Infante, Jon

Abstract Background. nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. Materials and Methods. Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. Results. Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. Conclusion. The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.

Abstract Enzymatic degradation of hyaluronan (HA), a key component of the extracellular matrix (ECM), can enhance tumor perfusion, improve delivery of chemotherapeutics, and enhance the effects of anti-tumor agents. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational therapeutic agent under clinical development for the treatment of patients with solid tumors that may accumulate HA. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Twenty-six patients with advanced solid tumors were enrolled in a Phase 1 multi-center trial. Patients received weekly or twice weekly doses of IV PEGPH20 (0.5 - 5 μg/kg) for the first 4-week cycle, followed by once-weekly dosing for the subsequent 4-week cycles. Serial blood samples were drawn from each patient, and plasma concentrations were measured by an ultrasensitive hyaluronidase activity assay to assess PEGPH20 pharmacokinetics (PK). Plasma levels of HA catabolites were measured using a quantitative HPLC method to characterize PEGPH20 pharmacodynamics (PD). Other measures of PD activity were evaluated in selected patients, including DCE-MRI, DW-MRI, 18FDG-PET, textural analysis on CT, and histochemical staining of HA in tumor biopsies collected both before and after PEGPH20 treatment. Peak plasma PEGPH20 concentrations increased with dose, and plasma pharmacokinetics (PK) were well described by a linear PK model. Pre-treatment plasma HA levels were typically <1 μg/mL and increased in a dose-dependent fashion after PEGPH20 treatment. Increased plasma HA corresponded with decreased HA staining in patients with available tumor biopsies. DCE-MRI analysis indicated early (24-48 hr) and rapid increase in tumor perfusion compared to baseline in 4 patients with serial MRI assessments. Pharmacodynamic activity was also demonstrated when pre-treatment 18FDG-PET scans were compared with images collected at scheduled times after PEGPH20 dosing. Reduction in FDG uptake exceeding 25% was demonstrated in 3 of 4 patients after one cycle of treatment, consistent with a partial metabolic response. These data are consistent with the mechanism of action reported in preclinical models, and results support continued evaluation of PEGPH20 in combination with anti-tumor agents via modification of the ECM. Citation Format: Ping Jiang, Daniel C. Maneval, Ramesh K. Ramanathan, Jeffrey R. Infante, Mitesh Borad, Alberto Bessudo, Patricia LoRusso, Barry J. Sugarman, Deborah Carson, Marie A. Printz, Curtis B. Thompson, Paneer Selvam, Joy Zhu, Ronald Korn, H Michael Shepard, Gregory I. Frost. Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2013-3375

Abstract Purpose: The objectives of this phase 1, first-in-human study were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary activity of the hypoxia-activated prodrug TH-302 in patients with advanced solid tumors. Experimental Design: TH-302 was administered intravenously over 30 to 60 minutes in two regimens: three times weekly dosing followed by 1 week off (arm A) and every 3-week dosing (arm B). Results: Fifty-seven patients enrolled (arm A: N = 37 and arm B: N = 20). The TH-302 dose was escalated from 7.5 to 670 mg/m2 in arm A and from 670 to 940 mg/m2 in arm B. The most common adverse events were nausea, skin rash, fatigue, and vomiting. Hematologic toxicity was mild and limited. Grade 3 skin and mucosal toxicities were dose limiting at 670 mg/m2 in arm A; the MTD was 575 mg/m2. In arm B, grade 3 fatigue and grade 3 vaginitis/proctitis were dose limiting at 940 mg/m2; the MTD was 670 mg/m2. Plasma concentrations of TH-302 and the active metabolite Br-IPM (brominated version of isophosphoramide mustard) increased proportionally with dose. Two partial responses were noted in patients with metastatic small cell lung cancer (SCLC) and melanoma in arm A at 480 and 670 mg/m2. Stable disease was observed in arms A and B in 18 and 9 patients, respectively. Conclusions: The MTD of TH-302 was 575 mg/m2 weekly and 670 mg/m2 every 3 weeks. Skin and mucosal toxicities were DLTs. On the basis of responses in metastatic melanoma and SCLC, further investigations in these indications were initiated. Clin Cancer Res; 17(9); 2997–3004. ©2011 AACR.