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Cancer Drug Information

  • Updated: 09/06/2013

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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.

Metastatic Pancreatic Cancer

On September 6, 2013, the Food and Drug Administration (FDA) approved paclitaxel albumin-stabilized nanoparticle formulation (Abraxane® for injectable suspension, made by Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation), in combination with gemcitabine for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas.

The approval of paclitaxel albumin-stabilized nanoparticle formulation for this indication was based on the demonstration of improved overall survival (OS) in a multi-center international, open-label randomized trial that enrolled 861 patients with metastatic pancreatic cancer. Patients were randomly assigned to receive either paclitaxel albumin-stabilized nanoparticle formulation plus gemcitabine (n=431) or gemcitabine alone (n=430). Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, or North America), performance status, and presence of liver metastasis. The major efficacy outcome measure was OS; 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 percent age 65 years or older; 58 percent were men, and the Karnofsky performance score was 90 or 100 in 60 percent. Nearly half (46 percent) of the patients had three or more sites of metastatic disease, and 84 percent had liver metastases. The primary lesion was located in the pancreatic head in 43 percent of the patients, in the body in 31 percent, and in the tail in 25 percent of patients.

The trial demonstrated a statistically significant prolongation of OS for patients randomly assigned to receive paclitaxel albumin-stabilized nanoparticle formulation plus gemcitabine. The median OS was 8.5 months in patients treated with paclitaxel albumin-stabilized nanoparticle formulation  plus gemcitabine and 6.7 months in patients treated with gemcitabine alone [HR 0.72 (95 percent CI: 0.62, 0.84); p < 0.0001, stratified log-rank test]. A significant improvement in PFS was also observed, with median PFS of 5.5 months in patients treated with paclitaxel albumin-stabilized nanoparticle formulation  plus gemcitabine and 3.7 months in patients treated with gemcitabine alone [HR 0 .69 (95 percent CI: 0.58, 0.82) p < 0.0001, stratified log-rank test]. Objective response rates were 23 percent in patients treated with paclitaxel albumin-stabilized nanoparticle formulation  plus gemcitabine and 7 percent in patients treated with gemcitabine (p<0.0001, Chi-square test). 

The most frequent (at least 20 percent incidence) adverse reactions, for which the incidence was at least 5 percent higher in patients who received paclitaxel albumin-stabilized nanoparticle formulation  plus gemcitabine than in patients who received gemcitabine alone, included neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration.

The most frequent serious adverse reactions in patients who received paclitaxel albumin-stabilized nanoparticle formulation plus gemcitabine were pyrexia, dehydration, pneumonia, and vomiting. Sepsis was reported in 5 percent of patients who received paclitaxel albumin-stabilized nanoparticle formulation plus gemcitabine, and pneumonitis was reported in 4 percent of such patients. 

The recommended dose and schedule for paclitaxel albumin-stabilized nanoparticle formulation 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 no longer tolerated by the patient. Gemcitabine is administered immediately after paclitaxel albumin-stabilized nanoparticle formulation  on days 1, 8, and 15 of each 28-day cycle.

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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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Breast Cancer

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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Drug Warning

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 "Learn How Drugs and Devices Get Approved.") 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.