ODAC Suggests Abraxane Efficacy Study as Adjuvant Rx

SILVER SPRING, Maryland—The Oncologic Drugs Advisory Committee (ODAC) has recommended that FDA work with Abraxis Bioscience to design a well-controlled, randomized, reasonably sized clinical trial of Abraxane-paclitaxel protein-bound particles for injectable suspension (albumin bound)—to support a future supplemental application for the drug as an alternative to standard paclitaxel (Taxol) in the adjuvant treatment of node-positive breast cancer.

The panel's 13-to-1 vote rejected the company's contention that no additional efficacy study should be required and upheld the FDA's contention that it needs the trial to support the efficacy and safety of Abraxane in this indication. The panel urged the agency and sponsor to collaborate in determining a suitable and reasonably sized patient population to provide the answers. "We intend to move as quickly as possible to discuss the next steps with FDA," said Michael J. Hawkins, MD, Abraxis' chief medical officer.

Abraxane is the first of a new class of protein-bound taxanes that uses albumin, a natural carrier of water-insoluble molecules, to transport the active drug (paclitaxel). Abraxane was developed to eliminate the hypersensitivity reactions induced by Cremophor, which serves as the paclitaxel carrier in Taxol. Abraxane won initial FDA approval in January 2005 for use after failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy.

Abraxis sought approval for the drug as an adjuvant therapy through a seldom used regulatory route known as Section 505(b)(2). Typically, drug sponsors support their applications with their own studies. However, 505(b)(2) applies to new formulations of existing drugs and allows FDA, "where appropriate," to base its approval entirely or partially on studies that the applicant did not conduct and for which it has not a obtained a right of use.

Taxol is approved for adjuvant use in node-positive breast cancer. In seeking supplemental approval of Abraxane under Section 505(b)(2), Abraxis wanted to use data from the preclinical genetic toxicology studies and the clinical trial submitted to FDA to support the approval of Taxol for adjuvant use, as well as the phase III trial it conducted comparing the two drugs in metastatic breast cancer, which served as the basis for the 2005 approval of Abraxane. Abraxis said it would willingly conduct a safety study of Abraxane as adjuvant therapy but saw no need for an efficacy trial.

Abraxane's formulation allows it to deliver a higher dose of paclitaxel than Taxol because it contains no Cremophor, and studies have shown that Abraxane has greater antitumor power in metastatic breast cancer than the older drug, Dr. Hawkins noted. "Therefore, there is no scientific basis to hypothesize that Abraxane will be less effective than Taxol as adjuvant therapy," he said.

FDA's medical review team challenged this assertion. For one thing, the use of albumin instead of Cremophor in Abraxane results in pharmacokinetics different from Taxol, said FDA pharmacologist Brian Booth, PhD.

A clinical pharmacokinetic study conducted by the sponsor in 14 Abraxane patients (260 mg/m²) and 12 Taxol patients (175 mg/m²) showed a 50% higher volume of distribution and more rapid plasma occurrence for Abraxane. According to the sponsor, this allowed for a 50% higher dose of Abraxane that still approximated the Taxol plasma concentration. In addition, the study showed the Abraxane dose gave a 6.5 times higher C_max, a 17% higher AUC, and 40% higher clearance. "Based on these data, the two drugs would not be considered bio-equivalent," Dr. Booth said.

Conventional thinking holds that the free drug available mediates the response of a medication. But at this time, Dr. Booth noted, the amount of free paclitaxel generated by Abraxane or Taxol remains unknown, as does the comparative biodistribution of free paclitaxel from the two drugs.

The randomized trial used to support Abraxane for advanced metastatic breast cancer showed a 21.5% tumor response rate for the drug vs 11.1% for Taxol. However, the newer drug also had a higher incidence of certain adverse events. "Abraxane had more neurotoxicity, nausea, vomiting, diarrhea, and neutropenia; however, no differences in infections or febrile neutropenia were observed," FDA said. "The different toxicity profile and tumor response rates indicate Abraxane and Taxol are different drugs."

The company noted that the development of peripheral neuropathy does not preclude continued treatment with Abraxane. In studies, Abraxane neuropathy improved within 22 days, and many patients were able to resume treatment at a reduced dose. Further, GI effects with Abraxane have been low grade and not a clinical issue, the sponsor said.

Michael C. Perry, MD, of the University of Missouri Ellis Fischel Cancer Center, the lone dissenter in the 13-to-1 vote, said he remained convinced that a trial was unnecessary and that conducting one would require too many patients, too many years, and in the end, would serve no useful purpose.