Phase II data deserves further investigation of TH-302 in patients with unresectable pancreatic cancer
The hypoxia-activated prodrug is designed to specifically target the hypoxic microenvironment
- Date : 05 Jul 2012
- Topic : Gastrointestinal cancers
Data of the phase II, randomised, open-label, crossover study, designed to evaluate the efficacy and safety of two doses of TH-302 in combination with gemcitabine compared to standard gemcitabine in previously untreated patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma shows promise and deserves further investigation in the context of phase III study. The results were presented by Dr David Ryan of the Massachusetts General Hospital in Boston at the ESMO 14th World Congress on Gastrointestinal Cancer in Barcelona, Spain (27 June – 1 July 2012).
A hypoxic microenvironment is a characteristic of solid tumours and is associated with resistance to chemotherapy. TH-302 is tumour-selective hypoxia-activated nitroimidazole prodrug of the cytotoxin, bromoisophosphoramide mustard (Br-IPM). Under conditions of normal oxygen level, TH-302 is essentially inactive, and relatively nontoxic in normal tissues. The compound is activated in hypoxic environments, such as within a tumour. Under these conditions, the nitroimidazole functionality of the drug is reduced and the Br-IPM is released. Once released, it is free to alkylate DNA, killing the cells. The researchers presumed that combining TH-302 with gemcitabine may enable the targeting of both the normoxic and hypoxic regions of pancreatic adenocarcinoma.
The phase II trial design
It was a randomised, open-label, crossover study designed to evaluate the efficacy and safety of two doses of TH-302 in combination with gemcitabine compared to standard gemcitabine in 214 previously untreated patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma. Patients were randomly assigned 1:1:1 to receive two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with gemcitabine versus gemcitabine alone (control arm). Both drugs were administered intravenously over 30 minutes on days 1, 8, and 15 of every 4-week cycle. Patients who successfully completed six cycles of treatment without experiencing significant treatment-related toxicity and cancer progression were eligible for continuing treatment. Cross-over into one of the TH-302 plus gemcitabine cohorts was allowed for patients who experienced cancer progression on standard gemcitabine.
Among included patients, 164 (77%) had stage IV and 50 (23%) stage IIIB disease, median age was 65 (range 29-86); male/female ratio 59%/41%, 40% patients had ECOG performance status (PS) 0 and 60% with PS 1. Head of pancreas was involved in 58% of patients, and 36% patients had biliary stent.
Median progression-free survival was 3.6 months in gemcitabine vs. 5.6 months in the combination arms (p=0.005). In patients with distant metastases the median progression-free survival was 3.5 months in gemcitabine and 5.1 months in each of the combination arms. In patients with unresectable locally advanced disease the median progression-free survival was 5.3 months in gemcitabine, 8.5 months in the 240 dose group and 9.5 months in the 340 dose group. The best response according RECIST criteria was 12% in gemcitabine, 17% in 240 dose group and 27% in 340 dose group. The response rate in the 340 group was 24% in patients with distant metastases and 35% in patients with locally advanced disease.
The most common adverse events were fatigue (49%), nausea (43%), constipation (34%) and peripheral oedema (34%), similar across groups. Rash (45% in the 340 group) and stomatitis (36% in the 340 group) were greater in combination groups with no grade 4 toxicity observed, and the researchers noticed grade 3 in only 4 patients. Grade 3/4 thrombocytopenia (11% gemcitabine, 39% 240 and 59% 340) and grade 3/4 neutropenia (28% gemcitabine, 56% 240 and 59% 340) were higher with the combination treatment.
The trial met primary endpoint of extension of progression-free survival
This study of Threshold Pharmaceutical's leading drug candidate TH-302 in pancreatic cancer was presented initially by Dr Mitesh Borad, the principal investigator at the American Association of Cancer Research (AACR) 2012 Annual Meeting in Chicago. The trial met primary endpoint of extension of progression-free survival and indicates that TH-302 may be operating by hypoxia-activated mechanism.
The data reported at Congress in Barcelona deserves further investigation of the compound in phase III studies in advanced pancreatic cancer regardless of disease stage. Overall survival data, which currently is immature, is expected to be released in the second half of2012.
Phase II/III trial data of other chemotherapies in pancreatic cancer support gemcitabine and erlotinib plus gemcitabine as current first-line options for newly diagnosed patients with unresectable metastatic or locally advanced pancreatic cancer. FOLFIRINOX demonstrated very impressive efficacy in a randomised phase III trial, but its usage is limited due to high toxicity. Other drugs are currently in phase II or III trials. New compounds are very much expected for this hard to treat disease.
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