Gentium S.p.A. has announced top-line results from a historically controlled, multicenter, open label, Phase III trial designed to evaluate the safety and efficacy of 25 mg/kg/day of Defibrotide for the treatment of severe veno-occlusive disease (sVOD) in hematopoietic stem cell transplant (SCT) patients.
The results demonstrate strong trends in favor of the Defibrotide-treated patients for complete response and survival, but did not reach the protocol-specified levels of significance for the primary and secondary endpoints at 100 days. With regard to safety, adverse events were well balanced between the historical control and treatment arms. The Company plans to present full results from this trial at the American Society of Hematology Conference in New Orleans, LA, December 5-8, 2009.
The primary endpoint of the trial was complete response at 100 days following SCT and utilized historical controls (patients who in the past received the best therapy and supportive care available at the time, but not Defibrotide) as a comparator. Secondary endpoints included survival rate at 100 days and six months post SCT. The historical control database was generated through a sequential, retrospective medical chart review, with final selection of the control group performed by an independent medical review committee (MRC). The MRC remained blinded to patient outcome data throughout the duration of the trial. Per the study protocol, data in the primary efficacy analysis were adjusted by quintiles of propensity score based on four stratification variables (allogeneic/autologous SCT, adult/pediatric, one/two+ SCTs, and ventilator/dialysis dependence) to aid in obtaining balance between the treatment and historical control arms in a non-randomized trial. As a stand-alone trial utilizing a historical control arm, the study protocol specified a p-value of less than or equal to 0.01 for the primary endpoint to achieve statistical significance, while the secondary endpoints required a p-value of less than or equal to 0.05, the more common threshold for statistical significance.
123 patients with symptoms consistent with VOD were identified and then reviewed for eligibility in the historical control arm by the MRC, with 32 cases selected as having an unequivocal diagnosis of sVOD (graft versus host disease was ruled out) and met all protocol-required entry criteria. 102 patients were enrolled in the Defibrotide treatment group and baseline characteristics were balanced between the two arms.
For the primary efficacy analysis on an intent to treat basis, 24% of patients in the Defibrotide arm compared to 9% of patients in the historical control arm achieved complete response at 100 days (p-value = 0.015). For the secondary efficacy analysis on an intent to treat basis, 38% of patients in the Defibrotide arm compared to 25% of patients in the historical control arm demonstrated survival at 100 days (p-value = 0.051). Thus, while the primary endpoint achieved a p-value less than 0.05 and the secondary endpoint showed a strong trend towards statistical significance, neither reached the level of significance required in the protocol for proof of efficacy with a single study.
“I am encouraged by the results of this trial, especially given the extremely sick patient population that was enrolled,” said Dr. Paul Richardson, Clinical Director of the Dana-Farber Cancer Institute’s Jerome Lipper Multiple Myeloma Center and principal investigator of the trial. “The data generated from this trial confirms the activity of Defibrotide seen in earlier studies, and supports the benefit of Defibrotide for the treatment of sVOD in improving complete response rates and survival, as well as its potential in less advanced stages of the disease.”
“Given the outcome of the data safety monitoring board’s interim review announced in November of last year, we expected that reaching the required statistical threshold for a single trial would be difficult,” said Gary Gemignani, Executive Vice-President and Chief Financial Officer. “We are pleased that the data are compelling and believe the results place us in a strong position to continue discussions with the FDA and others regarding next steps toward a regulatory filing. Additionally, we plan on announcing final results from our randomized, pediatric prevention study in the upcoming weeks.”
About VOD
Veno-occlusive disease is a potentially life-threatening condition, which typically occurs as an important complication of stem cell transplantation. Certain high-dose chemo-radiation therapy regimens used as part of SCT can damage the lining cells of hepatic blood vessels and so result in VOD, a blockage of the small veins of the liver that leads to liver failure and can result in significant dysfunction in other organs such as the kidneys and lungs (so-called severe VOD). SCT is a frequently used treatment modality following high-dose chemotherapy and radiation therapy for hematologic cancers and other conditions in both adults and children. There is currently no approved agent for the treatment or prevention of VOD in the U.S. or the EU.
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