US FDA clears Oxford Biomedica's cancer vaccine TroVax for further development
This article was originally published in Scrip
The US FDA has given the go-ahead for Oxford Biomedica to resume developing its novel cancer vaccine TroVax in renal cancer, and pursue further indications in multiple metastatic cancer settings, including colorectal, ovarian and triple-negative breast cancers.
The decision was made after the agency reviewed the Phase III TRIST study of TroVax in renal cancer and the company's proposed clinical development outline. The trial was halted in July 2008, after the study's independent data safety monitoring board (DSMB) concluded that the study would not meet its predefined primary endpoint of an improvement of overall survival (scripnews.com, July 14th, 2008).
The data evaluated by the DSMB were discussed with the FDA and it was agreed at a meeting last October that plans to initiate further Phase III trials in colorectal cancer would be delayed pending the FDA's review of additional data from the TRIST study. The FDA completed its review of these in June.
The 733-patient randomised, placebo-controlled TRIST study, which commenced in November 2006, was testing the benefit of adding TroVax to first-line standard of care in patients with locally advanced or metastatic clear cell renal carcinoma, hoping to find an approximately three-month survival advantage.
TroVax was added to interleukin-2, alpha-interferon, or Pfizer's new multi-targeted therapy Sutent (sunitinib), which has become the standard first-line treatment in the disease after showing much improved survival.
As of August 2008, there was a non-significant excess of 16 deaths in the TroVax arm compared with the control arm. However, at the most recent analysis in March, the survival curves of the two treatment arms had converged and there were 166 deaths in the TroVax arm compared with 168 deaths in the control arm.
Median survival had not been reached in either group with 399 (54%) patients remaining in the study.
The company said that the data analysis also confirmed the immunological activity of the drug and confirmed the correlation between the strength of the 5T4-specific antibody response and improved survival.
In its comments, the FDA acknowledged that confounding factors may have contributed to the increased number of deaths in the TroVax arm at the August cut-off date. It also noted that there was no evidence of specific adverse events that could attribute the imbalance of deaths to TroVax.
A prospectively agreed sub-set analysis of intent to treat (ITT) patients showed a significant advantage to TroVax in good prognosis patients receiving interleukin-2 (n= 50 in TroVax arm and n= 50 in placebo arm) at March 13th, 2009.
In addition, analyses suggest that abnormal baseline haematological parameters may have affected the ability of patients to mount effective immune responses to TroVax. Over 50% of patients in the TRIST study had "normal" baseline platelet, monocyte and haemoglobin levels (n= 372) and, in these patients, there was evidence of a survival benefit in favour of TroVax.
According to the company, these observations are potentially valuable for future studies of TroVax, enabling the selection of patients at screening that are more likely to respond and, hence, benefit from TroVax treatment.
The FDA noted that the analysis of patients receiving TroVax or placebo in combination with interleukin-2 was encouraging. It stated that it was reasonable to postulate that patients with a better haematological profile might respond more favourably to treatment with a cancer vaccine such as TroVax.
TroVax is a gene therapy system based on the generation of the 5T4 tumour-associated antigen, which is delivered via the intramuscular injection of a modified vaccinia virus Ankara (MVA) vector to generate a systemic anti-5T4 immune response.
It was originally being developed in partnership with Sanofi-Aventis, but that company terminated its agreement with Oxford Biomedica in May (scripnews.com, May1st, 2009).
Oxford Biomedica confirmed that it needed a partner in order to develop TroVax, and has hinted that it has received interest from potential suitors.
"We do not intend to fund large studies of TroVax ourselves," said Nick Wolf, the company's chief business officer. "We are well positioned to advance and widen our partnership initiative."