Ziopharm Palifosphamide: Evaluating the prospects for the PICASSO-3 study

Small-cap biotech investors love the thrill and drama surrounding the release of phase 3 study results. ZIOPHARM Oncology is about to provide just that in the run up to publishing topline results for their PICASSO-3 study in the last week in March.

Ziopharm is developing palifosfamide for the treatment of advanced soft tissue sarcomas (STS) (a rare form of cancer affecting ~10,000 people in the US annually). Palifosfamide is an active form of an existing chemotherapy drug called ifosfamide which is frequently used in the treatment of STS. Unfortunately, ifosfamide has serious side effects when used at high doses, or when combined with other forms of chemotherapy such as doxorubicin, a drug that is considered standard of care. Palifosfamide appears to lack such toxicities and can be given safely in combination with other chemotherapies without incremental side effects, thus making it an attractive agent in the treatment of STS.

Unfortunately, in the majority of cases, STS is not cured and eventually spreads to other organs or parts of the body (metastatic disease). Once STS has spread, the prognosis for patients is very poor, and the expected survival is typically about one year. New treatments are needed that will help control the disease and improve survival outcomes for these patients.

Ziopharm began testing palifosfamide in cell models and animal models of cancer and found that it was active in combination with doxorubicin. They then tested the drug in humans in a dose finding phase 1 study where it showed promising activity, and in the phase 2 PICASSO study. The results of the phase 2 PICASSO study were presented at ASCO 2010. PICASSO was a randomized, multi-center, open-label study of patients with unresectable or metastatic soft-tissue sarcoma randomized to receive doxorubicin (standard of care) or doxorubicin plus palifosfamide. The two arms were well matched for age and tumor type. The primary end point was progression free survival (PFS) and was highly positive: median PFS was 7.8 months in the active treatment arm vs.  4.4 months for doxorubicin alone HR (0.427) [95% C.I. 0.191, 0.951]. The partial response rate for palifosfamide was 23% vs. 9% for doxorubicin.  There were no major differences in safety between the two arms indicating that the combination of palifosfamide and doxorubicin was safe.

Obviously based on these highly statistically significant data, it is hard not to be very optimistic about the prospects for a positive outcome to PICASSO-3, the phase 3 registration study. However, here are some aspects that bulls should think about before declaring this a slam dunk positive outcome.

1)      Promising phase 2 signals rarely pan out to the same extent in phase 3 studies, especially in cancer studies.

I can barely think of a single example where a drug with promising phase 2 data replicated compelling outcomes in larger phase 3 studies. Sadly, there is a reason that doxorubicin and ifosfamide have been the standard of care in STS for the past 20 years.

2)      Why would the phase 2 results not be replicated in phase 3?

In order to answer this, we need to look at differences between the two studies.

Study populations: PICASSO enrolled a mixture of patients who had previously received chemotherapy (~1/3) and those who had not received prior chemotherapy (~2/3), those who had both unresectable and metastatic disease, predominantly from US centers. All these patients were treated open-label (meaning everyone on the study knew which patients received which medications).  Open label studies can introduce a level of bias to the results. Patients who have received prior chemotherapy for metastatic disease and who have subsequently progressed, have in general, a worse prognosis than those who are naïve to treatment so this would also potentially influence the results if there was an imbalance in exposure to prior chemotherapy between the two studies.  Similarly, if phase 2 data were used for the assumptions to power phase 3 for effect size, this may lead to a mis-match as the two patient populations are quite different.

PICASSO-3 is a randomized, multi-center, multi-national, double-blind study, that has enrolled only patients with metastatic STS who have never received chemotherapy, a large proportion of whom are from outside the US.  PICASSO was predominantly conducted in the US, however PICASSO-3 is a multi-national study enrolling patients from areas of the world where access to care and population health in general may influence survival outcomes. This is also a consideration when trying to extrapolate results between phase 2 and 3. Just based on the mix of 1^st line and 2^nd line patients in PICASSO, I would anticipate that the median PFS in both arms of PICASSO-3 would be longer as this group is all treatment-naïve, and they more recently may have had exposure to newer chemotherapies in a neoadjuvant/adjuvant  setting when they initially underwent surgery to remove their tumors. This too will influence the natural history of their disease and you would potentially expect them to live slightly longer.

3)      The control arm “did better than expected”

Sometimes phase 3 studies fail to show a statistically significant difference in effect, not because the drug didn’t have an effect, but because the control group did a lot better than expected, “closing the gap” so to speak between the two study arms.  In the phase 2 study, the response rate for doxorubicin was only 9%.  However, most studies indicate that ORR with doxorubicin in STS is usually 20-30%, so did the underperforming control arm exaggerate an effect size in phase 2? Does PICASSO actually show a true absolute benefit with the addition of palifosfamide over what we would expect with standard of care? The response rate for the palifosfamide+ doxorubicin was only 23% which is consistent with most single agent doxorubicin studies.

Most oncologists will agree that the best standard of care for a patient with metastatic STS is a clinical trial. By the nature of being in the study itself and the intensive review and monitoring patients receive, you would expect all the patients including those on the control arm to do slightly better than the overall general population, another reason why control arms can fare better than expected in blinded studies.

4)      No drugs have ever shown an improvement in overall survival outcomes when added to doxorubicin.

Hundreds of studies have been conducted over the past decades exploring the optimal dosing and combinations of chemotherapy to treat STS. Unfortunately none have ever translated into an improvement in overall survival when added to doxorubicin. A complete response (CR) is known to improve survival rates, but sadly treatment with palifosfamide does not demonstrate CRs.

5)      FDA does not recognize PFS as being a predictor of clinical outcomes in STS

Ziopharm intitiated the pivotal Phase III trial without reaching a special protocol assessment (SPA) with FDA.  FDA did not consider the endpoints as designated for the proposed pivotal trial as supportive of SPA in this disease setting, although they would have granted a SPA with modified endpoints. Instead Ziopharm communicated external experts and chose to retain PFS as the primary endpoint with a prespecified method for radiologic evaluation of PFS (independent central review). The company estimates that a median increase in PFS of 3 months or greater over the estimated 4.3 month median PFS for the control arm (doxorubicin only) could achieve the targeted hazard ratio (HR = 0.60; p = 0.0005, one-tailed) and also predicts a demonstrable improvement in overall survival (OS). I have already mentioned the concerns I have with the basis for these assumptions based on extrapolating the phase 2 results and it is quite possible that the control arm performs a lot better than the expected 4.3 months, diminishing any treatment difference between the two arms.

Ultimately, FDA has indicated that regulatory acceptability of the trial’s results for approval would depend on the magnitude of the difference between the trial study arms, as well as a risk-benefit analysis.  ZIOPHARM could potentially file for accelerated approval based on positive PFS (whereby they would be required to conduct a second confirmatory study), or if they hit the secondary end point of an improvement in overall survival, they could file for regular approval.

It’s not all bad news, as recently GSK was able to receive approval for Votrient for the treatment of patients with advanced soft tissue sarcoma who have received prior chemotherapy on the basis of a 3 month improvement in PFS. This was a second line study versus placebo and despite the 3 month PFS benefit, this did not translate to a benefit in overall survival. However, the NDA was reviewed by ODAC, and the FDA advisory committee voted in favor of approving the drug.

I think the chance of palifosfamide showing some incremental benefit over standard of care is fair, but I am dubious that it will hit the primary PFS (0.6 HR) or secondary OS end point for PICASSO-3. Given the lack of additional options for patients with STS, any NDA will invariably be reviewed by ODAC, and an absolute benefit in PFS of even 2 months coupled with no additional toxicity, could potentially be enough to swing a positive ODAC opinion.

Disclosure:  I have no positions in any of the companies mentioned in this article.

An edited version of this article was published on TheStreet.com