ImmunoCellular Therapeutics (OTCPK:IMUC) is anticipating top-line results from the ICT-107 Phase 2 clinical trial in the next few months. There has been a lot of speculation recently about whether the results will be positive or negative. NO ONE knows what the results will be, but investors should be aware of the important facts before making investment decisions.
ICT-107 is a cancer vaccine
ICT-107 is a personalized, cell-based cancer vaccine that works a lot like Dendreon's Provenge, which was approved by the FDA to treat prostate cancer in 2010. ICT-107 uses patients' dendritic cells (DCs) to stimulate a specific immune response against tumor cells in the brain. Unlike Provenge, however, ICT-107 utilizes more potent cells, is much cheaper to manufacture, and targets multiple tumor antigens, as well as cancer stem cells, which can play a major role in cancer recurrence.
Promising early clinical results
In a Phase 1 study, 16 newly diagnosed glioblastoma (GBM) patients treated with ICT-107 had a median survival rate of 38.4 months. GBM is a very aggressive form of brain cancer, and patients typically survive only about a year and a half. A potential improvement in survival of more than a year is amazing. Seven of the 16 patients treated with ICT-107 have survived more than 5 years, which is also unprecedented.
Survival benefit uncertain
Despite promising results from the Phase 1 trial, it needs to be repeated that NO ONE knows for sure whether ICT-107 improves survival yet. Other factors may have contributed to the survival benefit that was observed. For example, the skill of the neurosurgeons at removing tumor at Cedar-Sinai, where the Phase 1 trial took place, may have played a role in the clinical outcome. We do not know the survival rates of GBM patients who were not treated with ICT-107 at Cedars to rule surgical skill out as a possible contributor. Several cancer vaccines that have had promising early results eventually failed to show any clinical benefit when studied in randomized, controlled, multicenter clinical trials; CancerVax's Canavaxin is just one example.
Importance of HLA
HLA is kind of like blood type. People are born with a certain HLA type (e.g. A1, A2, etc.). About 70% of people in North America have either HLA-type A1 or A2, and ICT-107 is designed to work only in these patients. The vaccine targets six different tumor antigens, but only two (MAGE1 and AIM2) in A1 patients and four (HER2, TRP2, gp100, and IL-13Ra2) in A2 patients. Thus, ICT-107 should only have an effect on A1 patients who have MAGE1 and AIM2 on their cancer cells; it cannot attack the other tumor antigens in A1 patients. For A2 patients, ICT-107 only targets four tumor antigens; A2 patients with tumors only having MAGE1 and AIM2 should see no benefit. ICT-107 is essentially two different products: one for A1 patients and the other for A2 patients.
Predicting the Phase 2 study outcome
Some investors are trying to predict the results of the Phase 2 trial based on timing of enrollment and interim analysis. Be mindful of the limitations of such methods given several unknown variables:
- Survival time is normally calculated as the period of time a patient is alive after diagnosis or surgery. Although the company reported enrollment rates for the Phase 2 study, it is not clear exactly when patients were diagnosed and underwent surgery. Patients could have been enrolled weeks to months after diagnosis and surgery.
- The interim analysis was triggered by 32 deaths in the study, but management never announced exactly when the 32nd death occurred; it could have happened as early as May or sometime in June.
- The survival time for the control group in the trial (patients not treated with ICT-107) may be better than what was previously expected. Median survival for newly diagnosed GBM patients was 14.6 months back in 2005. Results from recent Phase 3 clinical trials suggest that survival have improved over time. Placebo patients in the AVAglio and RTOG 0825 trials had a median survival of 16.8 and 16.1 months, respectively. Keep in mind that most of the patients in the ICT-107 trial had complete surgical resections, so their survival should be higher.
Importance of 124 patients in the trial
Management reported enrolling 278 patients but only randomizing 124 patients. Most of the patients who were not randomized probably did not have the right HLA-type (e.g. A1 or A2). The Phase 2 trial has enough patients to potentially demonstrate (with statistical significance) that ICT-107 can improve survival time by 9 months. If the survival difference between ICT-107 and control is less than 9 months, 124 patients will likely be too few to show a statistical significance.
If the Phase 2 results show a statistically significant survival benefit of 9 months or more, ICT-107 might be able to receive accelerated FDA approval, and no additional trials would be needed for approval. There is precedence for an early approval: Avastin received accelerated approval to treat recurrent GBM in 2009 based on results from two single-arm Phase 2 studies that only demonstrated durable objective response rates and not survival.
Some have raised concerns that the FDA might not grant accelerated approval because manufacturing during the Phase 2 trial occurred at two different facilities: University of Pennsylvania and Progenitor Cell Therapeutics (PCT). However, manufacturing for Provenge's Phase 3 study was conducted at multiple locations throughout the US; Dendreon also contracted with PCT for the Phase 3 study. Thus, having multiple manufacturing sites may not be a major concern to receive accelerated approval; however, there may be other manufacturing issues that could.
Unfortunately, the vast majority of randomized, controlled, multicenter cancer vaccine trials have been disappointing. If the median survival benefit is less than 9 months and/or not statistically significant, the company will have to raise additional capital and/or find a strategic partner to fund a Phase 3 study. Management will also likely conduct a subgroup analysis to try to find particular patients who responded to ICT-107. GBM is a relatively small indication: about 10,000 new patients in the US each year. The HLA requirement for ICT-107 already reduces the eligible patient population. If only a small group of A1 or A2 patients can be treated, the market size may just be too small for a personalized DC vaccine to be commercially viable given the costs to manufacture it.
Keep in mind that everyone is just making an educated guess as to the results of the ICT-107 trial. Do your own research and make knowledgeable investment decisions based on what you have determined to be the risks.I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.