Cancer Treatment Today

Abraxane (nab-paclitaxel) is an albumin-bound, 130-nm particle form of paclitaxel that was developed to avoid cremophor/ethanol-associated toxicities associated with the parent compound. Abraxane is FDA-approved for the treatment of breast cancer after the failure of combination chemotherapy for metastatic disease or relapse within 6 months.

There was a study of 44 patients presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago in 2010. These findings were discussed during a keynote address by Daniel Von Hoff, M.D., “Epithelium and Stroma: Double Trouble,” during the “Progress in Pancreatic Cancer” session on April 18 at the 101st Annual Meeting of the American Association for Cancer Research (AACR) being held in Washington, D.C. the median overall survival (OS) time was 12.2 months, a doubling of survival compared to historical control of gemcitabine administered alone. This combination of nab-paclitaxel and gemcitabine also resulted in a confirmed overall response rate in 50 percent of patients treated, and a disease control rate (CR, PR and stable disease for 16 weeks or longer according to RECIST criteria) of 68 percent. In the overall study (n=67), three patients achieved a complete response.

There was as well a small phase II trial presented at ASCO 2010. One of 19 patients (5.3%) achieved partial response.

In 2009, Abraxane for Injectable Suspension (paclitaxel albumin [human]-bound particles for injectable suspension) was granted orphan status for the treatment of pancreatic cancer and Stage IIB-IV melanoma. An orphan designation means only that the FDA sees a need to investigate a drug for a specified indication. A Phase III study had been opened that will evaluate ABRAXANE plus gemcitabine versus gemcitabine alone as a first line therapy for advanced metastatic pancreatic cancer.

On 3/2/11 NCCN updated its principles of chemotherapy guideline(PANC-6) to include gemcitabine + nab-paclitaxel (Abraxane) as a category 2B recommendation for the management of locally advanced unresectable and metastatic disease in patients with good performance status.

There are few good options for pancreatic cancer patients who had received gemcitabine. They include Xeloda, Folfox, Folfirinox and possibly GTX, but no option has been demonstrated superior to others in second line. Folfirinox has an advantage in first line but is very toxic. With this, the NCCN listed gemcitabine/Abraxane should be considered a reasonable option. On 2013 ASCo ( Abstract 148) the MPACT study was presented and it showed a a statistically significant survival difference  for the gemcitabine and Abraxane arm versus gemcitabine alone .

Based on the aforementioned phase III study by Dr. Hoff,  on Sept. 6, 2013, the U. S. Food and Drug Administration approved paclitaxel protein-bound particles (albumin-bound) (Abraxane®  in combination with gemcitabine for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas.
The tudy was a  multi-center, international, open-label, randomized trial enrolling 861 patients with metastatic pancreatic cancer.  Patients were randomized to receive either the combination of Abraxane plus gemcitabine (n=431) or gemcitabine alone (n=430).  Additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST (version 1.0).

The median age of the patients was 63 years (range 27-88 years) with 42% age 65 years or older, 58% were men, and the Karnofsky performance was 90 or 100 in 60%.  Nearly half (46%) of the patients had three or more sites of metastatic disease and 84% had liver metastases.  The primary lesion was located in the pancreatic head in 43%, the body in 31%, or tail in 25% of patients.

The trial demonstrated a statistically significant prolongation of OS for patients randomized to receive the combination of Abraxane plus gemcitabine [HR 0.72 (95% CI: 0.62, 0.84); p < 0.0001, stratified log-rank test].  The median OS was 8.5 months in the Abraxane plus gemcitabine arm and 6.7 months in the single agent gemcitabine arm.  A significant improvement in PFS was also observed with median PFS of 5.5 months in the Abraxane plus gemcitabine arm and 3.7 months in the gemcitabine arm [HR 0 .69 (95% CI: 0.58, 0.82) p < 0.0001, stratified log-rank test].  Objective response rates were 23% and 7% in the Abraxane plus gemcitabine and single agent gemcitabine arms, respectively (p<0.0001, Chi-square test).

The most frequent (greater than or equal to 20% incidence) adverse reactions reported at a greater than or equal to 5% higher incidence in patients who received the combination of Abraxane plus gemcitabine as compared to gemcitabine alone included neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration.

The recommended dose and schedule for Abraxane is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on days 1, 8 and 15 of each 28-day cycle until disease progression or if no longer tolerated by the patient.  Gemcitabine is administered immediately after Abraxane on days 1, 8 and 15 of each 28-day cycle. Abraxane was FDA approved in September 2013.

The GAX regimen is in a clinical trial: Nab-paclitaxel (Abraxane), Gemcitabine, and Capecitabine (Xeloda) for Pancreatic Adenocarcinoma, NCT01161186. The purpose of this study is to evaluate optimal dose and safety of the combination of Abraxane, gemcitabine, and Xeloda (capecitabine) (AGX) as first-line therapy in patients with metastatic pancreatic cancer. A single agent study is: Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer That Did Not Respond to First-Line Therapy With Gemcitabine, CT00691054.

I note an intersting recent abstract by Dr. Isacoff. It employs Continuous infusion 5-fluorouracil (5 FU), calcium leucovorin plus paclitaxel and oxaliplatin. The abstract concludes: Low-dose continuous (metronomic therapy) cytotoxic chemotherapy when combined with antiangiogenic therapy is safe and effective for patients with advanced pancreatic cancer. An expanded multi-institutional trial is being developed to confirm this single-institution experience.”

W. H. Isacoff, H. A. Reber, F. M. Purcell, B. M. Clerkin, K. M. Clerkin; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; University of Colorado, Boulder, CO  Low-dose continuous infusion 5-fluorouracil combined with weekly leucovorin, nab-paclitaxel, oxaliplatin, and bevacizumab for patients with advanced pancreatic cancer: A pilot study. J Clin Oncol 28, 2010 (suppl; abstr e14545)

Hosein PJ, Pastorini VH, Gomez CM, Macintyre J, Merchan JR, Ferrell A, et al.A phase II trial of nab-paclitaxel (NP) in patients with advanced pancreatic cancer (PC) who have progressed on gemcitabine-based therapy. 2010 ASCO Gastrointestinal Cancers Symposium. Abstract No. 214.

Von Hoff DD, et al. Promising clinical activity of a NAB paclitaxel plus gemcitabine combination in a disease-specific Phase I trial in patients with advanced pancreatic cancer. 2008 annual meeting of the American Association for Cancer Research. Abstract 4179.

Hosein PJ, Pastorini VH, Gomez CM, Macintyre J, Merchan JR, Ferrell A, et al.A phase II trial of nab-paclitaxel (NP) in patients with advanced pancreatic cancer (PC) who have progressed on gemcitabine-based therapy. 2010 ASCO Gastrointestinal Cancers Symposium. Abstract No. 214.

Abraxane, Prescribing Information, 2018