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In this age of targeted, gene and cellular therapies, it is somewhat difficult to understand why a company would choose to pursue development of a nitrogen mustard, but that is exactly what Ziopharm Oncology (NASDAQ:ZIOP) has elected to do.

Nitrogen mustards are potent alkylating agents and were among the first class of drugs approved by the FDA for cancer treatment (circa 1949). Palifosfamide, a nitrogen mustard, is a metabolite of ifosfamide that is purportedly stabilized as a tris(hydroxymethyl)-aminomethane salt.

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In preclinical studies, palifosfamide was active in several ifosfamide-refractory tumors, thus providing a rationale for further development.

Palifosfamide was evaluated in a randomized Phase-II study (PICASSO) in doxorubicin-naive patients with unresectable or metastatic soft-tissue sarcoma (STS). The trial randomized 67 patients to receive either doxorubicin +/- palifosfamide. Sixty-six patients were treated and 62 patients were eligible for evaluation. The study showed a statistically-significant difference in progression-free survival (PFS) in favor of the combination (P=0.023) but showed no difference in overall survival (OS). The most common grade 3-4 events were neutropenia and elevated creatinine, both observed with similar frequency in the two treatment groups.

Based on the results of the PICASSO study, Ziopharm initiated a randomized Phase-III study called PICASSO 3. PICASSO 3 is similar in design to PICASSO and randomized (1:1) 424 patients with treatment-naive patients with metastatic STS to receive doxorubicin +/- palifosfamide. The primary study endpoints are PFS and OS.

The outcome of Ziopharm Oncology's PICASSO 3 study has been the subject of considerable debate. While the author believes that the combination of palifosfamide plus doxorubicin has a reasonable likelihood of demonstrating a statistically significant benefit in progression-free survival over single-agent doxorubicin, that outcome alone may not be sufficient to garner FDA approval.

The author's thesis is based upon the results of EORTC 62012, a randomized Phase-III trial that evaluated doxorubicin +/- ifosfamide in patients with soft tissue sarcoma.

The trial enrolled 455 patients with STS patients aged 60 years and less who were randomized to doxorubicin at 75 mg/m2 (N=228) or doxorubicin (N=227) at the same dose plus ifosfamide given at 10 g/m2 over four days together with mesna and pegfilgrastim as 1st-line therapy. Patients were treated every three weeks for a maximum of six cycles or until progression.

At a median follow-up of 56 months, overall survival at one year was slightly, but not significantly improved with the combination; overall survival was 60% with ifosfamide/doxorubicin compared to 51% with doxorubicin (hazard ratio HR 0.82; P = 0.061).

No difference between treatment arms was observed in the two-year overall survival. Median progression-free survival was significantly increased to 7.4 months in ifosfamide/doxorubicin patients compared to 4.6 months for doxorubicin alone (HR 0.72; P = 0.002). The take-home message from this study is that a statistically significant PFS benefit does not assure a survival benefit.

Based on the results of EORTC 62012, it is unlikely that the FDA would grant palifosamide an accelerated 1st-line approval based on PFS as many have speculated; the more likely scenario is that FDA will wait until survival data are available before rendering a decision. The author assesses the probability of a positive survival benefit from the PICASSO 3 trial at less than 50%. Because Ziopharm opted out of the SPA process, FDA's criteria for approval remain unclear.

Concern over the approvability of palifosamide is the likely reason that Ziopharm's share price has traded in a range for the past 20 months; investors are awaiting the release of the PICASSO 3 data with considerable caution and with good reason.

Source: Ziopharm Oncology May Win The Battle But Will They Win The War?