FDA Approval for Paclitaxel Albumin-stabilized Nanoparticle Formulation
Brand name(s): Abraxane®
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
Non-Small Cell Lung Cancer
On October 11, 2012, the Food and Drug Administration (FDA) approved paclitaxel protein-bound particles for injectable suspension, albumin-bound (Abraxane® made by Abraxis Bioscience, a wholly owned subsidiary of Celgene Corporation) for use in combination with carboplatin for the initial treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are not candidates for curative surgery or radiation therapy.
This approval for the first-line treatment of locally advanced or metastatic NSCLC was granted under the provisions of 505(b)(2) of the Food, Drug, and Cosmetic Act. FDA relied on the prior approval of Taxol (paclitaxel) injection for this indication, supported by an additional trial establishing that paclitaxel protein-bound particles for injectable suspension, albumin-bound was as at least as active (as determined by overall response rate) as paclitaxel when used in combination with carboplatin.
The additional trial (Protocol CA031) was a randomized open-label multi-national trial that enrolled 1052 patients with locally advanced or metastatic NSCLC. Patients were randomly assigned to receive paclitaxel protein-bound particles for injectable suspension, albumin-bound at a dose of 100 mg/m2 as a weekly intravenous infusion (n=521) or paclitaxel injection at a dose of 200 mg/m2 as an intravenous infusion every 3 weeks (n=531). Patients in both treatment groups also received carboplatin at the same dose and schedule (AUC 6 mg•min/mL) every 3 weeks. All patients treated with paclitaxel were required to be premedicated with corticosteroids and an antihistamine, whereas those treated with the paclitaxel protein-bound particles for injectable suspension, albumin-bound received premedication at the investigator’s discretion.
The primary efficacy objective was to demonstrate that patients receiving paclitaxel protein-bound particles for injectable suspension, albumin-bound plus carboplatin had a significantly higher overall response rate (ORR) with no evidence of a significant impairment in overall survival compared to those receiving paclitaxel plus carboplatin. The primary endpoint of ORR, defined as percentage of patients who achieved a durable complete or partial response, was determined by a radiological review committee masked to treatment assignment.
The CA031 trial met its primary endpoint, demonstrating a statistically significantly higher overall response rate for patients treated with paclitaxel protein-bound particles for injectable suspension, albumin-bound of 33 percent (95 percent CI: 29, 37) compared with 25 percent (95 percent CI: 21, 28) for patients treated with paclitaxel (p = 0.005, chi square test). The absolute increase in ORR was 8 percent (95 percent CI: 2, 8). The durability of responses was similar for responding patients in the two treatment groups, with median response durations of 6.9 months for patients treated with paclitaxel protein-bound particles for injectable suspension, albumin-bound and 6.0 months for patients treated with paclitaxel. There was no statistically significant difference in overall survival between the two treatment groups.
Safety was evaluated in 1038 patients who received at least one dose of planned treatment. The most common ( at least 10 percent incidence) grade 1-4 adverse drug reactions reported in patients treated with paclitaxel protein-bound particles for injectable suspension, albumin-bound included anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, fatigue, decreased appetite, asthenia, constipation, diarrhea, arthralgia, vomiting, dyspnea, peripheral edema, rash, and myalgia. The most common (at least 5 percent) grade 3-4 adverse reactions were neutropenia, anemia, and thrombocytopenia.
Serious adverse reactions occurred in 18 percent of patients in both treatment groups. The most common serious adverse reactions in patients treated with paclitaxel protein-bound particles for injectable suspension, albumin-bound were anemia (4 percent) and thrombocytopenia (3 percent).
The recommended dose and schedule for initial treatment of patients with locally advanced or metastatic NSCLC is paclitaxel protein-bound particles for injectable suspension, albumin-bound 100 mg/m2, administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg•min/mL on day 1 of each 21-day cycle following the completion of paclitaxel protein-bound particles for injectable suspension, albumin-bound infusion.
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On January 7, 2005, the U.S. Food and Drug Administration approved paclitaxel protein-bound particles for injectable suspension, albumin-bound (Abraxane™, a trademark of American BioScience, Inc.) for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Nanoparticle paclitaxel is also called paclitaxel albumin-stabilized nanoparticle formulation. Prior therapy should have included an anthracycline unless clinically contraindicated.
The clinical database included two single arm studies enrolling a total of 106 patients and one multicenter randomized trial. The multicenter trial was conducted in 460 patients with metastatic breast cancer who were randomized to receive either nanoparticle paclitaxel 260 mg/m2 administered as a 30-minute infusion or paclitaxel 175 mg/m2 given over three hours.
Fifty-nine percent of patients had received one or more prior chemotherapy regimens, and 77 percent had received an anthracycline-containing regimen. The objective response rate verified by central review was 21.5 percent (95 percent CI: 16.2 percent to 26.7 percent) for nanoparticle paclitaxel compared to 11.1 percent (95 percent CI: 6.9 percent to 15.1 percent) for paclitaxel (p=0.003).
Clinically important adverse events (all grade) in the randomized trial comparing nanoparticle paclitaxel to paclitaxel included neutropenia (80 percent with nanoparticle paclitaxel and 82 percent with paclitaxel), anemia (33 percent vs. 25 percent), infections (24 percent vs. 20 percent), hypersensitivity reactions (4 percent vs. 12 percent), sensory neuropathy (71 percent vs. 56 percent), edema (10 percent vs. 8 percent), nausea (30 percent vs. 21 percent), vomiting (18 percent vs. 9 percent), diarrhea (26 percent vs. 15 percent), and mucositis (7 percent in both arms).
Severe adverse events (grade 3 or 4) included neutropenia (9 percent with nanoparticle paclitaxel and 22 percent with paclitaxel), myalgia/arthralgia (8 percent vs. 4 percent) and vomiting (4 percent vs. 1 percent). Ten percent (24 patients) treated with nanoparticle paclitaxel developed grade 3 peripheral neuropathy; 14 of these patients showed some improvement of neuropathy at a median of 22 days. Two percent of patients receiving paclitaxel developed grade 3 peripheral neuropathy.
The recommended dose of nanoparticle paclitaxel is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. No premedication to prevent hypersensitivity reactions is required prior to nanoparticle paclitaxel administration.
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Do not administer paclitaxel protein-bound particles for injectable suspension, albumin-bound therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel protein-bound particles for injectable suspension, albumin-bound. An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. Do not substitute for or with other paclitaxel formulations.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.