High Relapse Rate after Allo 1 Relapsed Hodgkin’s Lymphoma • Up to half of patients with relapsed HL progress again after autologous transplant and others aren’t able to undergo autograft • Regimens for relapsed disease have short remission durations and most rely on combination chemotherapy: – ICE – GVD – IGeV – ChlVPP – GDP • Anti-CD30 antibodies alone (SGN-30) not beneficial. SGN-35/Brentuximab vedotin • Antibody-drug conjugate – CD30 monoclonal antibody – Monomethyl auristatin E 2 Phase I Study of SGN-35 • 4 center trial for patients with CD30+ malignancies • 45 patients treated (42 w/ HL) • MTD of 1.8mg/kg every 3 weeks • DLT’s: – Neutropenia/sepsis leading to death (n=1) [3.6mg/kg] – Grade 3 renal failure (n=1) [2.7mg/kg] – Grade 3 hyperglycemia (n=1) [2.7mg/kg] – Grade 3 prostatitis/febrile neutropenia (n=1) [2.7mg/kg] – Grade 4 thrombocytopenia (n=1) [1.8mg/kg] Younes et al, NEJM 2010 Phase I Study of SGN-35 • Responses at MTD (1.8mg/kg; N=12): • CR-4 • PR-2 • SD-5 • PD-1 • Common adverse events: – Neuropathy (36%) – Grade 3 or 4 neutropenia (16%) – Grade 3 or 4 thrombocytopenia (9%) Younes et al, NEJM 2010 3 Phase 2 Study-Eligible Patients • HL relapsed after autologous transplant • Documented CD30+ disease w/ measurable disease • ECOG 0-1 • ANC >1000 • Plts > 50,000 • No prior allogeneic transplant 4 Phase 2 Study Design • Open label study at 25 centers in US, Canada, Europe • Accrual: Feb-Aug 2009 • SGN-35 1.8mg/kg q3 wks up to 16 doses • CT’s and PET/CT’s scheduled at regular intervals (i.e., after cycles 2, 4, 7, 10….) • Reviewed in an Independent Radiology Review Facility (IRF) Phase 2 Statistical Plan • Primary endpoint: Overall Response Rate • Secondary endpoints: – CR Rate – Progression-free survival – Overall survival – Incidence and severity of adverse events • 100 planned patients allowed a response rate of 29% to exclude a rate ≤ 20% with 95% confidence. • Pre-planned intra-patient PFS comparison 5 Results- Patient Characteristics • N = 102 ( 48 males, 54 females) • All had prior autologous transplant • Median 3.5 prior chemotherapy regimens (Range 1-13) • 71% had primary refractory disease • 42% refractory to prior therapy • Median 6.7 months from transplant to first post-transplant relapse Results-Efficacy Median time to response: 5.7 weeks (Range 5.1 to 56 weeks) Median time to CR: 12 weeks (Range: 5.1 to 56 weeks) Subgroup analyses showed no group who did not achieve anti-tumor activity. 6 Results-Efficacy Intrapatient PFS Comparison • Median PFS most prior therapy: – 4.1 months • Median PFS w/ SGN-35: – 7.8 months 7 Results-Safety • Median no of cycles: 10 (Range 1-16) • Most common adverse events: – Neuropathy (42%) – Nausea (35%) – Fatigue (34%) – Neutropenia (19%) – Diarrhea (18%) – Fever (14%) Results-Adverse Events 8 Discussion • Promising, highly active, well-tolerated outpatient therapy. • But…. Discussion • Allogeneic transplant still only chance for cure and has been successfully undertaken after SGN-35. • Recently concluded study evaluating SGN-35 in post-transplant maintenance. • Long-term benefit may be in combination and not as mono-therapy in relapsed setting, or possibly utilized in the up-front setting. 9 Discussion • Brentuximab + ABVD or AVD HL – Multicenter phase I study – 96% ORR – 95% CR in ABVD; 92% CR in AVD – 44% of patients in ABVD arm discontinued bleomycin due to pulmonary toxicity – 24% of patients in ABVD had Grade 3 or 4 pulmonary toxicity Ansell et al, ASH 2012 10
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