Robert Mulroy, President and CEO of Merrimack. "Given that there have only been a handful of successful Phase 3 trials in pancreatic cancer in the past 25 years, it is gratifying to have the first positive Phase 3 trial in the post-gemcitabine setting. The results reinforce our confidence in our entire nanoliposomal pipeline.
MM398 or nanopaarticle encapsulated Irinotecan plus FolF or Folf(Iri) yielded 6.1 mos MOS in the post Gemcitabine setting. How have other regimenns faired in this setting? Let's look at G-FLIP:
Single agents have only modest activity as treatment for metastatic pancreatic cancer with response rates of less than 10% and median survivals of less than 6 months. Evaluations of single-agent gemcitabine and rubitecan as second-line treatment for relapsed pancreatic cancer have reported good patient tolerability and median survivals of 3.85 months and 4.7 months, respectively. Regimens incorporating two drugs have demonstrated encouraging activity and clinical impact compared with single-agent therapy. G-FLIP is a regimen designed to incorporate four active single agents into a tolerable and active combination. This analysis is a retrospective evaluation of the efficacy and safety of the G-FLIP regimen as second-line chemotherapy in a series of consecutively treated patients with metastatic pancreatic cancer.
Methods. G-FLIP was administered over 48 hours and repeated every 2 weeks. Day 1 treatment consisted of sequentially administered gemcitabine 500 mg/m2, irinotecan 80 mg/m2, leucovorin 300 mg, 5-fluorouracil (5-FU) 400 mg/m2 bolus followed by infusional 5-FU 600 mg/m2 over 8 hours. Day 2 treatment consisted of leucovorin 300 mg and 5-FU 400 mg/m2 bolus, followed by cisplatin 50 to 75 mg/m2, and then infusional 5-FU 600 mg/m2 over 8 hours.
Results. Thirty-four patients with histologically confirmed metastatic pancreatic cancer were consecutively treated. The median patient age was 64.5 years (range 41-82 years) and all patients had objective disease progression on prior therapy: 32 patients had disease progression with gemcitabine and 31 had disease progression with a gemcitabine/5-fluorouracil/cisplatin combination. Grade 3-4 hematological toxicities included anemia (23%), thrombocytopenia (53%), and neutropenia (38%). There were no grade 3-4 neutropenic fevers, treatment-related mortalities, or withdrawals. Nonhematological grade 3-4 toxicities were rare: nausea/vomiting (3%), neurotoxicity (3%), nephrotoxicity (6%), and diarrhea (3%). Based on RECIST criteria a partial response (PR) was attained in eight patients (24%) and seven patients had stable disease (NYSE:SD). Seven and six patients who attained a PR or SD, respectively, had disease progression with prior gemcitabine-based therapy. The median time to disease progression for all 34 patients was 3.9 months and 5.9 months for the eight patients who attained a PR. Median overall survival for all 34 patients was 10.3 months.
But, of course G-FLIP didn't include nanoparticled Irinotecan.
The company said patients taking only MM-398 experienced a higher level of adverse events than those given the combination.
Merrimack said the most common serious adverse events in patients given the combination were an abnormally low count of a type of white blood cells, fatigue, diarrhea and vomiting.
MM-398 works by delivering a chemotherapy drug known as irinotecan to a tumor in an enclosed particle, enabling it to accumulate and be retained in the tumor.
So, the purpose of nanoparticles?
International Journal of Nanomedicine
Drug delivery and nanoparticles: Applications and hazards
Wim H De Jong and Paul JA Borm
The use of nanotechnology in medicine and more specifically drug delivery is set to spread rapidly. Currently many substances are under investigation for drug delivery and more specifically for cancer therapy. Interestingly pharmaceutical sciences are using nanoparticles to reduce toxicity and side effects of drugs and up to recently did not realize that carrier systems themselves may impose risks to the patient. The kind of hazards that are introduced by using nanoparticles for drug delivery are beyond that posed by conventional hazards imposed by chemicals in classical delivery matrices. For nanoparticles the knowledge on particle toxicity as obtained in inhalation toxicity shows the way how to investigate the potential hazards of nanoparticles. The toxicology of particulate matter differs from toxicology of substances as the composing chemical(s) may or may not be soluble in biological matrices, thus influencing greatly the potential exposure of various internal organs. This may vary from a rather high local exposure in the lungs and a low or neglectable exposure for other organ systems after inhalation. However, absorbed species may also influence the potential toxicity of the inhaled particles. For nanoparticles the situation is different as their size opens the potential for crossing the various biological barriers within the body.
So, Nanoparticles can actually introduce added risk. How important then is the use of encapsulated Irinotecan?
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. 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 frequent 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.
Alright, so Merrimac shows both no benefit of encapsulation, and only a 6.1 mo MOS , compared to 10.3 mo MOS with G-Flip, in the same setting. But it is still even valid to study the setting of secondary chemotherapy post-single agent Gemcitabine for Pancreatic CA-4b?
Pancreatic Cancer: Treatment Options
This section has been reviewed and approved by the Cancer.Net Editorial Board, 10/2013
In the past few years, two particular chemotherapy combinations are being used as the new standards of care. The first of these is a combination of drugs called FOLFIRINOX (5-FU, leucovorin [Wellcovorin], irinotecan [Camptosar], and oxaliplatin). However, because of the side effects, this regimen is only for patients who are in good physical condition and otherwise healthy despite the cancer. The second is a combination of gemcitabine plus nanoparticle albumin-bound nab-paclitaxel (Abraxane). Both FOLFIRINOX and gemcitabine/nab-paclitaxel have been shown to increase patients' lives, stop or stop tumor growth, and keep the disease from worsening for a longer time than with gemcitabine alone.
So, Why base a secondary treatment in 2014 on the Primary treatment discovered in 1997 which is no longer the standard of care? A treatment that does not perform as well or as safely as those that have come before it on that prior standard? Given the 11.1 month MOS seen with primary Folforinox, one must question whether the primary performance of failed Gemcitabine plus the 6.1 months added by FolF(Iri) even meets that mark. Finally the promise of early primary results from Gem-pegpH20- 18.1 months in Pancreatic Ph4b may raise the bar further- www.halozyme.com/files/ESMO%202013%20Pos...
2 Ph2 Studies of Gemcitabine-Abraxane with pegpH20 and Folfirinox with pegpH20 are underway. If pegpH20 doubles the PFS and Triples the MOS of Gem-Abraxane, as it did with Gem in 1b, we may see an MOS of 2 years, not 6.1 months.
Disclosure: The author is long HALO.