Phase I Study of Pazopanib in Combination with Paclitaxel and Carboplatin Given Every 21 Days in Patients with Advanced Solid Tumors

Abstract

Several phase III trials have shown that the addition of an antiangiogenic agent to conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors. This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic agent, with paclitaxel and carboplatin. This 3 þ 3 dose-escalation phase I study evaluated the maximum-tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m 2 and carboplatin [dosed at area under the curve (AUC) 5 or 6] given every 21 days in patients with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The MTR was paclitaxel 175 mg/m 2 and carboplatin AUC5 with pazopanib 200 mg. The most common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with esophageal cancer had a complete response and four patients, one each with breast, small-cell lung, pancreatic, and gastroesophageal junction cancer, had partial responses. Pazopanib at 200 mg increased paclitaxel maximal concentration (C max ) by 43% and carboplatin (AUC5 or AUC6) C max by 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of doselimiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and carboplatin and likely contributed to this effect. Given the antitumor activity of this regimen, further studies are underway to determine a clinically tolerable schedule of pazopanib with paclitaxel and carboplatin.

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

“…Previous studies of the combination of pazopanib with weekly paclitaxel have also reported high incidences of fatigue and nausea (25,32); therefore, it is possible that these events could represent potential synergistic toxicities for the combination of pazopanib and paclitaxel. Of note, hematologic toxicity was not dose limiting in this study; this contrasts with the experience with the combination of pazopanib with paclitaxel 175 mg/m 2 and carboplatin AUC 5, in which myelosuppression was the DLT for the combination (23,24). DLTs reported in this study included rash and hepatotoxicity.…”

“…In addition, preclinical evidence suggested the possibility of synergy from the combination of antiangiogenic agents with taxanes (21), and recent data suggested synergism between paclitaxel and pazopanib via inhibition of aurora A in anaplastic thyroid cancer (22). Previous studies demonstrated that pazopanib could not be readily combined with paclitaxel 175 mg/m 2 and carboplatin area under the plasma drug concentration curve (AUC) 5 administered every 3 weeks at doses higher than pazopanib 200 mg (23,24). However, it was feasible to administer pazopanib 800 mg with a weekly regimen of paclitaxel 80 mg/m 2 , which resulted in a 26% higher geometric mean paclitaxel AUC that was similar to the systemic exposure of a paclitaxel dose of 100 mg/m 2 (25).…”

Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle–Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer

“…Finally, one important concern of combining topotecan and pazopanib is the tolerability and toxicity of both drugs, especially the combination, in the clinic (13,14,37). In contrast, current clinical data suggest that CRLX101 is tolerable in combination with standard doses of bevacizumab in patients (38,39).…”

Dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin treatment for stage II-IV ovarian cancer patients

“…In the past 30 years, the surgery treatment and radical tumor cells destroy in the early phase ovarian cancer (phase I and II) or advanced cases (phase III and phase IV) using combined chemotherapy based on cisplatin make the patients have better prognosis, but the 5-year survival rate is still around 5-30%. Into the 1990s, as the clinical application of paclitaxel, paclitaxel, cisplatin replace cisplatin, cyclophosphamide combined chemotherapy as the post-surgery first-line treatment of ovarian cancer, prolongs the median survival time in advanced cases, to decrease the poisonousness of the PT scheme, carboplatin was used to replace cisplatin combine paclitaxel therapy, carboplatin is the second generation of platinum antitumor drugs, it's mechanism of action is the same with cisplatin, but the reaction of gastrointestinal tract and renal toxicity is lower than cisplatin (Burris et al, 2012;Kumagai et al, 2011;Mundhenke et al, 2008). Because of the advantages of patient tolerance, do not need to be hydrated, currently accepted by a lot of doctors and patients, at present the paclitaxel combine carboplatin therapy is the postsurgery first-line treatment of ovarian epithelial carcinoma at home and abroad (Harano et al, 2014).…”