Dose Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) Is Highly Active for Second Line Treatment in Relapsed/Refractory Classical Hodgkin Lymphoma: Final Results of a Phase I/II Study
Background: Classical Hodgkin lymphoma (CHL) patients (pts) requiring second line therapy may still be cured with multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT) The likelihood of long term remission following ASCT for relapsed/refractory (R/R) CHL is predicted by response to pre ASCT salvage therapy (Moskowitz et al. Blood 2012) The anti CD30 antibody drug conjugate brentuximab vedotin (BV) is effective as a single agent in R/R CHL. We hypothesized that concurrent therapy with dose dense BV and 2 cycles of ICE would be safe, efficient, and produce high CR rates necessary for superior outcomes after ASCT. #NCT02227199) Methods: Patients (pts) 18 years old with first relapse or primary refractory CD30+ cHL were eligible for this IRB approved prospective clinical trial. Treatment included BV on Days 1 and 8 at either 1.2 or 1.5 mg/kg (based on 3+3 dose escalation schema; capped at 150 mg) ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2 daily on Days 1 3. Two 21 day cycles were given with G CSF support. BV 1.5 mg/kg was selected as the phase II dose based on reported dose escalation data (ASH 2016, #1834) PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at discretion of treating investigator. Peripheral blood (PB) pre and post treatment, stem cell (PBSC) product, and (when available) archived formalin fixed paraffin embedded tissue (FFPET) from presentation and relapse were collected for correlative studies. Pre treatment PB cytokine levels were measured by Luminex. Immunohistochemistry (IHC) on FFPET identified components of inflammatory microenvironment. The primary endpoint was to determine the MTD and CR rate after 2 cycles. Secondary endpoints included PFS, OS, stem cell collection, and molecular correlates. Results: All 45 pts have enrolled and completed study treatment, including 42 pts who were assigned treatment at the MTD of 1.5 mg/kg on day 1 and 8 of each cycle. Median age was 31 (range, 21 61) 16/45 (36% were male, 28/45 (62% had primary refractory disease, and 11/45 (24% had extranodal involvement at relapse. 41 pts completed both cycles of therapy. One pt experienced grade 5 multi system organ failure during cycle 1, one pt was removed from protocol due to non compliance, and two pts omitted cycle 2 due to toxicity (grade 4 sepsis, grade 3 Sweet syndrome attributable to G CSF) 2 pts received all ICE dosing, but omitted at least one dose of BV due to toxicity. In addition, 13/41 (32% pts delayed initiation of cycle 2 by a median of 7 days (range 6 17) due to toxicity, primarily elevated transaminases (10/13, 77% 16/45 (36% pts experienced neuropathy, but grade =2 neuropathy was rare (3/45, 7% Other grade 3 4 non hematologic toxicity included febrile neutropenia/sepsis (11% elevated ALT (11% hyperglycemia (7% pulmonary embolism (4% and elevated AST (4% 36 pts underwent PBSC collection at our institution and had all data available for analysis. 30/36 pts were able to collect at least 5x106 CD34+ cells/kg. 5/6 of the remaining pts were still able to proceed with ASCT with the amount collected, and the other pt was not deemed an ASCT candidate due to social reasons. 37/43 pts (86% who were evaluable for response proceeded to ASCT (2 subjects declined ASCT, 2 were ineligible due to social issues, one was lost to follow up, one remained chemorefractory despite additional salvage chemotherapy) Only 4/37 pts who received an ASCT subsequently relapsed. 43 pts were evaluable for efficacy. Overall response rate (ORR) and CR for all enrolled patients were 91% and 74% respectively. Among primary refractory pts, ORR and CR were 86% and 68% respectively. With a median follow up of 26.5 months (range 0.7 62) months, 2 year PFS and OS were 82% and 98% Updated results will be presented at the meeting. Conclusions: BV ICE is a rapid, active and tolerable salvage regimen for R/R CHL patients, including those with primary refractory disease. Efficacy results are comparable to previously presented BV chemo salvage combinations often delivered over longer durations. BV ICE should be considered in R/R CHL prior to ASCT. Figure Lynch: Juno Therpeutics: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Incyte: Research Funding; Rhizen Pharmaceuticals: Research Funding; Bayer: Research Funding; Cyteir: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding. Cassaday:Merck: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Honoraria, Research Funding; Vanda Pharmaceuticals: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly traded company; Kite/Gilead: Consultancy, Research Funding. Smith:AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Beigene: Consultancy; Millenium/Takeda: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Bayer: Research Funding; Ayala: Research Funding; Karyopharm: Consultancy. Fromm:Merck: Research Funding. Cowan:Abbvie: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Shustov:Seattle Genetics: Research Funding. Till:Mustang: Patents Royalties, Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Gopal:IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy.