A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra‐cranial solid tumors: A Children's Oncology Group Phase I Consortium report

Abstract

Purpose Reovirus is a naturally occurring human virus that is cytopathic to malignant cells possessing an activated Ras signaling pathway. We conducted a phase I trial of Reolysin, a manufactured, proprietary isolate of purified reovirus, in children with relapsed/refractory extracranial solid tumors to define the recommended phase 2 dose (RP2D), toxicities and pharmacokinetic properties when administered as a single agent or in combination with cyclophosphamide. Experimental Design Reolysin was administered intravenously for 5 consecutive days, every 28 days. Using a 3 + 3 design, the following dose levels were evaluated: 3 × 108 Tissue Culture Inhibitory Dose 50% (TCID50)/kg; 5 × 108 TCID50/kg (maximum dose was 3 × 1010 TCID50); and 5 × 108 TCID50/kg plus oral cyclophosphamide (50 mg/m2/day × 21 days). Results Twenty-nine patients were enrolled; 28 were eligible and 24 were evaluable for toxicity and response. There were no hematologic dose-limiting toxicities. Grade 5 respiratory failure and a Grade 5 thromboembolic event were reported, both in the setting of progressive disease. The median time to clear the reovirus viremia was 6.5 days. Eight of twenty-four patients were viremic beyond the five days of therapy, all were negative by day 17. No patient had detectable viral RNA in saliva or stool. There were no objective responses. Conclusions Reolysin at a dose of 5 × 108 TCID50/kg daily for 5 days was well tolerated in children alone and in combination with oral cyclophosphamide. Virus was cleared rapidly from the serum and shedding in stool and salivawas not detectable.

Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients

“…The fact that an uninjected lesion also transiently flared on PET may indicate that localized HSV1716 infection had a systemic antitumor immune effect. Two non-pathogenic wild-type oncolytic viruses (seneca valley virus and reovirus), and one attenuated pathogenic virus (vaccinia virus), have also been studied in children and showed few toxicities but little evidence of disease response (19)(20)(21). Of these and the current pediatric trials, this trial using HSV1716 and the trial using vaccinia virus utilized intratumoral virus administration, whereas the other 2 trials used intravenous or systemic administration.…”

Trial Watch—Oncolytic viruses and cancer therapy

“…161,162,171,[174][175][176]182,185,190,267 Although official sources indicate that the status of NCT01469611 (a Phase I testing the biweekly intravenous administration of JX-594 as standalone immunotherapeutic intervention in CRC patients) is "Unknown," preliminary findings have already been published (see above). 184 Results from NCT01048892 (a Phase I trial evaluating NTX-010 in combination with metronomic cyclophosphamide in children with neuroendocrine tumors), and NCT01227551 (a Phase II study testing Cavatak TM as standalone immunotherapeutic intervention in subjects with advanced melanoma), both of which were "Completed" when we submitted our latest Trial Watch dealing with this topic, 247 are also available (see above), 175,194 and so are findings from NCT01740297 (a Phase I/II trial assessing the therapeutic profile of Imlygic Ò plus ipilimumab in melanoma patients), and NCT01766739 (a Phase I study testing intrapleural GL-ONC1 as single immunotherapeutic agent in individuals with malignant pleural effusion) (see above), 165,187 even though their status ("Recruiting") has not been updated during the last 21 mo.…”

“…161,162 Moreover, the clinical profile of Imlygic Ò combined with the FDA-approved cytotoxic T lymphocyte-associated 4 (CTLA4)-targeting monoclonal antibody ipilimumab 163,164 has been assessed in 18 patients with unresectable Stage IIIB-IV melanoma (NCT01740297). 165 Reolysin Ò (a proprietary variant of reovirus serotype 3 -Dearing strain) 166 has been tested either as standalone immunotherapeutic agent in 12 myeloma patients and in 15 subjects with recurrent malignant gliomas, 167,168 or combined with low-dose cyclophosphamide 169,170 in 29 children with relapsed or refractory extra-cranial solid tumors (NCT01240538), 171 and in 36 individuals affected by advanced neoplasms. 172 The safety and efficacy of Cavatak TM (a proprietary variant of Coxsackievirus A21) 173 administered intratumorally or intravenously as standalone immunotherapeutic agent have been evaluated in 57 subjects with unresectable Stage IIIC-IV melanoma (NCT01227551), 174,175 and in 30 individuals with other advanced solid malignancies (NCT02043665).…”

Exploring the antitumor effect of virus in malignant glioma

“…This strategy enhanced therapeutic efficacy of oHSV in a rat glioma model (138). Cyclophosphamide treatment has been used with OV in several clinical trials for other solid tumors (NCT00450814, NCT01598129) (25, 139). …”