A Phase I study to evaluate the feasibility, safety and biological effects of intratumoural administration of wild-type Reovirus (REOLYSIN®) in combination with radiation in patients with advanced malignancies.

B81 Background: Wild-type reovirus (REOLYSIN®) is a dsRNA virus which results in asymptomatic infection in humans and has been demonstrated to replicate in and prove cytopathic to Ras activated cells, while sparing normal cells.
 Methods: An open label, dose escalating, multicentre phase I study of intratumoural injections of REOLYSIN with concurrent fractionated radiotherapy in patients with advanced solid tumours. The primary objectives are to determine the feasibility and safety of this intervention as well as assessing the antitumour activity, viral replication and the development of immune response. Patients were treated in sequential 3-patient cohorts. The treatment plan initially involved local irradiation of 20Gy in 5 consecutive daily fractions in combination with two intratumour injections of REOLYSIN (10 8 TCID 50 on days 2 and 4 in week 1) with successive cohorts receiving escalating doses of virus to a maximum 10 10 TCID 50 . As no dose-limiting toxicity (DLT) was encountered the radiotherapy dose was increased up to 36Gy in 12 fractions. The number of REOLYSIN injections were escalated in conjunction from two doses of 10 10 TCID 50 (days 2 and 4 in week 1) for the first cohort then four doses of 10 10 TCID 50 (days 2 and 4 in week 1 and days 9 and 11 week 2) and finally 6 doses of 10 10 TCID 50 (days 2 and 4 in week 1 and days 9 and 11 week 2 and days 16 and 18 in week 3).
 Tumour evaluation using imaging(RECIST criteria) or clinical examination was performed at days 33 and 61 in the 20Gy cohorts and days 29 and 59 in the 36Gy cohorts. Blood was collected for assessment of T cell subsets, T cell proliferation and cytokine production in association response to tumour associated antigens.
 Results: 24 patients have been enrolled to date with 15 having completed the study (7 withdrawals/replacements and 2 patients still on study) with one patient required to complete the study. Treatment has been well tolerated with grade 3 toxicities of fatigue(4), hypokalaemia(3), tumour pain(1), tumour necrosis(1), diarrhoea(1), dysphagia(1), cellulitis(1) and anorexia(1) seen. Common grade 1 and 2 toxicities include lymphopenia, fatigue, vomiting, fever, rash and neutropenia. In the low dose cohort two pts (oesophageal and skin squamous carcinoma) had significant partial responses (PR) (70% and 50%) and stable disease(SD) of treated site was seen in 8 of 11 evaluable patients with disease progression noted at non treatment lesion sites in 2 of those with stable disease. Of note the patient with oesophageal cancer had a PR in non-irradiated mediastinal disease. In the high dose cohort 1 partial response(PR) (in colorectal cancer) in the 7 evaluable patients, and 6 SD were seen with one showing progression at non-treated sites.
 Conclusion: The use of intratumoural injections of REOLYSIN combined with radiotherapy is tolerated without significant toxicity. The administration of multiple injections in association with radiotherapy is feasible in selected patients. The data on immune response and viral replication is ongoing at present with the study nearing planned completion.