Results from a study presented at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona, Spain, shows that adding a novel novel long-circulating nanoliposomal formulation of irinotecan (nal-IRI) called MM-398 to standard treatment for metastatic pancreatic cancer patients who have already received gemcitabine improves survival.

MM-398, under development by Merrimack Pharmaceuticals, Inc (Cambridge, Mass) is being evaluated in several clinical trials including a Phase III study in metastatic pancreatic cancer, a Phase II study in patients with metastatic colorectal cancer and a Phase I clinical pilot study.

Pancreatic cancer
Over the past decade, rates of pancreatic cancer have been increasing slightly. Today, based on estimates from the he American Cancer Society, about 46,420 people (23,530 men and 22,890 women) will be diagnosed with pancreatic cancer. Furthermore, about 39,590 people (20,170 men and 19,420 women) will die of pancreatic cancer.[1]

Pancreatic cancer accounts for about 3% of all cancers in the US, and accounts for about 7% of cancer deaths.[1]

“Patients with metastatic pancreatic cancer or pancreatic cancer in general have very limited options,” said study author Andrea Wang-Gillam , MD, PhD, assistant professor in the Division of Oncology at Washington University in St. Louis, USA. “These patients just simply don’t do well. This was a positive trial and will provide a new treatment option for patients with metastatic pancreatic cancer.”

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One of the biggest challenges in pancreatic cancer is drug delivery. “MM-398 (nal-IRI) is a nanoliposomal irinotecan: this delivery system allows longer drug exposure in the circulation and more accumulation of the drug and its active metabolite SN38 at the tumour site,” Wang-Gillam said. “MM-398 therefore generates higher anti-tumour activity and is more effective than conventional irinotecan alone in the preclinical setting.”


…the tolerability of the nal-IRI plus 5FU/leucovorin regimen was acceptable and toxicity manageable… This trial has important clinical implications in a difficult setting… This new option gives us the ability to add the new drug to standard treatment and increase activity and efficacy…


The phase II study had demonstrated the anti-tumour activity of MM-398 monotherapy as second-line treatment in patients with metastatic pancreatic cancer refractory to gemcitabine [2].

The current NAPOLI-1 trial was a global randomised phase III trial at more than 100 sites. There were 3 treatment arms: MM-398, standard treatment with 5-fluorouracil (5FU)/leucovorin, and MM-398 plus 5FU/leucovorin. The trial included 417 patients who had progressed or received prior gemcitabine-based therapy. The primary endpoint was overall survival.

Study results
Overall survival was significantly improved with the combination therapy of MM-398 plus 5FU/leucovorin compared to 5FU/leucovorin alone. Median overall survival was 6.1 months in the MM-398 plus 5FU/leucovorin group compared to 4.2 months in the group receiving standard treatment with 5FU/leucovorin alone (hazard ratio [HR]=0.67, p=0.012). Progression-free survival also improved significantly, from 1.5 months with the standard therapy to 3.1 months in patients receiving MM-398 plus 5FU/leucovorin (HR=0.56, p<0.001). MM-398 alone did not provide any additional survival benefit over standard therapy.

“The results are very exciting because the trial met its primary endpoint and found a highly statistically significant benefit of MM-398 plus 5FU/leucovorin on overall survival and progression-free survival compared to 5FU/leucovorin alone. We also found a significant benefit of the combination therapy on overall response rate and biochemical response,” Wang-Gillam noted.

Adverse events
Combination therapy led to more gastrointestinal adverse events than standard treatment alone. Diarrhoea occurred in 12.8%, 21.1% and 4.5% of the MM-398 plus 5FU/leucovorin, MM-398 and 5FU/leucovorin groups, respectively. Vomiting occurred in 11.1%, 13.6% and 3.0%, respectively, and fatigue in 13.7%, 6.1% and 3.7%, respectively.

“Our results are indicative of a successful effort in developing new drugs toward pancreatic cancer. We now have another viable option in this devastating disease,” Wang-Gillam concluded.

Unmet need
“There is still a need for new treatments in metastatic pancreatic cancer and every attempt to increase the activity of chemotherapy is welcome. NAPOLI-1 evaluated a new formulation of irinotecan (nal-IRI). With the new drug added to 5FU and leucovorin, patients had improved overall survival, overall response rate, progression-free survival and time-to-treatment failure. The tolerability of the nal-IRI plus 5FU/leucovorin regimen was acceptable and toxicity manageable. This trial has important clinical implications in a difficult setting, because we will be able to add the new drug to standard treatment and increase activity and efficacy,” said Roberto Labianca, MD, Director of the Cancer Centre, Ospedale Giovanni XXIII in Bergamo, Italy and ESMO spokesperson, who was not involved in the trial.

“NAPOLI-1 demonstrated that nal-IRI plus 5FU/leucovorin was an effective second-line therapy in metastatic pancreatic cancer. Future trials should evaluate this combination as first-line treatment and in locally advanced pancreatic cancer,” he concluded.

Imaging Study
Interim results from an unrelated Phase I study presented at the 105th Annual Meeting of the American Association for Cancer Research (AACR), held April 5-9, 2014, in San Diego, California, demonstrated that ferumoxytol (Feraheme?; AMAG Pharmaceuticals), an iron oxide nanoparticle, was well tolerated when used as a tumor contrast agent prior to MM-398 treatment.

“This application of ferumoxytol magnetic resonance imaging has the potential to become a minimally invasive predictive biomarker for liposomal therapies. We hope that the continuation and expansion of this approach will allow us to identify patients most likely to benefit from MM-398 treatment,” said Jonathan Fitzgerald, Ph.D., Senior Director of Discovery at Merrimack. “Though our initial data are from a small sample of a diverse patient population, we are encouraged to see that almost all of the tumor lesions that shrank after MM-398 treatment were associated with higher levels of ferumoxytol, as seen on the MRI.”

Ferumoxytol’s propensity for uptake by tumor associated macrophages and similar distribution patterns to MM-398 in preclinical models led to the clinical feasibility study. The ability to image and analyze the levels of ferumoxytol in tumors may be correlated to estimating the MM-398 tumor concentration.

The presented data are also supported by Merrimack’s proprietary Systems Biology approach, as computational modeling of ferumoxytol MRI was used to calculate parameters describing its behavior in tumor tissue. This modeling platform, coupled with the imaging approach with ferumoxytol MRI, may be useful as a predictive biomarker of nanotherapeutics such as MM-398. Primary objectives of this study are to evaluate the feasibility of ferumoxytol to identify tumor-associated macrophages, which may positively correlate with MM-398 activity, and to measure tumor levels of irinotecan and SN-38, the active metabolite of irinotecan which is 1,000 times more active than iri
notecan itself
. The ongoing study has shown that there were no safety-related interactions between ferumoxytol and MM-398 in this preliminary patient population.

For more information
[1] What are the key statistics about pancreatic cancer? American Cancer Society. Last Accessed June 25, 2014. [Guide]
[2] Ko AH, Tempero MA, Shan Y-S, Su W-C, Lin Y-L, Dito E, Ong A, Wang Y-W, Yeh CG, Chen LT. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013; 109(4):920-925.[Article][PubMed]
[3] Abstract presentation: Wednesday, 25 June 2014, 17:00 hrs, Session II: Cancer of the pancreas and bile ducts Von Hoff D, Li CP, Wang-Gillam A, Bodoky G, Dean A, Jameson G, Macarulla T, Lee KH, Cunningham D, et al. NAPOLI-1: Randomised Phase 3 Study of MM-398 (nal-IRI), with or without 5-Fluorouracil and Leucovorin, versus 5-Fluorouracil and Leucovorin, in Metastatic Pancreatic Cancer Progressed on or Following Gemcitabine-based Therapy Annals of Oncology, Volume 25 suppl 2 June 2014 (Ann Oncol 2014 Jun; 25(Suppl 2): 1-117); Abstract AO-0003 [Abstract]

Photo: Andrea Wang-Gillam, MD, PhD, assistant professor in the Division of Oncology at Washington University in St. Louis, USA. Photo Courtesy:Washington University School of Medicine, St Louis, USA.

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