Peregrine has initiated 2 phase I trials, primarily aimed at evaluating safety of bavituximab for the treatment of several types of cancers, including breast, lung and pancreatic cancer. Although generally, phase I studies are not aimed at evaluating efficacy, in cancer, they commonly involve efficacy assessment in addition to safety and dosing issues.
The first clinical trial evaluating bavituximab for the treatment of cancer was initiated in late 2005, and was designed to accommodate up to 28 patients with advanced solid tumors who stopped responding to standard treatments. This trial is still ongoing. Patients receive bavituximab as their only treatment, which makes expectations from this trial modest, since it is clear that monoclonal antibodies are more effective as part of a combination of treatments. Since it is quite clear now that bavituximab has an excellent safety profile, we can only hope that a subtle anti-tumor response is observed in some of the patients. Even if bavituximab achieves a single digit response rate among these patients, it would be a positive indication for this unique antibody’s abilities. This trial might be the last trial in which bavituximab is evaluated as a single agent, as it seems very likely that follow-on clinical trials will involve regimens that combine bavituximab with other conventional treatments.
Last year, the company initiated an additional phase Ib study that was conducted in India. Due to the synergistic effect bavituximab demonstrated in pre-clinical trials, and since the majority of cancer monoclonal antibodies are administered in combination with other compounds, it was clear that bavituximab had to be evaluated in combination with other treatments. In this trial the two goals were proving the combination does not lead to increased toxicity and side effects, and the evaluation clinical response. For that purpose, the company recruited 12 patients with various solid malignancies (such as breast, lung, ovary and pancreatic) who received a combination of bavituximab and standard chemotherapy. In addition to evaluating the safety of bavituximab, the treatment’s clinical effect was also evaluated.
The company has published top line results from this small study, which were quite positive, relatively to a phase I study. Analyzing such a trial should be done very carefully, especially due to the small size, the lack of control group and the fact each patient knew what he/she was getting. These factors make the results very preliminary and unreliable, however, some insight can still be gained.
First and foremost, the combination of bavituximab with chemotherapy agents was verified as safe, as no substantial increase in side effects was observed. When patients were evaluated for efficacy, response rate was 50%, hence, 50% of patients demonstrated some sort of measurable clinical response. This trial was not a comparative trial, which means that we don’t have any idea what was bavituximab’s contribution to these responses. Basically, the clinical effect may be the outcome of the chemotherapy treatments alone. A final answer to this question may come only several years from now, after a large comparative phase III trial is conducted. For now, all we can do is look at historical performance of the chemotherapy agents, and compare the response rates they have achieved in order to get a vague impression about the performance of bavituximab in this trial. Since the company has yet to publish final analysis from the trial, we’ll have to do some speculating.
The combination of bavituximab and gemcitabine seemed to be very effective with a response rate of 75%. From this figure we can assume that there were 4 or 8 patients receiving gemcitabine and bavituximab. Gemcitabine is common for the treatment of NSCLC (Non-small cell lung cancer) and pancreatic cancer, so we can assume that this subgroup of patients had either of the two. An article published in July 2007, which evaluated results from 2 large clinical trials with 503 pancreatic cancer patients, revealed that overall response rate for patients treated with gemcitabine as their only therapy was 14%. Historical response rate for gemcitabine among advanced NSCLC patients was is in the range of 20%-26%. Either way we look at it, a response rate of 75% compares very favorably to historical results, and can be viewed as an indication for this kind of regimen. However, just to make things clear, it certainly does not mean that bavituximab combined with gemcitabine will have a 75% response rate among a larger patient population.
In addition, 50% of Patients receiving combination of bavituximab and carboplatin+paclitaxel achieved objective tumor response, which means that these patients saw their tumors shrink at least 30% (partial response). Carboplatin +paclitaxel are used for the treatment of breast, ovarian and NSCLC. During the call, company’s management revealed that both metastatic breast cancer patients who received bavituximab and carboplatin+paclitaxel had a partial response. In other words, among breast cancer patients, the objective response rate was 100%. Carboplatin+paclitaxel was assessed both as salvage as well as first-line treatment of advanced breast cancer patients in phase II studies which disclosed 40-60% response rates. This figure is an encouraging sign, but it also demonstrates why results of early, small clinical trials must be taken with a pinch of salt, as even the most optimistic observer understands a 100% objective response rate is unrealistic in advanced breast cancer. The great success rate among breast cancer patients also implies that patients with other types of cancers did not achieve partial response in this trial. There was an even number of patients who received carboplatin+paclitaxel, probably 4 or 6, and we know only half of them had a partial response, 2 of which were breast cancer patients. It means that 2-3 patients with either ovarian or NSCLC did not respond very well to the treatment. This compared with historical figures for carboplatin+paclitaxel of 25%-30% objective tumor response among NSCLC patients and more than 60% among ovarian cancer patients.
Encouraged by results from the phase Ib trial, Peregrine decided to launch several phase II clinical trials in order to focus on certain kinds of cancers specifically. In July, the company announced that it has submitted a clinical protocol with the Drug Controller General of India (DCGI) for a Phase II trial of bavituximab in combination with chemotherapy in patients with non-small cell lung cancer (NSCLC). Last week, the company announced another protocol submitted with the DCGI, for the evaluation of bavituximab in combination with paclitaxel/carboplatin in patients with metastatic breast cancer. The company expects to file at least two more protocols for evaluation of bavituximab for additional conditions. It is likely that advanced pancreatic cancer will be one of these conditions, due to the promising effect bavituximab had in combination with gemcitabine in a pre-clinical and the phase Ib clinical trial.
Apart from bavituximab for the treatment of cancer, Peregrine is pursuing 2 other clinical programs. The first is bavituximab as an anti-viral therapy, currently evaluated in a phase I trial. The second clinical program is evaluation of Cotara, a monoclonal antibody conjugated to a radioisotope for the treatment of brain tumors, currently in phase II. Each one of these programs seems attractive by itself, however, bavituximab for cancer treatment has the biggest potential, in our opinion.
In assessing the risk/reward ratio of Peregrine, investors should take several factors under consideration. The fact that bavituximab still hasn’t demonstrated efficacy in a phase II trial combined with the exploratory nature of PS as a target makes it very speculative. On the other hand, the impressive pre-clinical activity and synergies with other therapies, as well as the preliminary results from the phase Ib trial are encouraging. Another thing we really like about peregrine is the aggressive clinical program it is pursuing. Since antibodies for cancer have an annoying tendency to be effective only for a portion, and not for the majority of cancer types they are evaluated for, launching 4 phase II trials in one year means that chances for success (as well as expenses…) are greater. Bottom line, we wouldn’t bet the farm on Peregrine, but we can’t help thinking that the little company from Tustin may be on to something.