Synta launched a phase I trial in 2004 for the evaluation of elesclomol in combination with paclitaxel in advanced solid tumors. The trial enrolled 35 highly-pretreated patients, who received paclitaxel in combination with escalating doses of elesclomol. There were two partial responses (5.7%), one patient with kaposi’s sarcoma and another patient with ovarian cancer in addition to 15 patients who achieved stable disease. Because this was a combination trial, there was no way of knowing whether elesclomol had a synergistic effect with paclitaxel. Nevertheless, there was evidence that elesclomol can sensitize tumors to chemotherapy, as some of the patients who responded to the treatment had previously progressed during treatment with paclitaxel alone. Another important observation was that elesclomol and paclitaxel can be safely co-administered. Elesclomol entered three phase II trials in melanoma, non-small-cell lung cancer (NSCLC) and soft tissue sarcoma. Both the NSCLC and the sarcoma trials failed to show a benefit from adding elesclomol to paclitaxel. The melanoma trial, on the other hand, produced a very impressive set of data.

 The melanoma trial started as a single arm trial, enrolling 20 patients who received elesclomol and paclitaxel. There were 11 (55%) patients with stable disease, which was enough to trigger the second stage of the trial, a randomized, placebo controlled study. It is interesting to note that historical response rates of paclitaxel in metastatic melanoma are higher with a partial response rate of 7%-15%, but despite the modest activity and prior failures, Synta decided to carry on with the randomized phase II portion. The phase II study included 81 patients with stage IV metastatic melanoma with one or no prior chemotherapy treatment, and each patient was randomized to receive either paclitaxel+ placebo or paclitaxel+elesclomol. The primary endpoint of the study was progression-free survival (PFS).

According to results published in September of 2006, patients in the combination arm had a median PFS of 3.7 months compared with 1.8 months in the control arm, while the addition of elesclomol to paclitaxel did not result in increased side effects. As noted, the difference in PFS was statistically significant, making the trial one of the most important events in the field of metastatic melanoma. The 6 month PFS rate was also substantially higher in the combination arm (35%) than in the control arm (15%). A benefit of less than 2 months might appear insignificant, but considering that the typical PFS and survival times for these patients are 2 months and 6-9 months, respectively,  an addition of two months represent  a remarkable achievement.

Elesclomol also managed to increase objective response rate from 3.6% in the paclitaxel arm to 15.1% in the combination arm, but this difference was not statistically significant (although it trended toward being statistically significant). On the overall survival front, results were very encouraging although the majority (19 out of 28) of patients in the placebo arm crossed over to the treatment arm, compromising the differences between the two arms. The 53 patients from the combination arm had a median OS of 12 months, compared to 7.8 months of the 28 patients of the control arm (including patients who crossed over after progression). The actual difference between the cohorts might have been even greater had no cross over been allowed, as the median survival of the 9 patients who did not cross over was only 5.6 months. Importantly, the crossover design allowed patients who initially received paclitaxel alone to receive elesclomol plus paclitaxel only following evidence of disease progression, so the integrity of the data with respect to the primary endpoint, PFS, was not compromised.

The safety profile of elesclomol has been flawless from the early preclinical experiments to the recent phase II trial, as there was almost no increase in side effects. Having a synergistic effect without increasing side effects is a huge advantage for an investigational oncology drug. Ideally, physicians would like to use multiple chemo drugs simultaneously, but in many cases, combining multiple drugs takes its toll in the form of increased side effects. Consequently, investigators are limited in the number and doses of chemo drugs they can administer to patients in the same regimen. One of the characteristics which made targeted therapies such as monoclonal antibodies and tyrosine kinase inhibitors so popular is their excellent safety profile, which enables their addition to standard chemotherapy regimens. Likewise, the opportunity to  combine elesclomol with other chemo drugs seems substantial going forward.

One piece of data that looks “suspicious” is the fact that the 19 patients who crossed over had better median survival (14.3 months) than the patients in the combination arm. This is in contrast to the expectation that these patients would have a slightly lower survival rate, but such “glitches” can be explained by the small number of patients and the fact that the investigators had no influence on the number and identity of the crossover patients. Another piece of data that caught investigators’ eye is the median PFS among patients who had received no previous chemotherapy prior to the trial (first line patients), as these patients had an impressive median PFS of 7.1 months in the combination arm compared to 1.8 months in the placebo arm. However, first line patients accounted for less than half of the patients in the combination arm, and about a third in the placebo arm, so it is still premature to conclude anything from this data.

 Despite the promising results, the elesclomol trial drew criticism with respect to several issues. The first issue was the size of the control arm, which consisted of only 28 patients because the randomization was done at a 2:1 ratio. The second issue was the limited response in the control arm, as different regimens of single-agent paclitaxel achieved double digit response rates as first and second line therapy in several single arm phase II trials. In addition, a closer examination of the patients in each cohort showed an imbalance between the two cohorts with respect to disease stage. The combination arm had a lower percentage (53%) of M1c patients, than the control arm (75%). M1c patients have metastases in distant organs (except lungs), and are known to have worse prognosis, with overall survival at the lower end of the 6-9 month range.  

These issues should not be taken lightly but at the end of the day, none cast a real shadow on the phase II results. The small size of the control arm is clearly an issue, but this is the nature of controlled phase II trials. A control arm of 100 patients could be much more credible, but that would turn the trial into a mini-phase III trial with  the associated financial and timing implications. In addition, having a statistically significant difference over a small control arm is still better than a large single arm study with promising results. With regard to the uneven patient distribution, a retrospective analysis of the elesclomol trial showed that there was no difference between PFS the M1c patients had and that of overall trial population, so these patients did not have a negative effect on the overall PFS in the control arm. The relatively low response rate in the control arm is  constantly being addressed by company management at investor conferences. Although a response rate of 3.6% is one of the lowest response rates in recent metastatic melanoma trials, it is important to realize that in melanoma, response rate poorly correlates with PFS and overall survival. Paclitaxel did manage to achieve a double-digit response rate in previous trials, but the median PFS in these trials was not always superior to that of the control arm in the present trial. A recently published scientific article that analyzed results from 42 phase II trials in metastatic melanoma found that the median PFS was 1.7 months, very similar to the PFS of the control arm.