Ambinder, Richard F.

Abstract Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (Nivo), and ipilimumab (Ipi) in patients with R/R HL. Here we present the preliminary safety and response data on the full cohort of patients treated in Phase 1 with BV + Ipi + Nivo (Arms G-I). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg, Ipi 1mg/kg and BV 1.2mg/kg (Arm G) or 1.8mg/kg (Arm H) with a 3+3 design, and an expansion cohort (Arm I) of 9 patients with BV at 1.8mg/kg. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional 12 months. Ipi is given every 12 weeks except for the first 2 patients in Arm G who received Ipi every 6 weeks for the first 3 cycles. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 6/30/18 22 patients with a median of 2 prior therapies (range 1-5) have been treated; 7 in Arm G, 6 in Arm H, and 9 in Arm I. Median age was 35, range (19-60); 11 patients were male. Nine patients had prior SCT (1 alloSCT, 8 autoSCT); 1 patient had prior BV. Safety: All 22 enrolled patients are evaluable for safety. There were 3 DLTs, one in each arm. In Arm G one patient experienced grade 4 diabetic ketoacidosis and hyperglycemia, and went off treatment after cycle 1. In Arm H, one patient had transient grade 3 AST elevation; this was of no clinical significance and did not require a delay in therapy. In Arm I a post AlloSCT patient had grade 4 Steven-Johnson syndrome with grade 3 pruritis, rash, and GVHD, and came off therapy. Common toxicities considered at least possibly related to drug, are shown in Table 1, and grade 3 or greater toxicity in Table 2. There were no grade 5 AEs or additional grade 4 AEs. Significant grade 3 AEs were: rash, colitis, gastritis, pancreatitis, and arthritis each in one patient, resulting in dose delays but not discontinuation of therapy. One patient experienced grade 2 angioedema in cycle 1 and came off therapy. No significant infusion reactions were noted. Response: Nineteen of 22 patients are evaluable for response. Three patients discontinued treatment after cycle 1 and are not evaluable for response. For the full population the overall response rate (ORR) was 82% (18/22), with a complete response (CR) rate of 68% (15/22). For patients treated with at least 3 cycles of therapy who were evaluable for response, the ORR is 95% (18/19) with a CR rate of 79% (15/19). Six patients went from treatment to SCT. With a median follow-up of 0.52 years median progression free survival (PFS) has not been reached (Figure 1), and with a median follow-up of 0.82 years overall survival (OS) has not been reached (Figure 2). Conclusion: In this study of the triplet combination of BV, Ipi and Nivo for R/R HL, therapy was generally well tolerated, although more grade 3 AEs were seen than in the doublets. In a heavily pretreated patient population, with 9 patients post SCT, the ORR of 95% and CR rate of 79% in evaluable patients is extremely promising. Data will be updated to include longer term PFS and OS by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-Nivo to the triplet of BV-Ipi-Nivo. Disclosures Diefenbach: Trillium: Research Funding; Incyte: Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Hong:Merck: Consultancy. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kura: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Janssen: Research Funding; Millenium: Research Funding; Infinity: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Kyowa: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KITE: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Kahl:Genentech: Consultancy; Abbvie: Consultancy; Acerta: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy. Ansell:LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding.

Abstract Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually. HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival. We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Here we report the data on the patients treated with BV + IPI, the first cohort of the study. Methods: Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI: 1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV. The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year. Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/2015 19 of 23 planned patients have been treated with BV + IPI. We report the data on the full dose escalation population (13 patients: Dose level 1 (6), Dose level 2 (7)). The median age was 33 years (range: 20-49). Seven patients were male. Patients were heavily pretreated with a median of 4 prior therapies (2-13). Fourpatients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation. Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy. Other AEs of interest included: alopecia, transaminitis, and uveitis. Grade 3 and 4 treatment related adverse events (AEs) included: Dose level 1: one grade 3 infusion reaction, which led to a protocol amendment to include premedication, no further grade 3 infusion reactions were noted; Dose level 2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia. Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients). An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%. Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI). The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years. Conclusion: In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2. In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy. More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO. Data will be updated to include the full BV + IPI cohort by the time of the annual meeting. Table 1. Common and Immune Toxicities Toxicity Type Dose Level 1 (n=6) Dose Level 2 (n=7) Grade Grade 1,2 3 4 5 1,2 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) Fatigue 5 - - - 3 - - - Fever 1 - - - 3 - - - Pain 2 - - - 3 - - - Alopecia 2 - - - 1 - - - Pruritus 1 - - - 2 - - - Rash maculo-papular 4 - - - 2 1 - - Diarrhea 4 - - - 4 - - - Dyspepsia 2 - - - 1 - - - Nausea 6 - - - 4 - - - Vomiting 3 - - - 2 1 - - Papulopustular rash 1 - - - 1 - - - Alanine aminotransferase increased 3 - - - 3 - - - Aspartate aminotransferase increased 3 - - - 2 - - - Platelet count decreased - - - - - - 1 - Anorexia 3 - - - - - - - Headache 2 - - - 2 - - - Peripheral sensory neuropathy 5 - - - 4 1 - - Dry eye 2 - - - - - - - Uveitis 1 - - - - - - - Cough 2 - - - 1 - - - Disclosures Diefenbach: Molecular Templates: Research Funding; Immunogen: Consultancy; Celgene: Consultancy; Idera: Consultancy; Jannsen Oncology: Consultancy; Gilead: Equity Ownership, Research Funding, Speakers Bureau; Incyte: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Off Label Use: Presentation will discuss the experimental use of the checkpoint inhibitor Ipilimumab in relapsed/refractory Hodgkin lymphoma.. Cohen:Celgene: Consultancy; Millennium: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Robertson:Eli Lilly: Equity Ownership. Fenske:Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin’s lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.

Abstract In classical Hodgkin lymphoma, circulating clonotypic malignant cells express CD20, which potentially explains the observed activity of rituximab. This multicenter phase 2 study investigated the combination of rituximab-ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for stage II-IV untreated classical Hodgkin lymphoma. A goal was to assess the behavior of circulating clonotypic B cells clinically. Of 49 evaluable patients, 69% had stage IIB-IV disease; 8% had CD20+ Hodgkin and Reed-Sternberg cells. Rituximab-ABVD was generally well tolerated. Delivered relative dose intensity was 94% for AVD and 79% for bleomycin. After 6 cycles, 81% of patients were in complete remission. Only 8% received radiation therapy. The actuarial 3-year event-free and overall survival rates were 83% and 98%, respectively. EBV copy number in plasma fell dramatically during cycle 1 in patients with EBV+ tumors. Persistence of detectable circulating clonotypic B cells was associated with a greater relapse frequency (P < .05). Rituximab-ABVD and clonotypic B cells warrant additional study in classical Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as NCT00369681.

Purpose To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice. Patients and Methods Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin’s lymphoma received cyclophosphamide 200 mg/m2/d, doxorubicin 12.5 mg/m2/d, and etoposide 60 mg/m2/d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group). Results Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P = .039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P = .037), thrombocytopenia (31% v 52%; P = .033), and anemia (9% v 27%; P = .021), and had fewer treatment-associated deaths (0% v 10%; P = .013). Conclusion Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.