Relapsed Ovarian Cancer - Submitted New Drug Application To FDA For Trabectedin

Main Category: Ovarian Cancer
Also Included In: Cancer / Oncology;  Regulatory Affairs / Drug Approvals
Article Date: 20 Nov 2008 - 8:00 PDT

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PharmaMar announced today that Ortho Biotech Products, L.P. has submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for trabectedin when administered in combination with DOXIL® (pegylated liposomal doxorubicin) for the treatment of women with relapsed ovarian cancer (ROC). If approved, trabectedin combined with DOXIL® will provide a new, non-platinum treatment option for these patients in the United States.

The submission of trabectedin dossier to the FDA by Ortho Biotech Products, LP entails a milestone payment to PharmaMar.

The application follows the completion of a multicenter, randomized Phase III study, ET743-OVA-301, one of the largest studies conducted in ROC, comparing the combination of trabectedin and DOXIL to DOXIL alone in 672 patients. The study showed that patients treated with the combination treatment had a statistically significant improvement in the primary endpoint of progression-free survival (PFS, or the length of time during and after treatment in which the disease does not progress) compared to patients treated with DOXIL alone.

Relapsed ovarian cancer refers to epithelial carcinoma of the ovary that recurs after treatment. According to the National Cancer Institute (NCI), it is estimated that 21,650 women will be diagnosed with, and 15,520 women will die from ovarian cancer in the U.S. in 2008.

Trabectedin is being developed under a license from Pharma Mar, and DOXIL is marketed by Ortho Biotech Products, L.P. in the U.S.

PharmaMar will submit the registration dossier to the EMEA in December 2008 for relapsed ovarian cancer. Trabectedin is is currently being marketed in the European Union as YONDELIS® for the treatment of soft tissue sarcomas in adults after the failure of standard therapy.

About the ET743-OVA-301 Study

Patients were enrolled at 124 centers in 21 countries. Per the study protocol, the data was evaluated by a blinded, independent radiology review and a blinded, independent oncology review. The trabectedin/DOXIL combination demonstrated a statistically significant improvement in PFS compared to DOXIL alone (median PFS 7.3 versus 5.8 months, respectively) and a statistically significant reduction of 21% in the risk of progression or death during the observation period in the independent review of patients with radiologically measurable disease (HR=0.79, 95% CI (0.65;0.96), p=0.0190). This result is consistent with the results of the independent oncology review that takes into account clinical as well as imaging data in the assessment of progression. In this review, there was a 28% risk reduction for disease progression or death with the trabectedin/DOXIL combination (HR = 0.72, 95% CI (0.60; 0.88), p = 0.0008).

Secondary endpoints included response rate, overall survival, and safety. A statistically significant increase in response rate was seen with the trabectedin and DOXIL combination (28%) compared to DOXIL alone (19%), as measured by the independent radiology review. A final protocol-specified survival analysis is planned after the occurrence of 520 events. The safety profile in the study was consistent with previous experience with trabectedin and DOXIL.

The most common adverse reactions (³20%) for the trabectedin/DOXIL combination compared to DOXIL alone, respectively were:

- Hematological reactions including neutropenia (77% versus 38%, with febrile neutropenia occurring in 8% of the cases and sepsis in 1% of the cases), leucopenia (48% versus 26%), anemia (48% versus 25%) and thrombocytopenia (36% versus 8%);

- Gastrointestinal reactions including nausea (74% versus 42%), vomiting (56% versus 30%) and diarrhea (26% versus 19%);

- Liver enzyme (transaminase) elevations were more common in the combination arm, but were generally reversible and not associated with evidence of chronic liver damage or other clinical consequences. These included increased alanine aminotransferase (55% versus 9%) and increased aspartate aminotransferase (40% versus 10%); and

- Fatigue (46% versus 36%).
Additionally, commonly associated DOXIL adverse events, such as hand-foot syndrome (HFS) and stomatitis, occurred in fewer patients receiving the combination compared to DOXIL alone (24% versus 54% and 20% versus 33%, respectively).

About Trabectedin

Trabectedin is a novel cytotoxic antitumor agent that was originally derived from the Caribbean tunicate, Ecteinascidia turbinate ("sea squirt"). The compound is now produced synthetically. Trabectedin binds to the minor groove of DNA, interfering with cell division and genetic transcription processes and DNA repair machinery.

Trabectedin is currently in Phase II and III development in ovarian cancer, breast cancer, hormone refractory prostate cancer and to expand its uses in sarcoma. According to the licensing agreement, PharmaMar has rights to market the compound in Europe and Japan, while Ortho Biotech Products, L.P. has marketing rights for the product in the rest of the world.

PharmaMar

PharmaMar is the world-leading biopharmaceutical company of the Zeltia Group, and is committed to advancing the treatment of cancer through the discovery and development of new marine-derived medicines. PharmaMar has five novel compounds in clinical development: Yondelis has received Authorization for Commercialization from the European Commission for treating advanced soft tissue sarcoma. In addition to the Phase III ovarian cancer study Yondelis is also in phase II studies for prostate, breast, and paediatric cancers. Aplidin®, Kahalalide F, Zalypsis®, and PM02734 are in clinical trials. PharmaMar also has a rich pipeline of preclinical candidates, and a strong R&D program.

PharmaMar