Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity

Table 2 Phase I/II, II, and III trials involving reovirus

Phase	Malignancy	Dosing regimen	Clinical response
I/II (REO 011)	Various advanced or refractory solid malignancies	60-min IV infusion from 3 × 109 TCID50 to 3 × 1010 TCID50 days 1-5 (dose escalation) with IV paclitaxel 175 mg/m2 over 3 h and IV carboplatin AUC5 (over 30 min) on day 1 every 21 d (3 × 1010 TCID50IV reovirus days 1-5 every 21 d became recommended phase II dose with paclitaxel and carboplatin)	Out of 26 patients, best overall response was CR in 1 patient (3.8%,head and neck cancer), PR in 6 patients (23.1%, 3 each with SCC of head and neck and head and neck cancer), major clinical response not evaluable by RECIST criteria in 2 patients (7.7%, SCC of head and neck), and SD in 9 patients (34.6%, 3 with SCC of head and neck, 3 with head and neck cancer, 1 with gynecological cancer, 1 with melanoma, 1 with sarcoma) with median duration of SD and PR of 6 mo (range 3-10 mo). Of the 24 patients with head and neck cancer, median OS was 7.1 mo (CI: 4.2-11.5 mo)
I/II (OSU-07022, NCI trial)	Recurrent or refractory ovarian, peritoneal, and fallopian tube carcinomas	60-min IV infusion 3 × 1010 TCID50 days 1-5 with daily IP administration days 2-3 beginning cycle 2 every 28 d (dose escalation with IP dosing)	Thus far 8 patients have received treatment. Biopsied ovarian and peritoneal tumor samples reveal detection of viral proteins in tumor tissues compared to control after systemic (IV) administration of reovirus and presence of reovirus replication in tumors due to overlap of reovirus protein and microtubules
II (REO 008)	Various advanced or refractory solid malignancies	Open-label, single-arm, multicenter: 1 × 1010 TCID50 intratumoral injection on days 2 and 4 with 4 Gy local irradiation daily × 5 (total 20 Gy) every cycle	Out of 16 patients enrolled (5 with melanoma, 4 colorectal, 1 gastric, 1 ovarian, 1 pancreatic, 1 lung, 1 cholangiocarcinoma, 1 sinus, 1 thyroid), 14 were evaluable and best overall response was SD or better in 13 patients (93%). Of these patients, 4 had PR (2 with melanoma, 1 lung, 1 gastric) and 2 had minor responses (1 thyroid and 1 ovarian)
II (MAYO-MC0672, NCI trial)	Metastatic melanoma	Open-label, single-arm, multicenter: 60-min IV infusion 3 × 1010 TCID50 days 1-5 every 28 d	Out of 21 evaluable patients, best overall response was SD > 8 wk in 6 patients. The median TTP was 45 d (range 13-96 d) and median OS was 165 d (range 15 d-15.8 mo). Trial was closed as did not meet previously defined efficacy criteria to proceed to second stage of accrual
II (REO 014)	Advanced or refractory sarcomas metastatic to lung	Open-label, single-arm, multicenter: 60-min IV infusion 3 × 1010 TCID50 days 1-5 every 28 d	Out of 53 enrolled patients, best overall response was SD ≥ 12 wk in 18 patients (34%) with a subgroup of 12 patients (3 with synovial sarcoma, 2 with leiomyosarcoma, 2 with MFH, 1 with ES, 1 with non-specified spindle cell sarcoma, 1 with chordoma, 1 with ASPS), 1 with myxoid liposarcoma) having prolonged SD > 16 wk. Three of these patients demonstrated SD > 1 yr (1 with MFH, 1 with synovial sarcoma, 1 with ES). The median TTP was 58.0 d (95%CI, 54-110, range 8-726 d). The prolonged SD demonstrated fulfilled the study criteria for consideration as an active agent
II (REO 015)	Refractory, recurrent, or metastatic SCC of the head and neck	Open-label, single-arm: 60-min IV infusion 3 × 1010 TCID50 days 1-5 with IV paclitaxel 175 mg/m2 over 3 h and IV carboplatin AUC5 (over 30 min) on day 1 every 21 d	Out of 13 evaluable patients (sites included 3 larynx, 6 oral cavity, 4 pharynx, 1 other), 4 had PR (31%) and 2 had SD ≥ 12 wk for a CBR of 46%
II (REO 016)	Recurrent or metastatic NSCLC	60-min IV infusion 3 × 1010 TCID50 days 1-5 with IV paclitaxel 175 mg/m2 over 3 h and IV carboplatin AUC5 (over 30 min) on day 1 every 21 d	Out of 37 patients enrolled, 20 patients had detected K-Ras mutations, 3 patients had EGFR mutations, 10 patients had EGFR amplifications alone, and 4 patients had BRAF V600E mutations. Median PFS was 4 mo (95%CI: 2.9-6.1), median OS was 13.1 mo (95%CI: 9.2-21.6), and 1-yr OS rate was 57% (95%CI: 39%-72%)
II (REO 017)	Advanced or unresectable pancreatic cancer	60-min IV infusion 1 × 1010 TCID50 on days 1, 2, 8 and 9 with IV infusion of gemcitabine 800 mg/m2 days 1 and 8 every 21 d	Out of 34 enrolled patients, median PFS was 4 mo and OS was 10.2 mo. One- and 2-yr survival rates were 45% and 24%, respectively
II (REO 021)	Recurrent or metastatic SCC of the lung	Open-label, single-arm: 60-min IV infusion 3 × 1010 TCID50 days 1-5 with IV paclitaxel 200 mg/m2 over 3 h and IV carboplatin AUC6 every 21 d	Out of 25 patients who received more than 1 cycle of therapy, best overall response was PR in 12 patients (48%) and SD in 10 patients (40%) for a CBR of 88%. Of 21 patients with > 6 mo follow-up 7 had PFS ≥ 6 mo (33.3%)
III (REO 018)	Advanced or metastatic head and neck cancer	Randomized, double-arm, double-blinded, multicenter: 60-min IV infusion 3 × 1010 TCID50 days 1-5 with standard doses of IV paclitaxel and IV carboplatin on day 1 only every 21 d (treatment arm) vs standard doses of IV paclitaxel and IV carboplatin alone (control arm)	Out of 167 enrolled patients, 118 patients were segregated into an intent-to-treat basis group with loco-regional head and neck cancer (with or without metastases). In this group, median PFS was 94 d (13.4 wk, n = 62) in the test arm vs 50 d (7.1 wk, n = 56) in control arm maintained through 5 cycles. In the 88 patients discontinued from the study from this group, median OS was 150 d (21.4 wk, n = 50) in the test arm vs 115 d (16.4 wk, n = 38) in the control arm. Survival analysis in the other group (distal metastases-only) has not been conducted

IV: Intravenous; TCID₅₀: Tissue culture infectious dose-50; AUC_5/6: Area under curve-5/-6; CR: Complete response; PR: Partial response; SCC: Squamous cell carcinoma; RECIST: Response evaluation criteria in solid tumors; SD: Stable disease; OS: Overall survival; IP: Intraperitoneal; Gy: Gray; TTP: Time to disease progression; PFS: Progression-free survival; MFH: Malignant fibrous histiocytoma; ES: Ewing sarcoma; ASPS: Alveolar soft part sarcoma; CBR: Clinical benefit rate; NSCLC: Non-small cell lung cancer; EGFR: Epidermal growth factor receptor.