A new phase III study confirmsthat the breast cancer drug nanoparticle albumin-bound paclitaxel (Abraxane?, Celgene) in combination with gemcitabine (Gemzar?, Eli Lilly and Company), the current standard of for advanced pancreatic cancer, demonstrated highly statistically significant and clinically meaningful results across primary and key secondary endpoints and patient subgroups.

Patients treated with the combination of the two drugsshowed 59% increasein one-yearmediian survival from less than 22% to more than 35%. The researchersfurther observed that survival rates doubled after two years from less than 4% to 9% with the nab-paclitaxel/gemcitabine combination.Based on these results this treatment option may become a new standard of care for patients with advanced pancreatic cancer. [1]

The study results will be presented on Friday, January 25th at ASCO’s Gastrointestinal Cancers Symposium Annual Meeting in San Francisco.

Pancreatic cancer
The pancreas is a large organ located behind the stomach. It makes and releases enzymes into the intestines that help the body absorb foods, especially fats. Hormones called insulin and glucagon,help thebody control blood sugar levels, are made in special cells in the pancreas called islet cells. The exact cause of pancreatic cancer is unknown. However, it is more common in people with diabetes, people withlong-term inflammation of the pancreas (chronic pancreatitis) and smokers. The disease isslightly more common in women than in men and therisk increases with age. Studies have shown that a small number of cases are related to genetic syndromes that are passed down through families.

Advanced pancreatic cancer is a difficult-to-treat cancer with the lowest survival rates among all cancer types. Across all patients with pancreatic cancer, relative 5-year survival is 6% and is less than 2% for those with advanced disease. There are two main types of pancreatic cancer – adenocarcinomas, which accounts for approximately 90% of all pancreatic cancer, and neuroendocrine tumors. Pancreatic cancer is relatively uncommon with new cases accounting for only 2.1% of all newly diagnosed cancers. However, pancreatic cancer is the fourth most common cause of cancer death for men and women in the United States and Australia, and the ninth most commonly diagnosed cancer in Australia.[2] The actualincidence of pancreatic cancer is increasing worldwide with an estimated 279,000 cases per year, including nearly 44,000 in the U.S. in 2012, and resulting in more than 37,000 American deaths in 2012.

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MPACT study
In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, a Celgene-sponsored, open-label, randomised, international trialof 861 patients with metastatic pancreatic cancer were randomised to receive either nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a solvent-free, chemotherapy treatment option for metastatic breast cancer. [3] plus gemcitabine (125 mg/m2 followed by 1000 mg/m2 gemcitabine for 3 weeks followed by a week of rest) or gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks followed by a week of rest followed by cycles of weekly administration for 3 weeks followed by one week of rest).

Statistically Significant
The primary endpoint for the study is improvement in overall survival. Secondary endpoints were progression-free survival, and overall response rate determined by independent radiological review. Other endpoints included progression-free survival, overall response rate determined by investigator and the safety and tolerability of this combination in this patient population. Researchers found those patients treated with nanoparticle albumin-bound paclitaxel plus gemcitabine had a statistically significant improvement in overall survival compared to patients receiving gemcitabine alone [(median of 8.5 vs. 6.7 months) (HR 0.72, P=0.000015)].[1]

Moreover, nanoparticle albumin-bound paclitaxel plus gemcitabine demonstrated a 59% increase in one-year survival (35% vs. 22%, p=0.0002) and demonstrated double the rate of survival at two years (9% vs. 4%, p=0.02) as compared to gemcitabine alone.[1]

Nab-paclitaxel plus gemcitabine also demonstrated statistically significant improvements in key secondary endpoints compared to gemcitabine alone, including a 31% reduction in the risk of progression or death with a median progression-free survival (PFS) of 5.5 vs. 3.7 months (HR 0.69, P=0.000024) and an overall response rate (ORR) of 23% compared to 7% (response rate ratio of 3.19, p=1.1 x 10-10). Another endpoint assessed included time to treatment failure, which was significantly improved with the nanoparticle albumin-bound paclitaxel combination compared to gemcitabine alone [(median 5.1 vs. 3.6 months) (HR 0.70, P<0.0001)].[1]

?We are ecstatic that this clinical trial of nanoparticle albumin-bound paclitaxel plus gemcitabine improves survival for patients with advanced stage IV pancreatic cancer,? saidDaniel D. Von Hoff, M.D., F.A.C.P.,Lead Principal Investigator of the MPACT study and Chief Scientific Officer for Scottsdale Healthcare’s Virginia G. Piper Cancer Centre Clinical Trials and Physician-In-Chief for TGen.?It once again demonstrates that laboratory science based medicine can make a difference for patients.?

“The past few decades have brought us very few treatment advances for patients with advanced pancreatic cancer, which is both deadly and incredibly difficult to treat with success,” Von Hoff said. “The fact thatnanoparticle albumin-bound paclitaxel plus gemcitabine demonstrated an overall survival benefit, and also did so at one and two years, is a significant step forward in offering potential new hope for our patients.”

Major improvement
The study showed significant improvement among some of the sickest patients including those with increased metastases. Significantly there was no increase in life-threatening toxicity. Other drug combinations that have demonstrated benefit have been limited by increased toxicities.

?This is a major improvement in a cancer with the lowest survival rates among all cancer types,? noted Ramesh Ramanathan, medical director of Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare and principal investigator for the clinical trial in the United States. ?Advanced pancreatic cancer … is difficult to diagnose with a majority of the cases diagnosed at a late stage after the disease has already advanced.?

Professor John Zalcberg, MBBS, Ph.D., FRACP, MRACMA, GAICD, Chief Medical Officer and Executive Director of Cancer Medicine at thePeter MacCallum Cancer Centre in Melbourne, Australia,said the evidence strongly supported using nanoparticle albumin-bound paclitaxel in combination with gemcitabine as a new standard of care to treat appropriate patients, many of whom were not diagnosed until the disease was metastatic.

While acknowledging that this advance could not be seen as a cure for pancreatic cancer,Zalcberg said the 59% increase in the number of patients who lived beyond 12 months was very encouraging. “We are extremely encouraged by the results of this study involving nanoparticle albumin-bound paclitaxel and regard this outcome as
a significant breakthrough in terms of the future management of this disease,” he noted. “In addition to treating women with metastatic breast cancer with nanoparticle albumin-bound paclitaxel in the appropriate setting, we look forward to its approval in Australia for treating patients with advanced pancreatic cancer.”

Commenting on the trial results, Specialised Therapeutics Australia (STA) Chief Executive Officer Mr. Carlo Montagner said the positive data paved the way for Australian patients with advanced pancreatic cancer to access more effective treatment options. “In Australia, pancreatic cancer is the fourth most common cause of death from cancer for both men and women [2] and very few treatment options exist for this group of patients. We are extremely pleased to demonstrate that Abraxane is capable of prolonging survival for patients with advanced pancreatic cancer and we hope to have Abraxane approved by the Australian Therapeutic Goods Administration (TGA) in the latter half of 2014.”

The most common grade ? 3 treatment-related adverse events in the study for nanoparticle albumin-bound paclitaxel plus gemcitabine vs. gemcitabine alone were neutropenia (38% vs. 27%), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). In the arm with nanoparticle albumin-bound paclitaxel plus gemcitabine arm, the median time to neuropathy improvement was 29 days. There was no difference in serious life threatening toxicity (4% in each arm).[1]

How it works
Nanoparticle albumin-bound paclitaxel wraps traditional chemotherapy, paclitaxel, in near-nano sized shells of albumin, a protein that the tumor sees as food. The tumor uses various mechanisms to preferentially attract the albumin, which then acts like a “Trojan Horse” to release its package of chemotherapy inside the tumor.

[1] Von Hoff DD et al. Final results of a randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas. Abstract: LBA #148. American Society of Clinical Oncology’s (ASCO) 2013 Gastrointestinal Cancers Symposium in San Francisco, CA. (ASCO GI 2013)Friday, January 25 th between 2:00 to 3:30 pm PST
[2] Cancer in Australia. An Overview 2012. Australian Institute of Health and Welfare (AIHW) ISSN 1039-3307; ISBN 978-1-74249-386-2; Cat. no. CAN 70; 216pp –
[3] Nanoparticle albumin-bound paclitaxe (Abraxane) Product Information
[4] Gradishar WJ, Tjulandin S,Davidson N, Shaw H,Desai N,Bhar P,Hawkins M, O’Shaughnessy J. Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil?Based Paclitaxel in Women With Breast Cancer. J Clinical Oncology 2005;23:7794-7803
[5] Vukelja SJ, O?Shaughnessy J, Krasnojon D, Cheporov SV, Makhson A,Manikhas G, Bhar P, Gradishar W. Efficacy of Nab-paclitaxel in patients with poor prognostic factors or with anthracycline-resistant metastatic breast cancer (MBC). General Poster Session, Breast Cancer ? Metastatic, ASCO 2008, Abstract 1082; J Clin Oncol 26: 2008(May 20 suppl; abstr 1082)

Clinical trials
NCT00844649– Phase III Study of ABI-007(Albumin-bound Paclitaxel) Plus Gemcitabine Versus Gemcitabine in Metastatic Adenocarcinoma of the Pancreas
NCT00398086– Gemcitabine (GEMZAR) Plus ABI-007 (ABRAXANE)In Patients With Advanced Metastatic Pancreatic Cancer
NCT01442974– Assessment Of Stromal Response To Nab-Paclitaxel In Combination With Gemcitabine In Pancreatic Cancer

Photo 1: Daniel D. Von Hoff, M.D., F.A.C.P., Lead Principal Investigator of the MPACT study and Chief Scientific Officer for Scottsdale Healthcare’s Virginia G. Piper Cancer Centre Clinical Trials and Physician-In-Chief for TGen. Photo courtesy: TGen Foundation, Phoenix, Arizona, USA. Photo 2: John Zalcberg, MBBS, Ph.D., FRACP, MRACMA, GAICD, Chief Medical Officer and Executive Director of Cancer Medicine at the Peter MacCallum Cancer Centre in Melbourne, Australia. Photo courtesy: Peter MacCallum Cancer Centre in Melbourne, Australia

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