (OS) estimates were 91% and 100%, respectively. Peripheral sensory neuropathy (PSN) was low grade and only 1 patient had persistent PSN at the last follow-up (Abramson 2021). Part C of this study will evaluate BV, nivolumab, doxorubicin, and dacarbazine (AN+AD) in patients with Stage I or II cHL without bulky disease, a patient population similar to that studied in Abramson 2021. Based on the results of the trials summarized above, it is reasonable to expect that the combination of AN+AD will result in high response rates and be well tolerated, with potentially less toxicity compared with A+AVD.

Study Design and Methods

SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial of BV in patients with Stage III or IV cHL evaluating the efficacy and safety of A+AVD when administered with growth factor prophylaxis (Part A). Part B will evaluate the combination of AN+AD in patients with Stage I or II cHL with bulky mediastinal disease or Stage III or IV cHL. Part C will evaluate the efficacy and tolerability of AN+AD in patients with Stage I or II cHL without bulky disease. The primary objective of Parts B and C is to estimate the CR rate at EOT in patients with treatment-naïve cHL.

Approximately 240 patients will be enrolled in this study: 40 in Part A, 50 in Part B, and 150 in Part C. Parts A and B have completed enrollment. Patients in Part C must have histologically confirmed cHL and have an ECOG performance status of ≤2. Patients with nodular lymphocyte-predominant HL or prior treatment with immune checkpoint inhibitors will be ineligible for enrollment. Patients in Part C will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m 2, and dacarbazine 375 mg/m 2, administered separately by intravenous infusion on Days 1 and 15 of each 28-day cycle. Patients in Part C will receive 4 cycles of treatment. The primary efficacy endpoint is the CR rate at EOT with AN+AD in patients with previously untreated cHL. Duration of response, duration of complete response, event-free survival, PFS, ORR, and safety and tolerability of AN+AD will be evaluated as secondary endpoints. Efficacy will be assessed by PET/CT scans at Cycle 2 and EOT; disease response and progression for Part C will be assessed using the LYRIC modification of the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014). Patients will be followed for disease progression and OS for 5 years. Safety and efficacy endpoints will be summarized with descriptive statistics. The CR rate at EOT and its two-sided 95% confidence interval will be presented (Clopper 1934). Time-to-event endpoints will be analyzed using Kaplan-Meier methodology.

Enrollment for Part C is ongoing in the US, with plans for global expansion.

Disclosures

Flinn: MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Friedman: Seagen Inc.: Research Funding. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company.

© 2021 by The American Society of Hematology
2021
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