Virginia K. Langmuir

Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer

PURPOSE This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. PATIENTS AND METHODS Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. RESULTS From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment--Breast were comparable in both treatment groups. CONCLUSION Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.

Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of TH-302, a Hypoxia-Activated Prodrug, in Patients with Advanced Solid Malignancies

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.

Impact of Exploratory Biomarkers on the Treatment Effect of Bevacizumab in Metastatic Breast Cancer

Purpose: The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial. Experimental Design: In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta-like ligand (Dll) 4, Bv8, p53 and thymidine phosphorylase) on formalin-fixed, paraffin-embedded tissue. PFS was associated with these variables in retrospective subset analyses. Results: Patients with low scores for Dll4, VEGF-C, and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (P values = 0.01, 0.05, and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing. Conclusion: These retrospective subset analyses suggest that expression of Dll4, VEGF-C, and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing. Clin Cancer Res; 17(2); 372–81. ©2011 AACR.

A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine

PURPOSE There are currently no approved therapies for patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine. This Phase III trial evaluated the efficacy and safety of glufosfamide as compared with best supportive care (BSC) in this patient population. METHODS Patients were randomised to glufosfamide plus BSC or to BSC alone with baseline performance status as a stratification factor. The primary end-point was overall survival. RESULTS Three hundred and three patients were randomised: 148 to glufosfamide plus BSC and 155 to BSC alone. There was an 18% increase in overall survival for glufosfamide that was not statistically significant: hazard ratio (HR) 0.85 (95% confidence interval (CI) 0.66-1.08, p=0.19). Median survival was 105 (range 5-875) days for glufosfamide and 84 (range 2+ to 761) days for BSC. Grade 3/4 creatinine increase occurred in 6 patients on glufosfamide, including 4 with dosing errors. CONCLUSION These results suggest low activity of glufosfamide in this very refractory patient population.

Abstract B185: Bench to bedside experience with TH‐302: A tumor‐selective hypoxia‐activated prodrug as a promising treatment for prostate cancer

Hypoxia is a defining feature of solid tumors, including prostate cancer. Metastases also exhibit subregional hypoxia and micrometastases may be severely hypoxic. Hypoxic cells are known to be resistant to standard chemotherapies and thus play a role in treatment failure and disease relapse. TH‐302, a tumor‐selective hypoxia‐activated prodrug of the cytotoxic warhead bromo‐isophosphoramide mustard (Br‐IPM), is currently in clinical development for the treatment of advanced solid tumors. We explored the preclinical efficacy of TH‐302 in both in vitro and in vivo models of prostate cancer. Based on these translational results, we identified prostate cancer as an indication for further clinical investigations. Preclinically, TH‐302 demonstrated hypoxia‐selective cytotoxicity in the human prostate cancer cell lines PC‐3, LNCaP, and DU‐145. We explored in vivo prostate cancer efficacy in PC‐3 xenograft models that included (1) an ectopic subcutaneous model, (2) an orthotopic model, and (3) a model of bone and soft tissue prostate cancer metastases. TH‐302 demonstrated efficacy both as monotherapy and in combinations with taxanes in all three settings. The combination of TH‐302 and docetaxel in the disseminated prostate cancer metastases model demonstrated 100% complete responses in the 8 of 10 animals surviving to the end of the study at approximately 8 weeks. The TH‐302 Phase 1 dose escalation clinical trial established the monotherapy maximum tolerated dose (MTD) of TH‐302 dosed weekly for 3 weeks of a 4 week cycle at 575 mg/m2. Mucosal and skin toxicity were dose limiting, while hematologic toxicity was minimal. Evidence of anti‐tumor activity was observed including four RECIST responses in patients with small cell lung cancer and metastatic melanoma. In the ongoing Phase 1/2 combination therapy clinical trials of TH‐302, the MTD of TH‐302 was established at 340 mg/m2 when dosed at days 1 and 8 with docetaxel 75 mg/m2 on day 1 every 3 weeks. Neutropenia was dose‐limiting. In the first two patients with metastatic castration‐resistant prostate cancer (CRPC) treated with the combination of TH‐302 and docetaxel, PSA responses (a > 50% reduction from baseline) have been observed along with a marked reduction in cancer‐related pain in one of the patients. An additional 12 CRPC patients will be enrolled. These translational studies and early clinical findings indicate that the addition of TH‐302 to docetaxel may be a promising new treatment option for prostate cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B185.