Following its fourth interim review of the TRIST (TroVax Renal Immunotherapy Survival Trial) study, the independent Data Safety Monitoring Board (DSMB) has advised that TroVax administered according to the protocol will not meet the predefined primary efficacy endpoint. The Phase III study is investigating the vaccine in locally-advanced or metastatic clear cell renal carcinoma (RCC) and has a primary endpoint of overall survival in the TroVax-treated versus the placebo group. TroVax is Oxford BioMedica's (OBM) novel therapeutic cancer vaccine, which is being developed in collaboration with sanofi-aventis.
The DSMB has recommended that the study continues because there is important scientific merit and more to be learned by additional follow-up of all patients, but further vaccinations are discontinued; OBM has implemented the recommendation. In addition, the company intends to amend the statistical plan of the study to determine whether patient outcome is dependent on the number of TroVax doses administered. The news hit the former’s share price hard, as its stock fell from a close of 18.5p on 10th July, to open at 7p on 11th July, before closing the day at 7.5p, a 59 per cent drop.
The companies will discuss the proposed TRIST protocol amendments with regulatory authorities. With these amendments, a focus of the ongoing TRIST study will be to explore the number of doses that provide optimal benefit. In particular, it may be that the optimal benefit-to-risk ratio is delivered without the requirement for as many vaccinations as specified in the original TRIST study protocol. It is unlikely that the TRIST study alone will support registration of TroVax in RCC, although the trial may ultimately demonstrate a survival advantage for TroVax, and the results may form part of a regulatory submission alongside an additional confirmatory trial.
The randomised, placebo-controlled TRIST study was initiated in November 2006 and completed recruitment of 733 patients in March 2008 at more than 100 sites in the US, EU and Eastern Europe. It is designed to evaluate TroVax in combination with standard-of-care in locally-advanced or metastatic clear cell RCC. The original trial protocol, which was the subject of a Special Protocol Assessment by the FDA, allowed for patients to receive up to 13 immunisations over 73 weeks.
TroVax targets the tumour antigen 5T4, which is broadly distributed throughout a wide range of solid tumours. The product consists of a modified vaccinia Ankara vector, which delivers the gene for 5T4 and stimulates a patient's body to produce an anti-5T4 immune response. This immune response destroys tumour cells carrying the 5T4 antigen.
OBM and sanofi-aventis will evaluate the available data and the implications on the development plan for TroVax, including the planned Phase III trials in colorectal cancer (CRC). The Oncology Clinical Trials Office, part of the Clinical Pharmacology Department of the University of Oxford, has stated that the DSMB's recommendations in relation to the TRIST study "does not impact on our enthusiasm to progress the QUASAR V TroVax study" in adjuvant CRC. But it remains to be seen what the companies' stance on future trials is.
Matthew Dennis - Editor, Cancer Drug News
Monday, July 21, 2008
Thursday, July 10, 2008
Europe moves in right direction
The first research to examine recent trends in European cancer incidence, mortality and survival together has shown that cancer prevention and management in Europe is moving in the right direction. However, the work reveals that variations between countries in policies for mass screening, access to healthcare and treatment are reflected in the different cancer rates. The research, consisting of ten papers, has been published in a special July edition of the European Journal of Cancer and coincides with the start of work by the EC to draw up a new EU Cancer Action Plan.
In one study (2008;44:1345-1389), scientists from the Erasmus Medical Centre obtained data on incidence, mortality and five-year survival from the mid-1990s to the mid-2000s from cancer registries in 21 European countries, and used it to analyse trends. The researchers found that generally in the more prosperous countries of Northern and Western Europe the trend was downwards for cancer incidence; the exceptions were for obesity-related cancers, such as colorectal and postmenopausal breast cancer (BC), and for tobacco-related cancers in women, such as lung cancer.
Incidence and mortality from tobacco-related cancer decreased for men in Northern, Western and Southern Europe, they increased for both sexes in Central Europe and for women nearly everywhere in Europe. With the exception of smoking-related cancers, mortality trends generally in most cancers were moving downwards for the majority of Europe.
Survival rates for most cancers generally improved. The investigators state that this is due to better access to specialised diagnostics, staging and treatment. For instance, although the incidence of BC continues to rise in most countries, deaths are declining and survival is improving. The rising incidence and survival rates are partly influenced by the presence of organised BC screening programmes and even opportunistic screening that increases the detection of smaller and less aggressive tumours. Survival and mortality is also influenced by improved staging and treatment, such as the use of tamoxifen in postmenopausal patients and chemotherapy in premenopausal patients.
The impact of mass screening is investigated in greater depth in another paper (2008;44:1404-1413), and in a further paper (2008;44:1425-1437), on the potential ways of closing the gap between Central and Eastern Europe through changes in lifestyles, which could reduce the incidence of some cancers. Another report (2008;44:1451-1456), by scientists from the Institute of Public Health of the Republic of Slovenia, outlines some of the issues for Europe, including the identification of five groups of key stakeholders: patients, health policy, reimbursement and financing agencies, research and finally, pharmaceutical and medical technology industries. Four key resources are identified as the most relevant to successful cancer management: human resources, physical resources, knowledge resources and social resources.
The paper concludes that Europe must focus on four types of interventions: primary prevention and health promotion; secondary prevention with proven screening programmes; more equitable access to optimal treatment and integration of all cancer care services; and sustained and consistent support for advanced independent research. All of those involved in the oncology field will hope that the EC listens to its experts and outlines a plan that will tackle these important issues.
Matthew Dennis - Editor, Cancer Drug News
In one study (2008;44:1345-1389), scientists from the Erasmus Medical Centre obtained data on incidence, mortality and five-year survival from the mid-1990s to the mid-2000s from cancer registries in 21 European countries, and used it to analyse trends. The researchers found that generally in the more prosperous countries of Northern and Western Europe the trend was downwards for cancer incidence; the exceptions were for obesity-related cancers, such as colorectal and postmenopausal breast cancer (BC), and for tobacco-related cancers in women, such as lung cancer.
Incidence and mortality from tobacco-related cancer decreased for men in Northern, Western and Southern Europe, they increased for both sexes in Central Europe and for women nearly everywhere in Europe. With the exception of smoking-related cancers, mortality trends generally in most cancers were moving downwards for the majority of Europe.
Survival rates for most cancers generally improved. The investigators state that this is due to better access to specialised diagnostics, staging and treatment. For instance, although the incidence of BC continues to rise in most countries, deaths are declining and survival is improving. The rising incidence and survival rates are partly influenced by the presence of organised BC screening programmes and even opportunistic screening that increases the detection of smaller and less aggressive tumours. Survival and mortality is also influenced by improved staging and treatment, such as the use of tamoxifen in postmenopausal patients and chemotherapy in premenopausal patients.
The impact of mass screening is investigated in greater depth in another paper (2008;44:1404-1413), and in a further paper (2008;44:1425-1437), on the potential ways of closing the gap between Central and Eastern Europe through changes in lifestyles, which could reduce the incidence of some cancers. Another report (2008;44:1451-1456), by scientists from the Institute of Public Health of the Republic of Slovenia, outlines some of the issues for Europe, including the identification of five groups of key stakeholders: patients, health policy, reimbursement and financing agencies, research and finally, pharmaceutical and medical technology industries. Four key resources are identified as the most relevant to successful cancer management: human resources, physical resources, knowledge resources and social resources.
The paper concludes that Europe must focus on four types of interventions: primary prevention and health promotion; secondary prevention with proven screening programmes; more equitable access to optimal treatment and integration of all cancer care services; and sustained and consistent support for advanced independent research. All of those involved in the oncology field will hope that the EC listens to its experts and outlines a plan that will tackle these important issues.
Matthew Dennis - Editor, Cancer Drug News
Friday, July 4, 2008
Advexin moves closer to market
Introgen Therapeutics has submitted a BLA to the FDA, while simultaneously Gendux Molecular (Introgen) has submitted an MAA to the EMEA, both seeking marketing approval for Advexin (INGN 201), the company's targeted p53 tumour suppressor gene therapy, to treat recurrent, refractory head and neck cancer. INGN 201 represents the first in a new class of tumour suppressor cancer therapy and is the first of its kind to be submitted for regulatory approval in the US and Europe. Introgen has requested priority review from the FDA for INGN 201, meaning that the treatment could be on the market in early 2009. The news buoyed Introgen's share price as it rose nearly 16 per cent, from a close of US$1.51 on 27th June, to start 30th June at US$1.75.
INGN 201 therapy harnesses the body's natural tumour suppression mechanisms to fight cancer, without the toxicities associated with conventional cancer treatments. Abnormalities in protective tumour suppressor p53 pathways are associated with the majority of all solid cancers. Designed to restore patients' ability to fight cancer, INGN 201 delivers large doses of the normal p53 gene to target abnormal p53 function present in tumour cells, which triggers natural tumour suppression mechanisms in cancer without harming normal cells.
According to Dr Jack Roth, inventor of Advexin and professor at the University of Texas MD Anderson Cancer Center: "This is an important milestone in the clinical application of gene therapy for cancer patients. With the use of p53 biomarkers, Advexin will provide more effective and less toxic treatment for head and neck cancer patients who have limited treatment options."
The submissions are based on pivotal Phase II and III trials evaluating survival, tumour response and safety in patients with recurrent, refractory end-stage, squamous cell carcinoma of the H&N. These studies incorporated common diagnostic tests to identify patients most likely to benefit from INGN 201 based upon pretreatment tissue analyses to determine p53 profile status.
The Phase III trial achieved the study's objectives and demonstrated clinical benefit of INGN 201 in comparison to the control drug, methotrexate. The patients most likely to benefit from INGN 201 treatment with increased tumour responses and survival were identified by prespecified p53 biomarker profiles. Overall, the study results demonstrated that INGN 201 addresses an unmet medical need and the combination of biomarker testing and treatment has the potential to provide recurrent H&N cancer patients with an effective therapy that is less toxic than standard chemotherapies.
INGN 201 is Advexin’s lead product candidate, approval of which may open the door for the company’s other gene therapy drugs. Indeed, INGN 201 is being investigated in Phase II trials for breast, non-small cell lung and oesophageal cancer, as well as earlier-stage studies in prostate, ovarian, bladder, brain and bronchoalveolar cancer. However, it is unclear whether regulatory bodies will even approve INGN 201. The FDA has faced considerable scrutiny in recent years for approving drugs that have turned out to produce dangerous side effects, and it has become more cautious as a result. How the Agency along with the EMEA will view the first in a new class of drugs remains to be seen.
Matthew Dennis - Editor, Cancer Drug News
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