10/05/2011
Celldex: Rindopepimut has potential in GBM despite terminated partnership; KLH blinding to allow for Phase III randomized study, neuro-oncologists say
Immunocellular's ICT-107 also reported good Phase I results, PFS benefit with rindopepimut was not as good in comparison.
Celldex's (NASDAQ:CLDX) rindopepimut still has potential in treating malignant gliobastoma (GBM), despite the terminated partnership with Pfizer (NYSE:PFE), neuro-oncologists said. They added that the use of keyhole limpet hemocyanin (KLH) blinding in a Phase III study should allow the company to generate randomized data for registration.
The company regained full worldwide rights from Pfizer Vaccines to develop and commercialize rindopepimut (CDX-110), effective 1 November 2010.
Pfizer thought that the agent could also work in treating head and neck cancers and lung cancer when it originally invested in the development, but then realized it was limited to GBM, said Dr James Vredenburgh, medical director of Adult Clinical Services at Duke University Medical Center. This is the only reason it was dropped, he said.
Pfizer abandoned rindopepimut because it did not have a worthwhile response, said Dr Joseph Landolfi, a neuro-oncologist at the New Jersey Neuroscience Institute at JFK Medical Center. Immunocellular's (OTC:IMUC) ICT-107 had good Phase I results, he said, noting that the PFS (progression free survival) benefit seen with rindopepimut was not as good in comparison. It is possible that Pfizer saw the vast difference between the two and felt it did not want to "roll the dice," he said.
Patients treated with ICT-107 demonstrated two-year survival rates of 80% with a median PFS rate of 17.7 months. Even with Temodar and radiation, the Celldex vaccine does not compete, he said.
ICT-107 seems to be generating significant buzz, said Landolfi, adding that even a 40% two-year survival rate would be good.
The data for ICT-107 is good, Vredenburgh said, noting that there is a strong push for randomized Phase I controlled studies.
ICT-107 candidates must be HLA-A1 or HLA-A2 positive, which represents approximately 50% of the population, versus the small subset who are positive for EGFRvIII, said Landolfi.
The message is that this drug is not for everyone, as an eligible patient needs to be healthy enough to have a gross total resection of their tumor and be EGFRvIII positive, Dr Herbert Bruce Newton, Ohio State University added. There is value in selected patients, he said, but it is important to catch them early. It is important to enroll patients in the study early, Landolfi said.
Rindopepimut is an investigational immunotherapeutic vaccine that targets the tumor-specific molecule, epidermal growth factor receptor variant III (EGFRvIII).
According to a company spokesperson, Celldex does not feel that the comparison of ICT Phase I data with rindopepimut or standard of care is appropriate because the trials have included different patient populations. Patients treated with rindopepimut have all been EGFRvIII positive and these patients have a worse prognosis and are not helped by surgery or other disease characteristics (Pelloski, 2007), unlike the ICT patients who may have a significantly better long term outlook due to their resection and other selection factors.
The spokesperson added that "all patients start vaccination with rindopepimut after they finish chemoradiation, at about three months post diagnosis, and the company compares these outcomes with matched patients from historical databases who meet the same criteria. Again, this is unlike the ICT patients who routinely went six, and even up to 12 months following diagnosis without progression before starting vaccination. Since the ICT data take credit for the time before vaccination, the extra months in their data could very well reflect a selected patient population who would be expected to do well."
Celldex presented complete data for the primary endpoint of ACT III, at the Annual Meeting of The Society for Neuro-Oncology (SNO), which showed that 66% of patients were progression-free at 8.5 months from diagnosis or 5.5 months from start of vaccination, a statistically significant increase over a predetermined progression-free rate (PFR) estimate.
A neuro-oncologist noted that the data for rindopepimut always seemed "too good to be true." Yet, a PFS benefit is significant in the indication, as the measurement along with overall survival benefits is helpful for assessing quality of life, Vredenburgh explained.
This is a nice percentage, said Landolfi, but he questioned how many patients were screened for eligibility. Pfizer would know, and perhaps this is why it decided it was not worth pursuing.
Rindopepimut is very promising as the early data look good, said Vredenburgh, but the company needs randomized Phase III data.
The study has not yet achieved median survival, so that data is forthcoming when a final median is reached, said the spokesperson. The company plans to initiate an international, double-blinded, placebo-controlled, randomized Phase III pivotal study of rindopepimut in patients with GBM that express EGFRvIII during the second half of 2011.
If Celldex is to successfully develop rindopepimut, they must conduct a placebo-controlled trial, said Newton.
The companies had previously been required to convert the ACT III trial to a single-arm Phase II clinical trial in which all patients received CDX-110 in combination with temozolomide, following the recommendation of the Independent Data Monitoring Committee. This was based on the observation that the majority of patients randomized to the control arm withdrew from this open-label study after being randomized to that group.
Celldex will initiate an international, double-blinded, placebo-controlled, randomized Phase III pivotal study of rindopepimut in approximately 300 patients with GBM that express EGFRvIII during the second half of 2011, the spokesperson said. The use of a low dose of KLH in control patients has been tested and appears to provide a very effective blind. It is also unlikely to alter the outcome in control patients. Celldex is in the process of assuring that major regulatory authorities agree with this plan.
KLH blinding will help in the pivotal study since patients will drop out of the study even with a higher chance of receiving vaccine as they would prefer to receive standard of care than take a 50% chance of receiving the vaccine, said Landolfi.
KLH blinding is the only way to test the agent in a randomized fashion, said Vredenburgh. Newton said it is unclear if KLH blinding will be sufficient to maintain patients on the placebo arm.
It was also reported that rindopepimut showed a similar benefit in patients whether or not they expressed MGMT, an active DNA repair gene that has been shown to limit the benefit from temozolomide treatment.
Yet, Vredenburgh noted that this the first study to show this, as this active MGMT gene is always a negative prognostic factor.
The side-effect profile of rindopepimut is very clean, as there were only a few mild anaphylactic reactions and patients were fine when treated with prednisone, Vredenburgh said.
The idea of a subcutaneous injection is appealing as it is less labor intensive and the drug appears to be well tolerated, with no major toxicities, Newton said.
ICT-107 is also well tolerated and there are some long-term responders, but data is limited to a small subset of patients, Newton noted. Work is ongoing to determine why some immune-based approaches are not working, but is still in flux he said.
Celldex has a market cap of USD 123m.
by Elizabeth Krutoholow
AI
