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Journal of Clinical Oncology, Vol 26, No 4 (February 1), 2008: pp. 639-643 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.8605 Phase I/II Trial of Weekly Intravenous 130-nm Albumin-Bound Paclitaxel As Initial Chemotherapy in Patients With Stage IV Non–Small-Cell Lung Cancer
From the Thoracic Oncology Service, Departments of Medicine and Radiology, Memorial Sloan-Kettering Cancer Center; Weill Medical College of Cornell University, New York, NY; and Abraxis BioScience, San Diego, CA Corresponding author: Naiyer A. Rizvi, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: rizvin{at}mskcc.org
Purpose Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) is an albumin-bound formulation of paclitaxel that has demonstrated improved efficacy compared with paclitaxel in the treatment of metastatic breast cancer. We undertook this trial to determine the maximum-tolerated dose (MTD) and single-agent activity of NAB-paclitaxel administered on a weekly basis to patients with stage IV non–small-cell lung cancer (NSCLC). Patients and Methods This was an open-label, single-arm, phase I/II study. Patients were treated with NAB-paclitaxel intravenously during 30 minutes without corticosteroid or antihistamine premedications on days 1, 8, and 15 of a 28-day cycle. Radiologic tumor assessment was performed every 8 weeks. Results Dose levels of 100 and 125 mg/m2 were tolerated without dose-limiting toxicities (DLTs). At 150 mg/m2 the MTD was exceeded; two of three patients experienced a DLT (grade 3 sensory neuropathy and febrile neutropenia). The 125 mg/m2 dose level was expanded and determined to be the MTD. A total of 40 patients were treated at 125 mg/m2. The objective response rate was 30% (12 of 40 patients; 95% CI, 16% to 44%), median time to progression was 5 months (95% CI, 3 to 8 months), and median overall survival was 11 months (95% CI, 7 months to not reached). The 1-year survival was 41%. Conclusion NAB-paclitaxel 125 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle was well tolerated and demonstrated encouraging single-agent activity. No corticosteroid premedication was administered and no hypersensitivity reactions were seen. Additional studies of single-agent NAB-paclitaxel as well as platinum-based combinations are warranted.
Docetaxel and paclitaxel are widely used in the treatment of non–small-cell lung cancer (NSCLC), both as single agents and in combination with other agents.1,2 Given that paclitaxel and docetaxel are poorly soluble, the current formulations require the use of solvents (polyethylated castor oil and polysorbate, respectively) to allow intravenous administration. These lipid-based solvents are associated with hypersensitivity reactions, which can be severe. To prevent these infusion reactions, patients routinely receive corticosteroids and antihistamines before each treatment. Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) is a formulation of paclitaxel complexed with albumin that is readily soluble in saline. This formulation allows the administration of paclitaxel without the use of lipid-based solvents and the need for corticosteroid and antihistamine premedication. NAB-paclitaxel was compared directly with solvent-based paclitaxel in a randomized phase III trial in 454 women with metastatic breast cancer.3 In this study, NAB-paclitaxel 260 mg/m2 administered every 3 weeks showed significantly higher response rates and time to progression, with a decreased incidence of grade 4 neutropenia when compared with solvent-based paclitaxel 175 mg/m2 administered every 3 weeks. In the patients treated with NAB-paclitaxel, there were no severe hypersensitivity reactions, despite the lack of corticosteroid premedication. As anticipated with a higher paclitaxel dose, grade 3 sensory neuropathy was 10% with NAB-paclitaxel compared with 2% with solvent-based paclitaxel (P < .001). A study with NAB-paclitaxel 260 mg/m2 administered every 3 weeks in chemotherapy-naïve, advanced-stage NSCLC patients was conducted recently.4 Forty-three patients were enrolled and the response rate was 16%, median time to progression was 6 months, and median survival was 11 months. A phase I and pharmacokinetic trial of NAB-paclitaxel administered weekly (days 1, 8, and 15 every 28 days) was conducted in patients with solid tumors.5 NAB-paclitaxel doses ranged from 80 to 200 mg/m2 in heavily and lightly pretreated patients, and the maximum-tolerated dose (MTD) was defined as 100 and 150 mg/m2, respectively. Dose-limiting toxicities (DLTs) included grade 3 and 4 peripheral neuropathy. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had been treated previously with paclitaxel. This trial was undertaken to identify the MTD of NAB-paclitaxel, administered on a weekly schedule, in patients with untreated advanced NSCLC, and to explore the safety and overall response rate for NAB-paclitaxel in patients with untreated advanced NSCLC. Secondary end points were time to disease progression and overall survival.
Patients with stage IV or recurrent NSCLC who had received no prior chemotherapy for advanced NSCLC were eligible. Patients may have received chemotherapy in the adjuvant or neoadjuvant setting. Prior treatment with gefitinib or erlotinib for advanced disease was allowed. Any patients who had received prior radiotherapy must have completed radiation more than 3 weeks before study entry. Laboratory requirements for eligibility were AST and ALT  2.5x the upper limit of normal range, total bilirubin within the normal range, creatinine 1.5 mg/dL, absolute neutrophil count  1.5 x 109 cells/L, platelets 100 x 109 cells/L, and hemoglobin 9 g/dL. Patients with peripheral neuropathy grade more than 1 were excluded. The protocol and informed consent documents were approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center and all patients provided written informed consent before procedures required for entry onto this study were performed.
Study Design
All patients who received at least one dose of NAB-paclitaxel were assessable for toxicity analysis. DLT was defined as any grade 3 or 4 treatment-related nonhematologic toxicity (National Cancer Institute Common Terminology Criteria of Adverse Events, version 3.0), excluding nausea, vomiting, and alopecia; any grade 4 treatment-related hematologic toxicity; or any grade 3 treatment-related hematologic toxicity requiring treatment delay of more than 2 weeks. Three patients were enrolled at each dose level starting at dose level 1. If no DLT was observed in cycle 1, three patients were enrolled at the next dose level. If one DLT was observed, the dose level was expanded to six patients. If two DLTs were observed, the MTD was exceeded and the previous dose level was expanded to six patients. The recommended phase II dose was the highest dose level at which A total of 40 patients were to be treated at the recommended phase II dose. The sample size was chosen based on a predicted response rate of 25%, with 40 patients, to obtain a 95% CI of 12% to 38%. Response rate (complete response and partial response) was determined using Response Evaluation Criteria in Solid Tumors.6 Responses had to be confirmed at least 4 weeks after initial documentation (confirmed responses). Survival time was defined as time from first study drug infusion to time of death. Time to progression was defined as the time from first study drug infusion to first objective documentation of tumor progression. Time to event distributions were estimated using the Kaplan-Meier method.
Drug and Treatment Dose reductions for toxicities were allowed with a reduction by 25 mg/m2 to a minimum dose of 100 mg/m2. Dose reductions were allowed for grade 3 or 4 thrombocytopenia or any grade 3 or 4 nonhematologic toxicity. The use of filgrastim and pegfilgrastim was encouraged for neutropenic fever and as prophylaxis in patients who had neutropenic fever in previous cycles of treatment or delay of previous treatments.
Phase I The phase I portion of the trial determined the MTD of intravenous NAB-paclitaxel administered weekly. Three patients treated at the 100 mg/m2 dose level had no DLT. Three patients were treated in the initial cohort of patients at the 125 mg/m2 dose level without DLT. Six patients were treated at the 150 mg/m2 dose level; one patient experienced febrile neutropenia and one patient experienced grade 3 sensory neuropathy during the first cycle of treatment. Dose escalation was discontinued, and after the 125 mg/m2 dose level was expanded to six patients without DLT, a total of 40 patients were enrolled onto the phase II portion of the study, the results of which are described in the following section.
Phase II
Objective response and survival. The confirmed response rate for NAB-paclitaxel was 30% (12 of 40; 95% CI, 16% to 44%; Fig 1). An additional patient had a maximal reduction in tumor size 30% but this was not confirmed on subsequent scans. Stable disease for 16 weeks was observed in eight of 40 patients. Of these patients with stable disease, best reduction in tumor size was 27%, 23%, 11% (n = 2), 9% (n = 2), 5%, and 3%. The waterfall plot (Fig 1, in which the best unidimensional response of Response Evaluation Criteria in Solid Tumors–defined indicator lesions for each patient is plotted) shows the disease control rate (complete response, partial response, or stable disease 16 weeks) of 50% (20 of 40; 95% CI, 35% to 66%). Median time to progression was 5 months (95% CI, 3 to 8 months). Median overall survival was 11 months (95% CI, 7 months to not reached; Fig 2). The 1-year overall survival was 41%.
Data on treatment after protocol were available for 37 patients (93%). Twelve patients received no additional therapy (three patients remain alive without additional treatment). The remaining patients received between one and three additional lines of chemotherapy (median, one additional line of chemotherapy). Patients received a wide variety of chemotherapeutic regimens. The two most common treatments were pemetrexed (12 patients) and the combination of gemcitabine and carboplatin (10 patients). Toxicity. The median number of cycles administered was four (range, one to 14). Most patients (85%) did not require dose reduction, although 18 patients (45%) discontinued study drug because of cumulative toxicity, primarily sensory neuropathy and fatigue. One patient died within 30 days of receiving NAB-paclitaxel. This patient died 27 days after receiving NAB-paclitaxel (cycle 3, week 2) with progressive liver metastases. This death was not treatment related. The most frequent adverse events in patients treated at 125 mg/m2 are listed in Table 2. No hypersensitivity reactions (observed rate, 0%; 95% CI, 0% to 9%) were reported. The most common grade 3/4 toxicities were neutropenia (grade 3 in 15% and grade 4 in 5%), leukopenia (grade 3 in 20%), sensory neuropathy (grade 3 in 15%), fatigue (grade 3 in 18%), diarrhea (grade 3 in 13%), and anemia (grade 3 in 8%). Resolution of sensory neuropathy was not assessed formally in this trial. Follow-up schedules for individual patients depended on subsequent treatment regimen, if any. Of the patients in this trial who developed grade 3 sensory neuropathy, one patient was lost to follow-up. The remaining patients all had improvement of neuropathy to grade 1 (three patients) or grade 2 (two patients) generally within 60 days. Most patients continued to have some symptoms of neuropathy.
The administration of solvent-based paclitaxel is associated with hypersensitivity reactions to the polyoxyethylated castor oil in which it is dissolved. These reactions cause morbidity and occasional mortality despite premedication with corticosteroids. Recent work in the treatment of patients with metastatic breast cancer has demonstrated that NAB-paclitaxel, a formulation of paclitaxel complexed with human albumin, can be administered without corticosteroid and antihistamine premedication to prevent hypersensitivity reactions during infusion.3 This study also demonstrated an improved efficacy profile for NAB-paclitaxel when compared with solvent-based paclitaxel. On the basis of the positive experience with NAB-paclitaxel in breast cancer, we performed this study to define the MTD of NAB-paclitaxel administered as a single agent on a weekly basis in a chemotherapy-naïve NSCLC patient population. NAB-paclitaxel was administered in this study on days 1, 8, and 15 every 28 days. The 100 and 125 mg/m2 dose levels were well tolerated without DLT, however, the 150 mg/m2 dose level exceeded the MTD, with dose limiting neutropenia and sensory neuropathy. We defined the recommended phase II dose of NAB-paclitaxel in this study as 125 mg/m2 on days 1, 8, and 15 every 28 days. This dose level was well tolerated in the phase II portion of the study. Of the 40 patients treated, no febrile neutropenia was observed and grade 3 and 4 neutropenia were 15% and 5%, respectively. The most common nonhematologic toxicities were sensory neuropathy and fatigue. The sensory neuropathy was cumulative over cycles of therapy and typically improved with cessation of NAB-paclitaxel. In the randomized phase III trial of NAB-paclitaxel in breast cancer patients, median time to improvement of grade 3 neuropathy was 22 days.3
More than 50% of lung cancer patients are diagnosed at age older than 65 years and approximately 30% are diagnosed at age older than 70 years.7,8 Optimal initial treatment of elderly patients with stage IV NSCLC is somewhat controversial.9 Patients age
Our single-institution results with NAB-paclitaxel compare favorably with initial small studies demonstrating the activity of solvent-based paclitaxel and docetaxel as a single agent in patients with previously untreated NSCLC, with a range of response rates between 10% and 38%,13-22 as well as with more recent work demonstrating a 17% response rate in previously untreated patients.23 Although not directly comparable to our small phase II trial, the largest experience with single-agent paclitaxel in chemotherapy-naïve NSCLC is from Cancer and Leukemia Group B trial 9730, in which patients were randomly assigned to single-agent paclitaxel 225 mg/m2 versus paclitaxel and carboplatin in combination.23 The median age was 63 years and the response rate was 17% for single-agent paclitaxel in this study. In addition, the median survival with single-agent paclitaxel in this study was 6.7 months. Notably, in Cancer and Leukemia Group B trial 9730, there was no significant difference in overall survival between patients treated with single-agent paclitaxel when compared with those treated with carboplatin and paclitaxel. The absence of a significant difference persisted in the prespecified subset analysis of patients The data from our study demonstrate that NAB-paclitaxel has significant single-agent activity in the treatment of NSCLC. With the reduced risk of hypersensitivity reactions reported with NAB-paclitaxel as compared with solvent-based paclitaxel, NAB-paclitaxel may play an important role in the treatment of NSCLC. This study demonstrated encouraging single-agent activity with weekly NAB-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days. Additional studies to evaluate the toxicity and efficacy of NAB-paclitaxel in platinum combination studies are warranted.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Michael J. Hawkins, Abraxis BioScience Leadership: N/A Consultant: N/A Stock: Michael J. Hawkins, Abraxis BioScience Honoraria: Gregory J. Riely, Abraxis BioScience Research Funds: Naiyer A. Rizvi, Abraxis BioScience; Gregory J. Riely, Abraxis BioScience; Christopher G. Azzoli, Abraxis BioScience; Vincent A. Miller, Abraxis BioScience; Kenneth K. Ng, Abraxis BioScience; John Fiore, Abraxis BioScience; Gloria Chia, Abraxis BioScience; Martin Brower, Abraxis BioScience; Robert Heelan, Abraxis BioScience; Mark G. Kris, Abraxis BioScience Testimony: N/A Other: N/A
Conception and design: Naiyer A. Rizvi, Michael J. Hawkins Financial support: Naiyer A. Rizvi, Michael J. Hawkins Administrative support: Naiyer A. Rizvi, Michael J. Hawkins, Mark G. Kris Provision of study materials or patients: Naiyer A. Rizvi, Christopher G. Azzoli, Vincent A. Miller, Kenneth K. Ng, John Fiore, Martin Brower, Michael J. Hawkins, Mark G. Kris Collection and assembly of data: Naiyer A. Rizvi, Gregory J. Riely, John Fiore, Gloria Chia, Robert Heelan, Michael J. Hawkins Data analysis and interpretation: Naiyer A. Rizvi, Gregory J. Riely, Vincent A. Miller, Gloria Chia, Robert Heelan, Mark G. Kris Manuscript writing: Naiyer A. Rizvi, Gregory J. Riely Final approval of manuscript: Naiyer A. Rizvi, Gregory J. Riely, Vincent A. Miller, Gloria Chia, Robert Heelan, Michael J. Hawkins, Mark G. Kris
Supported by Abraxis BioScience. Presented in part at the 42nd Annual Meeting of the American Society of Oncology, June 2-6, 2007, Atlanta, GA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
