A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors.

PURPOSE: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors. EXPERIMENTAL DESIGN: This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg. RESULTS: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962. CONCLUSIONS: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146-54. ©2015 AACR.

Treatment of advanced hormone-sensitive breast cancer in postmenopausal women with exemestane alone or in combination with celecoxib.

PURPOSE: Preclinical data showed that the combination of exemestane and celecoxib has synergistic effects. Therefore, a study was undertaken to explore the efficacy and tolerability of this combination in postmenopausal patients with advanced, hormone-sensitive breast cancer. PATIENTS AND METHODS: A randomized phase II study was conducted in postmenopausal patients with hormone-sensitive breast cancer and measurable disease who had progressive disease after treatment with tamoxifen. Patients were randomly assigned to either exemestane 25 mg daily or the combination of exemestane 25 mg daily with celecoxib 400 mg twice daily. Response Evaluation Criteria in Solid Tumors Group criteria were used to determine antitumor efficacy. Primary end point was the rate of clinical benefit. Secondary end points were tolerability, objective response rate, time to progression (TTP), and duration of clinical benefit. A pharmacodynamic and a pharmacokinetic study were conducted in parallel. RESULTS: One hundred eleven patients (exemestane, n = 55; combination, n = 56) were enrolled in 2002. The demographic characteristics and prognostic factors were similar in both arms. In the assessable population, 24 of 51 patients in the combination arm and 24 of 49 patients in the exemestane arm achieved clinical benefit. TTP was similar in both groups. Duration of clinical benefit was longer in the combination group (median, 96.6 v 49.1 weeks). The addition of celecoxib did not change the tolerability profile of exemestane alone. CONCLUSION: Similar rates of clinical benefit were achieved in both groups.

A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.