Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma
Authors: Friedman Judah , Lee Hun Ju , Ho Linda , Flinn Ian W. 
Published: November 2019

Background

For patients with advanced classical Hodgkin lymphoma (cHL), the most common frontline regimen has historically consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which originated in 1975 (Connors 2018). However, up to 30% of patients treated with ABVD as frontline therapy will relapse or are refractory to treatment (Canellos 1992; Carde 2016; Gordon 2013). Additionally, bleomycin is associated with potentially fatal pulmonary toxicity (Canellos 2004; Martin 2004), and vinblastine is associated with neutropenia and peripheral neuropathy. Brentuximab vedotin (BV, ADCETRIS®) has been approved for the treatment of adult patients with previously untreated Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine based on the results of the ECHELON-1 study (Connors 2017). Data reported from ECHELON-1 showed patients randomized to the BV + doxorubicin, vinblastine, and dacarbazine (A + AVD) treatment arm had a statistically significant 23% risk reduction in modified PFS events vs patients randomized to the ABVD arm of the study.

The combination of BV plus nivolumab was reported as showing potential for the treatment of cHL. The combination was evaluated as a potential frontline treatment option for patients with cHL who are over 60 years of age and ineligible for or declining conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 patients and the regimen appears well tolerated in this population. In another trial in 62 patients in the first salvage setting, the combination produced a 61% CR rate (Herrera 2018) and the patients were able to undergo subsequent stem cell transplant.

BV and nivolumab have been combined separately with doxorubicin, vinblastine, and dacarbazine and shown to be active and well tolerated. Furthermore, BV has been evaluated in combination with just doxorubicin and dacarbazine, omitting vinblastine, in 34 patients with previously untreated non-bulky stage I/II cHL and showed 100% complete response rate at end of treatment (EOT) and PFS and OS rates of 100% at last follow up (median=15 months; Abramson 2018). This combination resulted in a low incidence of neutropenia and alopecia, and moderate (Grade 1 or 2) peripheral neuropathy. It is therefore reasonable to expect that the combination of BV, nivolumab, doxorubicin, and dacarbazine (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity.

Study Design

SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate growth factor prophylaxis plus BV in combination with AVD in patients with stage III and IV cHL (Part A). A second cohort has been added to the study (Part B), which will evaluate the combination of AN + AD in this patient population. The primary objective of Part B is to estimate the CR rate at EOT with AN + AD in patients with previously untreated advanced cHL. All enrolled patients will be 12 years or older, with an ECOG performance status of ≤2. Patients in Part B will be treatment-naïve with Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky disease. Patients must have bidimensional measurable disease, as documented by radiographic technique, and qualifying baseline laboratory data. Patients will be excluded if they have nodular lymphocyte predominant HL or have symptomatic neurologic disease that compromises normal activities of daily living or requires medication. Patients with known cerebral or meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy, will also be excluded.

Approximately 50 patients will be enrolled in Part B. All patients will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2. All study drugs will each be administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles of treatment. Efficacy will be assessed by PET and CT scans at Cycle 2 and EOT. Disease assessments will be performed during follow-up every 3 months for the first year, every 6 months for 2 additional years, and then per institutional standard of care. Disease response and progression will be assessed by investigators using the Lymphoma Response to Immunomodulatory Therapy Criteria modification of Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2016).

Disclosures

Friedman: Amgen: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding.