Session Item

Mitomycin C (MMC) is a well-established radiosensitizer. However, MMC is associated with severe hematological and renal toxicity limiting its use. Early clinical studies indicate that a novel formulation of pegylated liposomal MMC lipidic prodrug (Promitil®) is safe and effective with limited hematotoxicity compared with MMC. Furthermore, in preclinical studies, it had promising radiosensitizing activity. The primary objectives of this phase 1B study of Promitil^® with radiotherapy (RT) were to evaluate safety and tumor response in the irradiated field in patients requiring palliative RT. Secondary objectives were to determine plasma prodrug (MLP) levels after each Promitil^® infusion and systemic anti-tumor response

The protocol was approved by the respective IRBs. 19 eligible pts with metastatic (18) or inoperable (1) disease, received a combination of Promitil^® and standard of care RT. Most pts (16) were diagnosed with advanced GI tract cancer. The treatment included two Promitil® doses, at 21-day intervals, and RT initiated 1-3 days after the first Promitil^® dose and completed within 2-weeks. Ten fractions of conventionally fractionated RT or 5 SBRT fractions were allowed. The study consisted of 3 dose-escalation cohorts of Promitil^® of 6 patients each: 1.25 mg/kg, 1.5 mg/kg, and 1.8 mg/kg. Dose escalation proceeded if no dose-limiting toxicities (DLT) were recorded by study day 43 in more than 1/6 patients.

Patients were assessed weekly during the Promitil^® cycle (42 days after last dose of Promitil^®). Status of the irradiated and non-irradiated lesions, if present, was reevaluated by CT between days 43-50, and every 6 weeks thereafter. In addition, MMC prodrug plasma levels were analyzed 1 h and 1 day after each dose of Promitil^®

18/19 pts completed two Promitil^® infusions and the entire RT course. No DLT was reported. Two SAEs were reported, one considered non-related and one possibly related Grade 4 neutropenia . Most of the AEs were deemed mild or moderate. The most common AEs - possibly related to the study drug - were thrombocytopenia, fatigue and vomiting. No severe RT-related reaction was reported. 18/19 pts were evaluable for efficacy. 16/18 patients were free of disease progression in the irradiated target lesion (1 complete response, 9 partial response, 6 stable, 2 progressive disease). Median survival of patients in the 3 cohorts was 103 weeks. Plasma analysis showed high level of MLP correlating with the increase in dose level and a similar profile before and after RT. About 50 % of MLP was still in circulation 24h after Promitil^® infusion. No free MMC was detectable in plasma

Promitil^® combined with RT is safe at a dose of 1.8 mg/kg every 3 weeks with a high rate of tumor control in a variety of tumor types. Drug clearance is not affected by radiation. Promitil^® is a novel and attractive option for radiosensitization that should be evaluated in future randomized studies in the palliative (and possibly the curative) setting