NDA Submitted for MM-398 With 5-FU and Leucovorin in Advanced Pancreatic Cancer

Robert Mulroy

Robert Mulroy

Following the FDA fast track designation in November 2014, Merrimack Pharmaceuticals and Baxter International have completed the submission of a new drug application (NDA) for MM-398 (nal-IRI) in combination with 5-fluorouracil (5-FU) and leucovorin, according to a statement from the two companies. The combination is for patients with metastatic pancreatic cancer following prior treatment with a gemcitabine-based therapy.

"This is an important achievement in our MM-398 collaboration and in our collective efforts to introduce a potentially valuable new standard of care treatment for patients with pancreatic cancer," David Meek, head of Oncology at Baxter BioScience, said in a statement. "We intend to maintain this positive momentum as we prepare for the European submission in the coming months, with additional global submissions to follow shortly thereafter."

The fast track designation allowed the developers of the drug to conduct a rolling submission. The application was based on promising data from the phase III NAPOLI-1 trial, which demonstrated a marked improvement with MM-398 in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with 5-FU and leucovorin alone.

The FDA reviews new applications within 60 days of submission, at which point the agency will assign a review deadline under the Prescription Drug User Fee Act. In the statement, the companies expressed hope for a priority review, which would provide a 6-month deadline for a decision on the NDA.

MM-398 is a nanoliposomal encapsulation of irinotecan, allowing for the drug to stay in circulation for a longer duration compared with standard irinotecan. Additionally, this mechanism allows for higher drug uptake within tumor cells and conversation of irinotecan to its active form, SN38.

In the phase III open-label NAPOLI-1 trial, 417 patients with gemcitabine-refractory metastatic pancreatic cancer were randomized to MM-398 monotherapy, 5-FU with leucovorin (control), or MM-398 plus 5-FU and leucovorin. Altogether, 61% of patients had cancer in the head of the pancreas and 68% had liver metastases. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in the combination arms.

Intravenous MM-398 was administered at 120 mg/m²every 3 weeks in the single-agent arm. In the control, 5-FU was administered at 2000 mg/m²with racemic leucovorin at 200 mg/m²every 4 weeks followed by 2 weeks of rest. In the combination arm, MM-398 was administered at 80 mg/m²prior to 5-FU at 2400 mg/m²and racemic leucovorin at 400 mg/m²every 2 weeks.

Patients in the combination arm had a median OS of 6.1 months versus 4.2 months with 5-FU and leucovorin alone (HR = 0.67; 95% CI, 0.49-0.92;P= .012). The median PFS was 3.1 months for the combination compared with 1.5 months with the control (HR = 0.56; 95% CI, 0.41-0.75;P= .0001).

The ORR was 16% versus 1% (P<.001) and CA19-9 levels were decreased by &ge;50% in 36% versus 12% of patients in the combination and control arms, respectively.

MM-398 monotherapy did not demonstrate superior efficacy compared with 5-FU and leucovorin. Moreover, in some cases, MM-398 alone was associated with more side effects than the drug in combination.

A per-protocol analysis presented at the 2015 GI Cancers Symposium looked at patients who received at least 80% of the target dose in the first 6 weeks and did not violate any inclusion or exclusion criteria. In this population, treatment with MM-398 plus 5-FU/leucovorin (n = 66) improved OS by 53% compared with 5-FU/ leucovorin alone (n = 71). The median OS was 8.9 months with MM-398 compared with 5.1 months with 5-FU/ leucovorin (HR = 0.47; 95% CI, 0.29-0.77;P= .0018).

In the full population of the study, the rates of diarrhea were 12.8% versus 21.1% and the rates of vomiting were 11.1% versus 13.6% for the combination and single-agent MM-398 arms, respectively. Additionally, febrile neutropenia occurred in 1.7% of patients in the combination arm compared with 4.1% with MM-398 monotherapy and not at all with 5-FU/leucovorin alone.

The most commonly reported grade 3/4 adverse events with MM-398 plus 5-FU/leucovorin were neutrophil count decrease (23.1%), fatigue (13.7%), diarrhea (12.8%), and vomiting (11.1%). Investigator assessed neutropenia occurred in 14.5% of patients receiving the MM-398 combination, whereas neutrophil count decrease was reported in the lab reports for 10.3% of patients.

"The submission of Merrimack's first ever NDA with the US FDA is a major milestone in the company's history and a significant step forward in our commitment to delivering new treatment options to cancer patients," Robert Mulroy, president and CEO at Merrimack, said in a statement. "We are encouraged by the FDA's support in the process and look forward to working with them throughout the NDA review."

In September 2014, Merrimack and Baxter entered into an agreement to develop and commercialize MM-398, with Merrimack retaining all rights to market the drug within the United States. In Taiwan, PharmaEngine controls commercialization rights for the drug.

MM-398 continues to be explored as a treatment for patients with types of cancer, including a phase I study looking into the drug in combination with cyclophosphamide for pediatric patients with solid tumors. Additionally, a pilot study is exploring MM-398 biodistribution and the feasibility of ferumoxytol as a tumor-imaging agent.