TY - JOUR
T1 - Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies
AU - Karapanagiotou, Eleni M.
AU - Roulstone, Victoria
AU - Twigger, Katie
AU - Ball, Mercel
AU - Tanay, Mary Anne
AU - Nutting, Chris
AU - Newbold, Kate
AU - Gore, Martin E.
AU - Larkin, James
AU - Syrigos, Konstantinos N.
AU - Coffey, Matt
AU - Thompson, Brad
AU - Mettinger, Karl
AU - Vile, Richard G.
AU - Pandha, Hardev S.
AU - Hall, Geoff D.
AU - Melcher, Alan A.
AU - Chester, John
AU - Harrington, Kevin J.
PY - 2012/4/1
Y1 - 2012/4/1
N2 - Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m 2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10 9, 1 × 10 10, and 3 × 10 10 TCID 50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10 10 TCID 50 dose characterized the response rate in patients with head and neck cancer. Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.
AB - Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m 2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10 9, 1 × 10 10, and 3 × 10 10 TCID 50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10 10 TCID 50 dose characterized the response rate in patients with head and neck cancer. Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.
UR - http://www.scopus.com/inward/record.url?scp=84859376209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859376209&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-2181
DO - 10.1158/1078-0432.CCR-11-2181
M3 - Article
C2 - 22316603
AN - SCOPUS:84859376209
SN - 1078-0432
VL - 18
SP - 2080
EP - 2089
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -