CytRx Corporation (NASDAQ:CYTR), a biopharmaceutical research and development company specializing in oncology, today announced it has received approval from the U.S. Food and Drug Administration (FDA) to continue dosing patients with aldoxorubicin until disease progression in a planned pivotal, global Phase 3 clinical trial with aldoxorubicin as a second-line treatment for soft tissue sarcomas. The clinical trial is scheduled to begin this quarter. For purposes of the clinical trial, disease progression is defined as an increase in the size of measurable tumors by 20% or the development of a new tumor lesion. The following table sets forth the cumulative dose of doxorubicin in prior and planned CytRx clinical trials:
The study design under the trial's Special Protocol Assessment (SPA) originally called for dosing to be stopped after six treatment cycles. FDA acceptance of a protocol amendment to include a dose-to-progression regimen demonstrates the superior cardiac safety thus far of administrating a cumulative 2,080 mg/m2 dose of aldoxorubicin as seen in the Company's recently announced global, Phase 2b clinical trial results (which is equivalent to 1,560 mg/m2 of doxorubicin), which is 3.5 times the recognized maximum cumulative dose of doxorubicin (450 mg/m2) associated with cardiac toxicity (heart damage).
Sant Chawla, M.D., of the Sarcoma Oncology Center in Santa Monica, Calif., and principal investigator of the Phase 3 pivotal trial, commented, "In addition to observing no significant cardiotoxicity of aldoxorubicin to this point, the FDA's agreement to extend dosing beyond six cycles offers the potential to achieve even greater progression-free survival efficacy results than were demonstrated in CytRx's recent highly successful global Phase 2b trial for advanced soft tissue sarcomas. As the principal investigator for this trial, I can say that we are very pleased to have the opportunity to provide the maximum benefits of aldoxorubicin to the patients around the world."
"Current chemotherapy treatments for soft tissue sarcomas have demonstrated limited impact, and other potential treatments have provided no improved benefits in Phase 3 trials," said CytRx President and CEO Steven A. Kriegsman. "As such there is a significant need for a second-line treatment with greater efficacy and reduced or no measurable cardiac toxicity. This FDA acceptance of extended dosing represents a potential major breakthrough for CytRx and STS patients throughout the world."
The international, open-label pivotal Phase 3 clinical trial will enroll approximately 400 patients with metastatic, locally advanced or unresectable soft tissue sarcomas who have either not responded to or have progressed following treatment with one or more systemic regimens of non-adjuvant chemotherapies. Trial patients will be randomized 1:1 to be treated with aldoxorubicin or the investigator's choice of an approved chemotherapeutic regimen to include dacarbazine, pazopanib (Votrient®), gemcitabine plus docetaxel, doxorubicin or ifosfamide, with up to three comparator regimens to be selected by the investigator at each clinical site. The clinical trial will be conducted at approximately 100 clinical sites in the U.S., Europe, Canada, Latin America and Australia. The primary endpoint of the study is progression-free survival (PFS), and secondary endpoints include overall survival and safety.
Review of Results for Phase 2b Trial with Aldoxorubicin as a First-line Treatment in Advanced Soft Tissue Sarcomas
As initially reported on December 11, 2013, patients treated with aldoxorubicin demonstrated highly statistically significant clinical outcomes compared to those receiving standard doxorubicin therapy for soft tissue sarcomas in both an investigator assessment and a central lab review. Specifically, both assessments showed an unambiguous 80% to 100% improvement in PFS among patients treated with aldoxorubicin.
In an intent-to-treat analysis, the investigator-assessed median PFS was 8.4 months for aldoxorubicin patients versus 4.7 months for doxorubicin patients(p=0.0002), while the blinded central lab review indicated that median PFS for aldoxorubicin patients was 5.7 months versus 2.8 months for doxorubicin patients (p=0.018). Per investigators, 67.1% of aldoxorubicin patients had not progressed at 6 months, compared with 36.1% of doxorubicin-treated patients (p=0.005). By blinded central lab review, 46.8% of aldoxorubicin patients had not progressed at 6 months, compared with 23.7% of doxorubicin patients (p=0.038).
On January 8, 2014, CytRx reported results of additional analyses that determined hazard ratios for the primary endpoint of PFS by both investigators at study sites and by a blinded radiology review performed at an independent central laboratory. The hazard ratio for investigator-read scans was 0.37 (95% confidence interval, range of 0.212 to 0.643)(p=0.0004), reflecting a 63% reduction in the risk of disease progression; and the hazard ratio for central lab scans was 0.59 (95% confidence interval, range of 0.36 to 0.96) (p=0.034), reflecting a 41% reduction in the risk of disease progression. Hazard ratios – the likelihood that the study endpoint (in this case tumor progression) will be reached during a given period – are an important measure of the reliability and uniformity of the absolute data for PFS as presented above. Hazard ratios where the upper limit is less than 1 indicate that there is a significant difference between the two study groups.
CytRx also reported that a Kaplan-Meier analysis of the trial results, which describes the time it takes for tumors to progress in individual patients, showed significant improvement in patients treated with aldoxorubicin versus patients treated with doxorubicin.