Ark's Cerepro meets endpoint in pivotal brain cancer trial
This article was originally published in Scrip
Ark Therapeutics' novel gene-based therapy, Cerepro, has met its primary endpoint in its pivotal Phase III trial in newly-diagnosed brain cancer, preliminary trial results show.
Nigel Parker, Ark's chief executive, told Scrip that Ark would have a meeting with the EU regulator in a couple of months after a more detailed analysis of the trial was complete, but could not comment on any filing plans. In April, the EU's CHMP recommended against granting approval to Cerepro, concerned over the low number of patients in the Phase II trials. The committee also had concerns over the ways in which the study had been carried out, which made it difficult to interpret the results, the CHMP said. Ark said at the time that it believed that the agency's concerns may be resolved by the 236-patient Phase III trial, Study 904.
The primary endpoint in the trial, which included patients with operable glioblastoma, was time to death or re-intervention with any kind of treatment (surgery, chemotherapy, or radiotherapy) after tumour recurrence. Secondary endpoints include overall survival, progression as assessed by MRI, and safety, and these data are expected to be available next January or February. Results of the study are expected to be presented at the European Association of Neuro-Oncology meeting in Barcelona this September.
Patients in the trial received either surgery plus radiotherapy alone, surgery plus radiotherapy plus temozolomide (Temodar), surgery plus radiotherapy plus Cerepro, or all four. Schering-Plough's chemotherapy drug Temodar has been shown in a pivotal trial to extend median survival from 12.1 months with surgery and radiotherapy alone to 14.6 months in patients with newly diagnosed glioblastoma, and is therefore a common standard-of-care treatment in the disease. However, some centres in the trial did not use it as standard practice, or it may not have been given to patients who could not tolerate it, Dr Parker said. .
In the trial, the procedure was to first conduct surgery, then to administer Cerepro if the patient had been randomised to that group, then radiotherapy, and finally chemotherapy if the patient was able to tolerate this and was in a centre that offered it.
The primary endpoint in the ITT population compared the two groups of patients who had not received Cerepro with those who had. It showed just over a month benefit (42 days) for the Cerepro-treated patients (310 days vs 268 days) in time to death or re-intervention, which was significant (p<>
Looking at the four subgroups, patients who received all four treatments did best, with a median 350 days of time to death or re-intervention. Patients who received either Cerepro or Temodar appeared fared similarly, with a median of 300 days and 307 days, respectively, in time to death or re-intervention. Patients who received only surgery and radiotherapy fared worst, with a median of 208 days of time to death or re-intervention. The difference between surgery and radiotherapy, and this control plus Cerepro treatment, is trending towards but has not yet achieved significance, with some patients still to report an event.
While increased in hemiparesis, aphasia, and pyrexia were observed following therapy, the serious adverse events for Cerepro were in line with those in previous studies, indicating that the product has an acceptable safety profile, Ark said.
The Phase II trial had shown a larger benefit with Cerepro over standard treatment. Dr Parker accounted for the difference, saying that this was a multicentre trial with a different trial population.
Samir Devani, analyst at Nomura Code, said that while Ark Therapeutics had yet to have a meeting with the FDA, it was likely that a further trial with survival as the primary endpoint would be needed to register the treatment. He stated that while the regulatory hurdle for an orphan indication is likely to be lower, Ark should consider undertaking a further study in the US purely investigating the survival benefit when Cerepro is used in combination with Temodar (which is more broadly used in the US than Europe), which at a minimum would strengthen the marketing proposition for use of the product.
Cerepro uses an adenoviral vector (Ad5) to introduce the gene for thymidine kinase to healthy cells around the site of the tumour resection. It is delivered by the surgeon using up to 70 small injections. Five days later, ganciclovir is given intravenously, and the enzyme produced by the cells converts the ganciclovir into the active drug that kills any dividing cells. Normal brain cells do not divide.
Other investigational approaches being taken towards brain cancer include anti-angiogenic treatments. Roche/Genentech's Avastin (bevacizumab) has shown an improved six-month rate of progression-free survival (PFS) amongst patients with recurrent glioblastoma, compared with patients receiving treatment with temozolomide. Therapeutic vaccines are also being studied, such as Northwest Biotherapeutics' DCVax-Brain, which has shown promise in early, uncontrolled clinical trials.