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Saint Petersburg, Russia

Hawkins R.E.,Christie NHS Foundation Trust | Gore M.,Royal Marsden Hospital NHS Trust | Shparyk Y.,State Regional Treatment and Diagnostics Oncology Center | Bondar V.,Public Clinical Treatment and Prophylaxis Institution | And 12 more authors.
Clinical Cancer Research | Year: 2016

Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) + IFNα versus IFN in metastatic renal cell carcinoma (RCC). Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 μg/kg i. v. in three cycles of four once-daily injections) + IFN (9 MU s. c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS). Results: This phase II/III study did not meet its primary endpoint. Median OS/PFS for Nap + IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P = 0.56; HR, 1.08/P = 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of anti-SEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n = 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap + IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P = 0.02; HR, 0.59/P = 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile. Conclusions: The study did not meet its primary endpoint. Nap + IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup. ©2016 AACR.

Thertulien R.,Cancer Centers of North Carolina Asheville | Manikhas G.M.,City Clinical Oncology Dispensary | Dirix L.Y.,AZ Sint Augustinus | Vermorken J.B.,Universitair Ziekenhuis Antwerpen | And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose: The primary objective of this study was to access the potential effects of trabectedin on the QT/QTc interval in patients with locally advanced or metastatic solid tumors. Methods: Patients (n = 75) who had received ≥3 previous lines of chemotherapy and had either relapsed or had progressive disease were enrolled. Patients were administered 3-h intravenous infusions of placebo (saline) on day 1 and trabectedin (1.3 mg/m2) on day 2. Time-matched serial triplicate ECG recordings and pharmacokinetic blood samples were collected over 24 h on both days. Heart rate corrected mean QT intervals and changes from predose baseline in QTc (ΔQTc) were assessed. The difference in ΔQTc between trabectedin and placebo was calculated at each time point (ΔΔQTc). Results: The upper limits of the 90% confidence interval for ΔΔQTcF and ΔΔQTcB at all time points were less than the prespecified noninferiority margin of 10 ms (≥6.65 ms). No patient had a QTc > 500 ms or a time-matched increase from baseline in QTc > 60 ms at any time point. Regression analyses indicated ΔΔQTc was poorly correlated with trabectedin concentration. No adverse events suggestive of proarrhythmic potential were reported. Conclusion: Trabectedin did not prolong the QTc interval. Safety and pharmacokinetic profiles of trabectedin were similar to that observed in other ovarian and breast cancer studies. © 2011 The Author(s).

Baselga J.,Sloan Kettering Cancer Center | Baselga J.,SOLTI Breast Cancer Research Group | Manikhas A.,City Clinical Oncology Dispensary | Cortes J.,SOLTI Breast Cancer Research Group | And 12 more authors.
Annals of Oncology | Year: 2014

Background: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet®) in combination with trastuzumabHerceptin® (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. Patients and Methods: Patients were randomly assigned to NPLD (M, 50 mg/m2 every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m2 weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). Results: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. Conclusion(s): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Lisyanskaya A.S.,City Clinical Oncology Dispensary
Voprosy Onkologii | Year: 2014

Ovarian cancer is one of the most aggressive malignant tumors in women. The role of hormone therapy in the treatment for ovarian cancer is not fully studied up to now. The literature contains data on the efficacy and safety of treatment with antiestrogens and aromatase inhibitors for recurrent ovarian cancer. The article summarizes the epidemiology, preclinical and clinical studies related to the role of estrogen and aromatase expression in this disease as well as the role of aromatase inhibitors in the treatment for ovarian cancer.

Hesketh P.J.,Lahey Hospital and Medical Center | Rossi G.,Data Management | Rizzi G.,Data Management | Palmas M.,Data Management | And 4 more authors.
Annals of Oncology | Year: 2014

Background: NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods: This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. Results: All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5%PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions: Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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