NCT03294486

Safety and Efficacy of the ONCOlytic VIRus Armed for Local Chemotherapy, TG6002/5-FC, in Recurrent Glioblastoma Patients

• Status: Unknown
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 78 (estimated)
• Sponsor: Assistance Publique - Hôpitaux de Paris · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Glioblastoma is the most common and the most aggressive primary brain cancer in adults. Indeed, despite very intensive treatments (i.e. maximal safe surgery, radiotherapy and several lines of cytotoxic chemotherapies), inducing significant adverse events, the prognosis of glioblastoma patients remains dismal with a median overall survival of \~15 months. Therefore, more efficient and less toxic therapies are urgently needed to improve survival and quality of life of glioblastoma patients. The oncolytic virus TG6002 has shown efficacy and good safety profile in several preclinical models of glioblastoma in vitro (i.e. cell line) and in vivo (i.e. xenografts in Swiss/Nude mice). Comprehensive toxicology studies of TG6002/Flucytosine have been completed in rabbits and monkeys supporting safety investigations of TG6002/Flucytosine in human patients. Taken these data all together, TG6002/Flucytosine appears as a very promising therapeutic strategy in glioblastoma patients that merits consideration for early phase clinical trial.

Detailed description

Phase 1: This is a Phase 1, open-label, dose-escalation trial using an accelerated titration 3+3 design in patients with recurrent glioblastoma. Eligible patients will first be consecutively enrolled in a one-patient cohort at lowest dose level and then in 3-patients cohorts up to a DLT observation. In case a DLT is observed specific rules apply to enrol additional (from 3 to 5) patients in the same cohort and to proceed to higher doses. All patients within a given cohort will be treated with the same dose schedule of TG6002, administered as 3 weekly IV infusions at Days 1, 8, and 15. Following the 1st and 2nd infusion of TG6002 on Day 1 and 8, patients will be given oral 5-FC for 3 days starting on Day 5 and 12 and ending on Day 7 and 14, respectively. Following the 3rd infusion of TG6002 on Day 15, patients will be given oral 5-FC for 21 days starting on Day 19 and ending on Day 39 (end of treatment). Patients will be followed until documented tumor progression. The starting dose of 1 x 105 pfu is determined after toxicology results in the most sensitive species on which a security factor (100x) has been applied; accelerated titration will consist in one patient being administered with the starting dose and one-log dose increment between the three first cohorts. The maximum tolerated dose (MTD) is defined as the highest TG6002 dose level at which at most 1 Dose-Limiting Toxicity (DLT) is observed in 6 patients exposed to that dose level.. The DLT period is defined as the interval between the first TG6002 IV infusion (Day 1) and the 8th day of the 21-day 5-FC treatment occurring on Day 26. Between consecutive cohorts during dose escalation, an at least 3-week safety interval will be applied, starting from the completion of the DLT period of the last patient of the previous cohort (D26), before the infusion of the first patient of the next higher dose cohort (D47). The initiation of the next higher dose cohort will be determined following an analysis by the DSMB of the safety results from one cycle of TG6002 treatment in combination with 5-FC. Phase 2a: Based on the outcome of the Phase 1 dose-escalation cohorts, i.e. RP2D, the Phase 2a will include 24 patients. Patients will be treated IV at the RP2D.

Conditions

• Glioblastoma
• Brain Cancer

Interventions

Type	Name	Description
DRUG	Combination of TG6002 and 5-flucytosine (5-FC, Ancotil®)	Phase 1, TG6002 administered in a total volume of 250mL of saline solution (0.9 %) as three intravenous infusions at the following doses: * Dose 1 : 5.0 log10 pfu •Dose 2 : 6.0 log10 pfu •Dose 3 : 7.0 log10 pfu •Dose 4 : 7.5 log10 pfu * Dose 5 : 8.0 log10 pfu •Dose 6 : 8.5 log10 pfu Additional dose levels •Dose 2-1 : 5.5 log10 pfu •Dose 3-2 : 6.5 log10 pfu Phase 2a, treatment IV at the recommended Phase 2 dose 5-Flucytosine (5-FC) is provided in its commercial packaging with brand name ANCOTIL 500 mg, tablet (Ancotil®) marketed by MEDA Pharma: polypropylene tube containing 100 tablets. 5-FC administered orally as 500 mg tablets taken 4 times per day (qid). Daily starting dose is 200 mg/kg. The daily dose will be adjusted at Day 19 following the measurement of 5-FC plasma concentration at steady state (Day 7), which should be kept below 100 mg/L.

Timeline

• Start date: 2017-10-12
• Primary completion: 2019-05-01
• Completion: 2021-09-01
• First posted: 2017-09-27
• Last updated: 2017-11-06

Locations

1 site across 1 country: France