Suresh Nair

Sex Differences in Fluorouracil-Induced Stomatitis

PURPOSEnA meta-analysis of six North Central Cancer Treatment Group (NCCTG) trials involving patients receiving their first ever fluorouracil (5-FU)-based chemotherapy was undertaken to explore the association of sex with reports of the incidence and severity of stomatitis.nnnPATIENTS AND METHODSnData were obtained on a total of 731 patients (402 men and 329 women). Comparisons of incidence and severity rates and average stomatitis across sex were performed using standard binomial testing and t tests, respectively. Logistic regression analysis and a weighted analysis using data summarized to study level served as evidence of cross-validation.nnnRESULTSnWomen reported stomatitis both more often and with greater severity than did men. The incidence of any stomatitis for women was 63% versus 52% for men (P =.002). The incidence of severe or very severe stomatitis for men and women was 22% and 12%, respectively (P =. 0006). On average, women reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal scale (P <.00001). Comparison of results across treatment and placebo arms was carried out to validate the initial findings. Logistic regression modelling further confirmed the results conditional on the presence of a number of potentially confounding covariates. Women were also 11% more likely than men to experience leukopenia of common toxicity criteria grade >/= 1, (70% v 59%, respectively; P <.00001) and grade 3+ (18% v 11%, respectively; P =.004).nnnCONCLUSIONnMore women than men reported 5-FU-induced stomatitis. The precise mechanism resulting in different degrees of stomatitis across sex is not evident.

A phase IA trial of sequential administration recombinant DNA-produced interferons: combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma.

This study investigated the effects of sequentially administered recombinant interferon gamma (rIFN gamma) and recombinant interferon alfa (rIFN alpha) in 36 patients with metastatic renal cell carcinoma (RCC). rIFN alpha was subcutaneously administered daily for 70 days at dosages that varied (2.5, 5, 10, and 20 x 10(6) U/m2) across four cohorts of patients. Within each cohort of patients receiving a given dose of rIFN alpha, three subsets of patients received either 30, 300, or 1,000 micrograms/m2 rIFN gamma. rIFN gamma was administered intravenously for 5 days every third week, 6 hours prior to administration of rIFN alpha. Dose-limiting toxicity (DLT) included constitutional symptoms, leukopenia, nephrotic syndrome with acute renal failure, hypotension associated with death, and congestive heart failure. DLT was related more often to the rIFN alpha dose level than to rIFN gamma dose level. Maximum-tolerated dose (MTD) was 10 x 10(6) U/m2 rIFN alpha and 1,000 micrograms/m2 rIFN gamma. Six patients failed to complete a minimum of 21 days of therapy due to toxicity or rapid progression of disease. Clinical responses were seen in eight of 30 assessable patients. Two patients experienced complete remission and have remained in complete remission 20+ and 22+ months. An additional six patients have shown partial responses for 4 to 18+ months. One patient in partial remission continues to show slow regression of pulmonary and liver lesions off therapy with rIFNs. Clinical responses have remained durable for patients with complete remissions and patients with partial remissions. The results of this study suggest that toxicities associated with combination rIFN therapy can be reduced by administering these agents sequentially as opposed to simultaneously.

Interferon-induced reversible acute renal failure with nephrotic syndrome

Although there has been considerable experience with interferons in clinical trials during the past decade, acute renal failure as a side effect of interferon treatments has rarely been reported. We report a case in which acute renal failure with nephrotic syndrome was associated with therapy with two types of interferons. We note incomplete return of renal function upon withdrawal of therapy.

A North Central Cancer Treatment Group Phase II Trial of Topotecan in Relapsed Gliomas

Current systemic treatment options for patientswith relapsed gliomas are limited. Thetopoisomerase I inhibitor topotecan has demonstrated broadantitumor activity in both preclinicalstudies as well as a number of phase I and II trials in humans.Studies in primates have shown goodcerebrospinal fluid levels of topotecan following systemicadministration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5mg/m2 intravenously daily for 5 consecutive days repeatedevery three weeks. For patients who had received priornitrosourea-containing chemotherapy, thestarting dose was 1.25 mg/m2. Thirty-three patients wereentered on this study. All patients wereeligible and evaluable for both response and toxicity. Sevenpatients experienced grade 4 leukopeniawith 2 of these patients dying of infection-relatedcomplications. Six of these seven patients werenot taking anticonvulsants during treatment. Nine patientsdeveloped grade 3-4 thrombocytopenia,seven of whom were not taking anticonvulsants. Nonhematologicside effects were infrequent andmanageable. One patient experienced a partial response to thistreatment for an overall response rateof 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9weeks and median survival 19.9 weeks. Topotecan at this dose andschedule showed no substantial activity in relapsed gliomas.

Abstract LB-055: Overall survival and safety experience from an expanded access program (EAP) of nivolumab (NIVO) for patients with advanced melanoma (MEL) who progressed after prior ipilimumab (IPI) treatment

Background: NIVO (anti-PD-1) was initially approved in the USA as a second-line treatment for MEL based on the results of the phase III CheckMate 037 trial, which enrolled patients (pts) who progressed after prior IPI (anti-CTLA-4) therapy. The results of this trial showed a significantly improved tumor response with NIVO vs. chemotherapy; at a minimum follow-up of 2 years, grade 3/4 treatment-related adverse events (AEs) were reported in 14% of NIVO-treated pts. We report initial overall survival (OS) and safety data from an ongoing EAP of NIVO monotherapy in MEL pts who progressed on IPI therapy (CheckMate 168). Participating countries are Brazil, Canada, the USA, and Argentina. Methods: In CheckMate 168 (NCT02142218), pts with stage III (unresectable) or stage IV MEL who progressed after prior IPI-containing therapy, with an ECOG performance status of 0 or 1, are eligible to receive NIVO 3 mg/kg Q2W for up to 24 months. Key exclusion criteria are active brain metastases, prior immune checkpoint inhibitor therapy other than anti-CTLA-4, and autoimmune disease. For the current analysis, the database lock occurred on November 1, 2016, and included 276 pts with at least 1 year of follow-up (total enrolled: 482). Results: Among the 276 pts included in the current analysis, MEL subtypes were cutaneous (70%), mucosal (8%), acral (5%), uveal (5%), and other or missing (12%). More than half of the pts (55%) had M1c disease (13% with treated brain metastases and 42% without), and 41% had elevated lactate dehydrogenase levels at baseline. Pts had received 1 (21%), 2 (42%) or ≥3 (37%) prior systemic therapies for MEL, which included prior BRAF inhibitor therapy in 24% of pts (in addition to IPI). In the EAP, pts received a median of 8 NIVO doses (range: 1-48), with a median duration of therapy of 3.8 months (range: 0.03-22.1). Median OS in the 276 pts was 14.6 months (95% CI: 11.8-21.2), with a 1-year OS rate of 55.8% (95% CI: 49.2-61.8). Treatment-related AEs of any grade were reported in 69% of pts, most commonly fatigue (24%), diarrhea (17%), nausea (13%), and pruritus (12%), and led to discontinuation of NIVO in 8% of pts. Treatment-related AEs of grade 3/4 occurred in 15% of pts, and led to discontinuation of NIVO in 4% of pts. Any-grade serious AEs related to NIVO treatment were reported in 8% of pts. One death (0.4%) was attributed to study drug (toxic encephalopathy). For treatment-related AEs of potential immunologic origin, those of any grade occurred most commonly in the skin (33%), gastrointestinal tract (18%), and endocrine systems (14%). Conclusions: The initial OS and safety experience from this EAP of NIVO after IPI therapy is consistent with clinical trial data, with no unexpected AEs. These findings suggest that NIVO clinical trial data can be generalized to the advanced melanoma population in a routine clinical practice setting. Citation Format: Milton Barros e Silva, Rafael Schmerling, Andreia Cristina de Melo, Sergio Azevedo, Bernardo Garicochea, Elaine McWhirter, Michael Smylie, Markus Gifoni, Carlos Henrique dos Anjos, Teresa Petrella, Matias Chacon, Martin Greco, Suresh Nair, Alexandre Avila, Sheena Demelo, Joel Jiang, Scott Ernst. Overall survival and safety experience from an expanded access program (EAP) of nivolumab (NIVO) for patients with advanced melanoma (MEL) who progressed after prior ipilimumab (IPI) treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-055. doi:10.1158/1538-7445.AM2017-LB-055

Targeting Intracellular Signaling Pathways in Soft Tissue Sarcoma (STS).

10595 Background: We previously presented variable positive immunohistochemical staining of soft tissue sarcoma for the phosphorylated forms of p70S6K (mtor pathway) and ERK (raf pathway)- pASCO 20...