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

Table 1 Phase I trials involving reovirus

Phase	Malignancy	Dosing regimen	Clinical response
I (REO 001)	Various advanced or refractory solid malignancies	1 × 107 PFU to 1 × 1010 PFU intralesional injection once or 3 × weekly (dose escalation)	Out of 19 patients, best overall response ≥ 6 wk was CR in 1 with Klatskin (5.3%), PR in 2 with head and neck cancer (10.5%), SD in 4 1 with head and neck, 1 with melanoma, 1 with breast cancer, 1 with Kaposi's (21.1%)
I/translational (REO 002)	Localized prostate cancer	1 × 107 PFU single intratumoral injection 3 wk prior to planned prostatectomy	Out of 6 patients, all did not exhibit significant fluctuations in PSA from baseline. Five of 6 patients showed staining for reovirus proteins localized to cancer areas but sparing of adjacent benign and remote cancer areas. Pathologic specimens showed peritumoral inflammation in 4 patients, apoptosis in 4 patients, and necrosis in 2 patients
I (REO 003)	Advanced or recurrent malignant gliomas	1 × 107 TCID50 to 1 × 109 TCID50 single stereotactic intralesional injection (dose escalation)	Out of 12 patients, best overall response was SD in 1 patient with oligo-astrocytoma with a TTP of 39 wk. The overall median TTP was 4.3 wk (range 2.6-39 wk), and median OS was 21 wk (range 6-234 wk)
I (REO 004)	Various advanced or refractory solid malignancies	60-min IV infusion from 1 × 108 TCID50 to 3 × 1010 TCID50 once every 28 d (dose escalation)	Out of 18 patients, best overall response was PR > 5 cycles in 1 patient with breast cancer (5.6%) and SD > 1 cycle in 7 (5 with ovarian cancer, 1 with carcinoid, 1 with STS, 38.9%); CBR of about 45%
I (REO 005)	Various advanced or refractory solid malignancies	60-min IV infusion from 1 × 108 TCID50 once every 28 d to 3 × 1010 TCID50 once daily for 5 d every 28 d (dose escalation); IV reovirus 3 × 1010 TCID50 once daily for 5 d every 28 d became recommended phase II dose	Out of 33 enrolled patients, best overall response was SD > 7 wk in 10 patients (2 with colon cancer, 2 with prostate cancer, 2 with STS, 1 with lung cancer, 1 with TCC of the bladder, 1 with melanoma, 1 with endometrial cancer)
I (REO 006)	Various advanced or refractory solid malignancies	1 × 108 TCID50 to 1 × 1010 TCID50 intratumoral injection on days 2 and 4 with 20 Gy local irradiation daily × 5 fractions phase 1b: 1 × 1010 TCID50 intratumoral injection twice weekly from 1-3 wk with 36 Gy local irradiation × 12 fractions over 16 d (two-stage dose escalation); intratumoral 3 × 1010 TCID50× 2 injections with 20 Gy × 5 fractions and intratumoral 1 × 1010 TCID50 × 6 injections with 36 Gy × 12 fractions became recommended phase II doses for short and prolonged palliative regimens, respectively	Out of 7 patients in phase 1a, best overall response was PR in 2 (esophageal adenocarcinoma and SCC of skin), SD in 5 (melanoma, pancreatic adenocarcinoma, SCC of larynx, and 2 with SCC of skin); out of 7 patients in phase 1b, 5 had PR (lung adenocarcinoma, colorectal cancer, ovarian adenocarcinoma, 2 with melanoma) and 2 had SD (melanoma) up to 3 mo post-treatment
I (REO 007)	Recurrent malignant gliomas	72-h intratumoral infusion from 1 × 108 TCID50 to 1 × 1010 TCID50 (dose escalation)	Out of 15 patients enrolled, best overall response was SD in 10 patients during the study period of 24 wk. The median TTP was 61 d (range 29-150 d), and median survival was 140 d (range 97-989)
I (REO 009)	Various advanced or refractory solid malignancies	60-min IV infusion from 1 × 109 TCID50 to 3 × 1010 TCID50 on day 1 (dose escalation) with 30-min IV infusion of gemcitabine 1000 mg/m2 days 1 and 8 every 21 d (1 × 1010 TCID50 reovirus on day 1 became recommended phase II dose with gemcitabine)	Out of 10 patients, best overall response was PR after 4 cycles in 2 patients (1 with nasopharyngeal carcinoma, 1 with breast cancer) and SD for 4-8 cycles in 5 patients (median SD 72 d, range 36-112 d); CBR of 80%
I (REO 010)	Various advanced or refractory solid malignancies	60-min IV infusion from 3 × 109 TCID50 to 3 × 1010 TCID50 days 1-5 (dose escalation) with 60-min IV infusion of docetaxel 75 mg/m2 day 1 every 21 d (3 × 1010 TCID50 reovirus days 1-5 every 21 d became recommended phase II dose with docetaxel)	Out of 16 patients, best overall response was PR ≥ 2 cycles in 4 patients (1 with breast cancer who experienced CR in liver lesion, 1 with gastric cancer, 1 with gastroesophageal cancer, 1 with ocular melanoma) and SD ≥ 2 cycles in 10 patients (cancers included prostate, mesothelioma, SCC of head and neck, unknown primary, melanoma, esophageal cancer, pancreatic cancer); CBR of 88%
I/translational (REO 013)	Colorectal cancer metastatic to the liver	60-min IV infusion of 1 × 1010 TCID50 daily × 5 d between 6-28 d prior to planned radical resection of liver metastases	Out of 10 patients, 9 patients with resected tumor specimens demonstrated positive staining for reovirus that was greatest in tumor metastases compared to surrounding tumor stroma or adjacent normal liver. In addition, tissue analysis in 4 patients showed findings consistent with reovirus-associated apoptosis
I (REO 022)	Metastatic colorectal cancer	60-min IV infusion from 1 × 1010 TCID50 to 3 × 1010 TCID50 days 1-5 every 28 d (dose escalation) with standard FOLFIRI doses (recommended phase II dose was irinotecan 150 mg/m2 with 3 × 1010 TCID50IV reovirus days 1-5 every 28 d)	Out of 18 patients, best overall response was PR in 1 patient (5%) and SD in 9 (50%) with median PFS in FOLFIRI-naïve patients of 7.4 mo (95%CI: 1.9-12.9 mo) and overall median PFS of 7.4 mo (95%CI: 0.6-14.1 mo)
I (OSU-11148, NCI trial)	Refractory or relapsed multiple myeloma	60-min IV infusion from 3 × 109 TCID50 to 3 × 1010 TCID50 days 1-5 every 28 d (dose escalation)	Out of 12 patients, best overall response was SD with longest duration being 8 cycles. During cycle 1, 5 patients had decreased myeloma proteins, 3 had minimal increases, and 4 had progressive disease

PFU: Plaque forming units; CR: Complete response; PR: Partial response; SD: Stable disease; PSA: Prostate-specific antigen; TCID₅₀: Tissue culture infectious dose-50; TTP: Time to disease progression; OS: Overall survival; IV: Intravenous; STS: Soft tissue sarcoma; CBR: Clinical benefit rate; TCC: Transitional cell carcinoma; Gy: Gray; SCC: Squamous cell carcinoma; FOLFIRI: Irinotecan/fluorouracil/leucovorin; PFS: Progression-free survival.