Novel hypoxia drug shows promise in pancreatic cancer

Combination therapy with the investigational hypoxia targeted drug, TH-302, and gemcitabine improved overall survival (OS) compared to gemcitabine alone in patients with advanced pancreatic cancer, according to results from an open label, Phase 2b study presented in the ESMO Proffered Paper session on Gastrointestinal tumors (non- colorectal) on Saturday September 29th.

Disordered tumour vasculature creates a hypoxic environment, with pancreatic cancer known to be one of the most hypoxic solid tumours. TH-302 is a novel anticancer agent that is converted to bromo-isophosphoramide mustard (Br-IPM), a potent DNA alkylator, under hypoxic conditions, thereby selectively targeting hypoxic tumour cells. In contrast, there is reduced drug-associated toxicity in surrounding healthy tissue since TH-302 remains inactive under normoxic conditions.

In this Phase 2b study, 214 previously untreated patients with locally advanced, unresectable or metastatic pancreatic cancer were randomized 1:1:1 to receive either TH-302 240 mg/m2 plus gemcitabine (n=71), TH-302 340 mg/m2 plus gemcitabine (n=74) or gemcitabine alone (n=69). All treatments were administered on days 1, 8 and 15 of a 28-day cycle. The study had an 80% power to detect a 50% improvement in progression free survival (PFS) with combination therapy.

Results presented yesterday by Dr Mitesh Borad from the Mayo Clinic, Scottsdale, Arizona, USA, showed that the addition of TH-302 appeared to improve OS compared with gemcitabine alone, although the difference was not significant. The median OS was 9.2 months with TH-302 340 mg/m2 plus gemcitabine, 8.7 months with TH-302 240 mg/m2 plus gemcitabine and 6.9 months with gemcitabine alone.

Skin and mucosal toxicity and myelosuppression were the most common TH-302-related adverse effects. With TH-302 340 mg/m2, rash and stomatitis occurred in 47% and 42% of patients, respectively, although this was rarely severe. However, the amount of haematological toxicity reported with TH-302 340 mg/m2 was much higher than that reported with gemcitabine alone: 63% thrombocytopenia (versus 11%) and 60% neutropenia (versus 31%).

Dr Borad commented that although improvements in overall survival did not reach statistical significance in this trial, the results were consistent with the improvement in median progression free survival reported in February this year. The trial, he added, had not been designed to detect a statistically significant improvement in overall survival and had been complicated by a cross-over component, where patients receiving gemcitabine alone could be crossed over to receive gemcitabine plus TH-302 upon disease progression.

Dr Borad informed delegates that the dose of 340 mg has been identified as the way forward for future trials, and that a Phase 3 trial is to be initiated.