Phase I/II Trial of Carboplatin and Paclitaxel Chemotherapy in Combination with Intravenous Oncolytic Reovirus in Patients with Advanced Malignancies

Abstract

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/m2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 109, 1 × 1010, and 3 × 1010 TCID50 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 × 1010 TCID50 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.

Evolution of Reovirus in Cancer Therapy

“…This study concluded that reovirus antitumor activity is unaffected by high doses of radiation, and that the combination of the two is safe for further investigations. Following the initial study, a subsequent Phase II trial 69 was performed using low-dose radiation, and demonstrated a 93% total disease-control rate (combined CR, PR, and SD) in treated lesions, thereby confirming the safety and positive clinical outcomes of the combination regimen. As opposed to palliative radiotherapy, it is expected that reovirus will be used in future trials in combination with radical radiotherapy for a curative intent.…”

“…[69] All aforementioned combinations have gone on to further Phase II or Phase III clinical trials. In either monotherapy or combination therapy studies, the recommended dose of reovirus is 3×10 10 TCID 50 once over 60 minutes on days 1-5 every 3 or 4 weeks.…”

“…The recommended dose of docetaxel in combination therapy is 75 mg/m 2 three times weekly. [49,50,78] As for paclitaxel and carboplatin, paclitaxel is recommended at a dose of 175 mg/m 2 , and carboplatin at an area under the curve (AUC) of 5 [54,55,69,79] or paclitaxel at 200 mg/m 2 and carboplatin at AUC 6 [79,80] on day 1 of a 3-week cycle. Other chemotherapeutic agents currently in or recruiting patients for Phase I trials with reovirus include cyclophosphamide, [74,81,82] FOLFIRI (folinic acid, fluorouracil, irinotecan)/bevacizumab, [83,84] paclitaxel alone [85,86] , FOLFOX (folinic acid, fluorouracil, oxaliplatin)-6/bevacizumab, 84,85 docetaxel and prednisone, [49,50] and docetaxel and pemetrexed.…”

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

“…In a phase I/II trial of REOLYSIN and carboplatin and paclitaxel chemotherapy, of the 31 patients who were evaluable, 1 patient had a complete response, 6 patients had partial response, and 9 patients had stable disease (52). The success of this study led to the launch of a phase III, randomized, double-blind study in patients with platinum-refractory head and neck cancers (NCT01166542).…”

“…nAbs bind virus and subsequently block viral attachment to cellular surface receptors, inhibiting viral infection and replication. Immunologic analysis of patients enrolled in reovirus clinical trials has consistently detected circulating nAbs (47,52,70). This humoral immune response presents a significant barrier to intravenously administered reovirus reaching, colonizing, and eliminating disseminated tumor beds.…”