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ZIOPHARM Oncology, Inc. Message Board

  • rob_cos rob_cos Mar 22, 2013 10:11 AM Flag

    JP Morgan - optimistic stat sig PFS - Picasso up for auction next week. Outperform

    JP Morgan "PICASSO Up for Auction Next Week.... . . We are optimistic that pali + dox can show a statistically significant mprovement in PFS vs. dox alone in PICASSO 3" Outperform


    · We see a relatively high probability of Phase 3 success for pali in frontline

    metastatic STS. We expect pali + dox to show improved progression free survival

    (PFS) vs. doxorubicin alone in Phase 3. Our view is based on 1) compelling

    randomized Phase 2 data where pali + dox showed a 3.4 month PFS benefit and

    57% risk reduction vs. dox alone; 2) the Phase 3 trial has a very similar design to

    the successful Phase 2 study with the same stratification criteria and dosing and

    similar inclusion/exclusion criteria; and 3) encouraging physician feedback. In

    addition, Phase 3 has enrolled more patients vs. Phase 2 (447 vs. 67 patients) and

    does not allow for patient crossover between arms (more patients should increase

    the power, and the lack of crossover could help the eventual survival analysis).

    · PICASSO 3 appears to have sufficient power to show a PFS benefit. PICASSO 3

    is 85% powered to detect a 0.60 hazard ratio (or 40% risk reduction) in PFS for pali.

    ZIOP estimates that an increase in median PFS of 3 months vs. control (estimated

    to be 4.3 mos) could achieve a HR of 0.60. Based on Ph2 data (which showed a 57%

    risk reduction) and the similarities in trial design between Ph2 and 3, we believe the

    PICASSO 3 trial appears to be sufficiently powered for PFS. The consistency of the

    PFS data for doxorubicin alone in the treatment of STS gives us added confidence as

    we do not see a high probability that doxorubicin performs meaningfully better than

    expectations (supported by PFS data presented at ESMO last year for doxorubicin

    alone in STS patients, see next bullet). Further, a biostatistician we consulted with in

    the past was comfortable with the PFS powering assumptions for PICASSO 3.

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    • · Data presented at ESMO 2012 for ifosfamide (a pro-drug for pali) further reinforces our confidence. We were encouraged by data presented at the European Society for Medical Oncology (ESMO) 2012 annual meeting in Austria, which showed that ifosfamide + doxorubicin significantly increased PFS vs. doxorubicin alone by almost 3 months (7.4 months vs. 4.6 months; p=0.002). As a reminder, pali is the stabilized active metabolite of ifosfamide but is potentially far less toxic. Importantly, PFS in the control arm of this study (4.6 mos) was very close to the 4.3 month median PFS assumption for the doxorubicin arm of PICASSO 3, which underpins the trial’s powering assumptions. We also note that this trial enrolled younger STS patients in general vs. PICASSO 3, which could have helped boost the PFS time as younger patients tend to take a little longer to progress vs. older patients.

      · We view PFS as an approvable endpoint for STS. Originally the protocol for PICASSO 3 stated that PFS was the primary endpoint for accelerated approval, with OS the primary endpoint for full approval. Recently, the protocol was amended to have PFS as the primary endpoint for full approval (with OS as a key secondary endpoint). There has been skepticism among some investors surrounding the risk of gaining approval based on PFS, but we believe this protocol amendment should help alleviate those concerns, although the FDA's decision will ultimately depend on the strength of the data itself. We also note that the FDA approved GSK’s Votrient for STS (in the 2L+ setting) in April last year based on a ~3-month PFS benefit (without a significant OS benefit) in a single Phase 3 trial. We believe a similar PFS benefit for pali could be sufficient for approval (assuming no meaningful safety concerns) and be viewed as clinically meaningful. In addition, we note that four products were approved based on PFS as a primary endpoint in 2011 (Sutent and everolimus for primitive neuroectodermal tumors, vandeti

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