ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer.

INTRODUCTION: RRx-001 is a novel cysteine-targeted alkylating agent that releases nitric oxide (NO). The primary biological activities of this hybrid molecule include macrophage repolarizing and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib in third/fourth line colorectal cancer that previously received treatment with irinotecan. PATIENTS AND METHODS: A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to single-agent regorafenib (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month "primer" followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the (ITT) efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months, at which point RRx-001 was discontinued, followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. There were 3 patients (3/24 = 12.5%) with prior single agent irinotecan on the RRx-001 randomized arm and 2 (2/10 = 20%) on the regorafenib randomized arm. Numerous patients had irinotecan combination therapies prior to randomized treatment. There were 15 patients on RRx-001 arm that received irinotecan post-RRx-001 in the randomized trial. There were 5 PRs on RRx-001 plus irinotecan leading to an overall response of 20.8% (5/24). There were 37.5% (9/24) of RRx-001 randomized patients with KRAS mutant type while 60% (6/10) regorafenib randomized patients were of KRAS type mutant. There were only 4 patients with available QOL and Edmonton Symptom Assessment System, an insufficient sample size to allow for any meaningful analysis. RESULTS: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, 2-sided log-rank test, P = .0030). The toxicity profile of RxI was substantially improved compared with RegI. CONCLUSION: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed "signal" accompanied by a sufficient safety profile.

Evaluation of current and upcoming therapies in oral mucositis prevention.

Cancer chemotherapy has evolved from a few therapeutic agents in three drug classes to more than 50 drugs in over ten drug classes. With generally cytotoxic mechanisms of action, there is continued research interest in preventing and managing adverse events of chemotherapy. Although treatment-induced symptom management has made significant progress, most therapies lead to intolerable reactions that result in a dose reduction or discontinuation of therapy. Mucositis is a common adverse event that can occur after administration of systemic chemotherapy and/or radiation therapy leading to inflammatory lesions anywhere from the oral cavity to the GI tract. Although pathophysiologically similar, gastrointestinal mucositis and oral mucositis (OM) differ in terms of symptom presentation and offending therapies. The focus of the article will be on OM; gastrointestinal mucositis will be mentioned when therapy efficacy is relevant to OM. OM prophylaxis has been a subject of interest for at least the past 30 years, yet progress has been limited due to a lack of understanding of the condition. With the recent introduction of palifermin (Kepivance™), novel therapies continue to be developed that may significantly reduce the incidence, duration and/or severity of OM. In addition, outcomes including an improvement in patient quality of life, increasing treatment dose intensity or reducing healthcare costs may result from successful management of OM prophylaxis. This article will review currently available OM prophylactic therapies. Agents in preclinical or clinical development and natural supplements will also be discussed.

Evaluation of in vivo P-glycoprotein phenotyping probes: a need for validation.

Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping.

Identifying the Causes of Cancer Health Disparities: Biologic and Non Biologic Determinants.

The causes of cancer health disparities amongst Pacific Islanders and other racial groups are complex and multifactorial. Both biologic and non biologic determinants have been identified as causal factors. Racial/ethnic classification can be used as a surrogate for non biologic determinants such as place of geographic origin, socioeconomic status, cultural practices, and diet. Given that non biologic and biologic determinants are not mutually exclusive, using racial/ethnic classification may be hypothesis generating and assist in the identification of biologic determinants such as infections, toxins, and/or environmental exposures that lead to carcinogenesis. This commentary provides several examples of cancer specific biologic determinants that may lead to cancer health disparities. It also discusses specific non biologic determinants of cancer health disparities that must be overcome in order to increase participation of underserved populations in clinical trial research. Taken together, these examples demonstrate the need to further our understanding of the determinants of cancer health disparities that can lead to the enactment of preventive measures and/or targeted therapies.

Human immunodeficiency virus type-1 integrase containing a glycine to serine mutation at position 140 is attenuated for catalysis and resistant to integrase inhibitors.

L-chicoric acid (L-CA) is a potent inhibitor of HIV integrase (IN) in vitro. In this report, the effects of a glycine to serine mutation at position 140 (G140S) on HIV IN and its effects on IN inhibitor resistance are described. HIV containing the G140S mutation showed a delay in replication. Using real-time polymerase chain reaction, the delay was secondary to a failure in integration. The mutant protein (IN(G140S)) was attenuated approximately four-fold for catalysis under equilibrium conditions compared to wild-type IN (IN(WT)) and attenuated five-fold in steady-state kinetic analysis of disintegration. Fifty percent inhibitory concentration assays were performed with IN inhibitors against both IN proteins in disintegration and strand transfer reactions. IN(G140S) was resistant to both L-CA and L-731,988, a diketoacid. HIV containing the mutation was resistant to both inhibitors as well. The G140S mutation attenuates IN activity and confers resistance to IN inhibitors, suggesting that diketoacids and L-CA interact with a similar binding site on HIV IN.