Daniel D. Von Hoff, MD
The addition of the investigational agent MM-398 (PEP02) to standard second-line chemotherapy significantly improved overall survival (OS) in a phase III trial for patients with metastatic pancreatic cancer. Based on these findings, Merrimack Pharmaceuticals, the company developing the drug, announced that it plans to submit a New Drug Application to the FDA for the combination.
In the phase III NAPOLI-1 trial, the combination of MM-398, a nanoliposomal encapsulation of irinotecan, with 5-fluorouracil (5-FU) and leucovorin improved OS by a median of 1.9 months compared with the chemotherapy alone in gemcitabine-refractory patients. Additionally, a significant progression-free survival (PFS) advantage was seen with the combination, Merrimack announced. Full data from the study will be presented at the 2014 ESMO World Conference on GI Cancer in June.
“This demonstration of a survival benefit from the MM-398 plus 5-FU and leucovorin combination is particularly important given that we have very few treatment options for patients in this tough clinical setting,” Daniel D. Von Hoff, MD, chief scientific officer and distinguished professor at the Virginia G. Piper Cancer Center at Scottsdale Healthcare/Translational Genomics Research Institute, said in a statement.
In the open-label phase III trial, 417 patients were randomized in a 1:1:1 ratio to receive either MM-398 monotherapy (arm A), 5-FU with leucovorin (arm B; control), or MM-398 plus 5-FU and leucovorin (arm C). Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist were allowed to be administered in arm A and arm C. All patients in the trial had progressed on a prior gemcitabine-based regimen. The primary endpoint was overall survival.
In the study, MM-398 monotherapy was administered at 120 mg/m2
every 3 weeks. In the combination, MM-398 was administered at 80 mg/m2
every 2 weeks. In the control arm, 5-FU was administered at 2000 mg/m2
with leucovorin at 200 mg/m2
racemic or 100 mg/m2
IV weekly for 4 weeks followed by 2 weeks of rest.
In arm C, 5-FU was administered at 2400 mg/m2
with leucovorin at 400 mg/m2
racemic or 200 mg/m2
IV every 2 weeks. Additionally, patients in arms A and C who were homozygous for the UGT1A1*28 allele received an initial reduced dose of MM-398. If tolerable, the dose could be increased.
According to a statement released by Merrimack, treatment with the combination of MM-398, 5-FU, and leucovorin resulted in a median OS of 6.1 months versus 4.2 months in the control arm (hazard ratio [HR] = 0.67; P
= .012). However, single-agent MM-398 (arm A) did not significantly extend survival. The median OS was 4.9 months versus 4.2 months in the control (HR = 0.99; P
The most common grade 3/4 adverse events in the combination arm were neutropenia (14.5%), fatigue (13.7%), diarrhea (12.8%), and vomiting (11.1%). The company noted that serious life-threatening sepsis occurred in 3.4% of patients in the trial.
“We are excited by the results of the NAPOLI-1 study because of the critical need to help patients with this devastating illness and are moving forward as quickly as possible to get MM-398 to patients,” Robert Mulroy, president and CEO of Merrimack, said in a release. “Given that there have only been a handful of successful phase III trials in pancreatic cancer in the past 25 years, it is gratifying to have the first positive phase III trial in the post-gemcitabine setting.”
In July 2013, results from a phase II study that explored MM-398 monotherapy in pancreatic cancer were published in the British Journal of Cancer
. This study enrolled 40 patients with gemcitabine-refractory metastatic pancreatic cancer.
The study met its primary endpoint, with 75% of patients surviving at least 3 months. The median OS was 5.2 months and the median PFS was 2.4 months. The most common severe adverse events included neutropenia, abdominal pain, asthenia, and diarrhea.
Ongoing trials are exploring MM-398 in patients with metastatic colorectal cancer, Ewing's sarcoma, and glioma. Additionally, a phase I trial is exploring a potential companion diagnostic for MM-398 in patients with multiple cancers, the Merrimack announced.