2nd Line (Post gemcitabine)
MM-398 and 5-FU/Leucovorin
In the United States alone, approximately 50,000 people are diagnosed with pancreatic cancer and about 40,000 patients die annually, making it the 4th most common cause of cancer death(American Cancer Society - Cancer Facts & Figures 2013). Because the signs and symptoms of pancreatic cancer may not appear until the disease has spread to other sites in the body, an aggressive treatment is usually initiated immediately upon diagnosis. Initial treatment generally consists of surgical removal of the tumor, where possible, followed by an antimetabolite (often gemcitabine). Unfortunately, many patients’ tumors will progress following treatment, making it necessary to develop novel, safe and effective options for this population.
MM-398 is a liposomal encapsulation of the conventional chemotherapeutic irinotecan. This packaging of an approved chemotherapy within a liposome results in an investigational product candidate designed to achieve extended systemic circulation and enhanced tumor deposition, while simultaneously minimizing exposure to healthy noncancerous tissue. These properties could enable prolonged cytotoxic effects of the drug in the tumor, which are supported by intra-tumor conversion of irinotecan into the active metabolite SN-38. SN-38 functions by inhibiting topoisomerase I, an essential enzyme involved in DNA transcription and replication, promoting cell death.
Fluoropyrimidine-based therapies (such as 5-FU) serve as a chemotherapeutic backbone for numerous gastrointestinal cancers. 5-FU is converted in cancer cells into a toxic metabolite that is incorporated into newly synthesized DNA and RNA, ultimately promoting cell death. The addition of leucovorin to 5-FU enhances this process, ultimately increasing the anti-tumor potential of this regimen. Further benefit can be observed with the addition of conventional formulations of irinotecan, resulting in a synergistic improvement in response when combined clinically.
MM-398 is being tested alone and in combination with 5-FU and leucovorin in a worldwide Phase 3 study in patients with metastatic pancreatic cancer who have experienced progression after a gemcitabine-containing therapy. This combination is designed to build upon the foundation of benefit for 5-FU containing regimens, as well as the synergy observed in preclinical when combined with irinotecan. By combining MM-398 and 5-FU/leucovorin, we hope to provide a favorable risk-benefit profile for pancreatic cancer patients.