Gupta, Ashok

TPS3113 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.

2510 Background: Blocking the interaction between programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, and its ligand PD-L1 may enhance T-cell function. Here we describe the safety and activity from the first clinical study of BMS-936559 in patients (pts) with advanced solid tumors, further validating the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: BMS-936559 was given Q2 wk IV in a 6-wk cycle at doses of 0.3−10.0 mg/kg during dose escalation and/or cohort expansion; pts could receive up to 16 cycles (48 doses). Results: As of August 1, 2011, 162 pts with melanoma (MEL, n=53), non-small-cell lung (NSCLC, n=50), colorectal (n=18), renal cell (RCC, n=17), ovarian (n=17), and pancreatic (n=7) cancer were treated. Median therapy duration was 11 wks (max 99 wks). Common related adverse events (rAEs; ≥5% pts) included fatigue, diarrhea, infusion reaction, arthralgia, rash, and pruritus. The incidence of grade 3-4 rAEs was 8.6%. AEs of special interest included hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and myasthenia gravis; there were no drug-related deaths. Clinical activity was observed in MEL, RCC, and NSCLC. Objective responses (ORs; RECIST 1.0) were observed in heavily pretreated pts. ORs were durable; among 16 pts with ORs, 7 had responses lasting ≥1 yr. Two other pts had ongoing ORs with durations of 2.3 and 8.5 mo at data lock. Several pts had prolonged stable disease. Some pts had a persistent reduction in overall tumor burden in the presence of new lesions but were not categorized as responders. In NSCLC, ORs were observed irrespective of histology. Conclusions: BMS-936559 was active and generally well tolerated in pts with NSCLC, RCC, and MEL. In conjunction with data from anti-PD-1/BMS-936558 trials, this study concurrently validates the importance of the PD-1/PD-L1 pathway for cancer immunotherapy and supports further clinical development of anti-PD-1/PD-L1 directed therapy. [Table: see text]