Multicenter Phase II Trial of ABI-007, an Albumin-Bound Paclitaxel, in Women With Metastatic Breast Cancer
http://www.100md.com
《临床肿瘤学》
The University of Texas M.D. Anderson Cancer Center, Houston, TX
Lutheran General Cancer Center, Park Ridge, IL
The Center for Cancer and Blood Disorders, Fort Worth, TX
Rajiv Gandhi Cancer Institute, New Delhi, India
Gujarat Cancer Research Institute, Ahmedabad, India
MNJ Institute of Oncology, Hyderabad, India
Regional Cancer Center, Thiruvananthapuram, India
American BioScience Inc, Santa Monica, CA.
ABSTRACT
PURPOSE: ABI-007 is a novel nanoparticle, albumin-bound paclitaxel that is free of solvents. This multicenter phase II study was designed to evaluate the efficacy and safety of ABI-007 for the treatment of metastatic breast cancer (MBC).
PATIENTS AND METHODS: Sixty-three women with histologically confirmed and measurable MBC received 300 mg/m2 ABI-007 by intravenous infusion over 30 minutes every 3 weeks without premedication. Forty-eight patients received prior chemotherapy; 39 patients received no prior treatment for metastatic disease.
RESULTS: Overall response rates (complete or partial responses) were 48% (95% CI, 35.3% to 60.0%) for all patients. For patients who received ABI-007 as first-line and greater than first-line therapy for their metastatic disease, the respective response rates were 64% (95% CI, 49.0% to 79.2%) and 21% (95% CI, 7.1% to 42.1%). Median time to disease progression was 26.6 weeks, and median survival was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included grade 4 neutropenia (24%), grade 3 sensory neuropathy (11%), and grade 4 febrile neutropenia (5%). Patients received a median of six treatment cycles; 16 patients had 25% dose reductions because of toxicities, and two of these patients had subsequent dose reductions.
CONCLUSION: ABI-007, the first biologically interactive albumin-bound form of paclitaxel in the nanoparticle state, uses the natural carrier albumin rather than synthetic solvents to deliver paclitaxel and allows for safe administration of high paclitaxel doses without premedication, resulting in significant antitumor activity in patients with MBC, including those receiving the drug as first-line therapy.
INTRODUCTION
Breast cancer, the most common malignancy in women, continues to be a major health concern. Almost one third of all cancers in women are breast cancer, and the disease is expected to kill an estimated 40,110 women in the United States in 2004.1 Treatments for early-stage disease have improved survival, and improvements in chemotherapies have shown demonstrable benefit for women with metastatic breast cancer (MBC).2,3
Paclitaxel plays a central role in the treatment of MBC.4 However, its use is limited by its poor solubility and the toxicities associated with Cremophor EL (polyethoxylated castor oil), the lipid-based solvent used as a vehicle for Taxol (Bristol-Myers Squibb Co, Princeton, NJ) and its generic equivalents. Polyethoxylated castor oil leaches plasticizers from standard intravenous (IV) tubing and has been associated with histamine release, severe anaphylaxis, hyperlipidemia, abnormal lipoprotein patterns, aggregation of erythrocytes, and prolonged, sometimes irreversible sensory neuropathy.5-7 As a result, the administration of paclitaxel requires a large volume of IV fluid, a long infusion period (1 to 24 hours), special IV-infusion sets, in-line filters, and premedication with steroids and antihistamines to minimize the risk of hypersensitivity reactions.4 Despite these precautions, severe and even fatal hypersensitivity reactions still occur.8 In addition, polyethoxylated castor oil forms micelles in the plasma compartment that entrap paclitaxel, resulting in nonlinear pharmacokinetics for paclitaxel.9
ABI-007 (Abraxane; American BioScience Inc, Santa Monica, CA) is a polyethoxylated castor oil-free, albumin-bound paclitaxel that has been developed to address these limitations. This novel approach delivers paclitaxel as a suspension of albumin particles (average size, approximately 130 nm) in saline that allows for a shorter infusion duration (30 minutes) without special delivery apparatus and without steroid and antihistamine premedication for hypersensitivity reactions. The use of albumin as the delivery vehicle for paclitaxel has the potential to enhance drug transport into tumors by taking advantage of albumin receptor (gp60)-mediated transcytosis across endothelial cells.10
A phase I study of ABI-007, administered IV over 30 minutes every 3 weeks, established 300 mg/m2 as the maximum-tolerated dose (MTD),11 notably higher than the MTD for paclitaxel with the 3-week regimen (175 mg/m2). Dose-limiting toxicities were keratitis, blurred vision, sensory neuropathy, stomatitis, and grade 4 neutropenia. No severe hypersensitivity reactions were observed despite the absence of premedication. Maximum paclitaxel concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-) increased linearly for the ABI-007 dose range of 135 to 300 mg/m2 administered over 30 minutes. Cmax and AUC0- values for individual patients correlated well with toxicity.
The phase II study reported here explored the efficacy and safety of ABI-007 at the MTD of 300 mg/m2 in patients with MBC. The primary end point was tumor response rate. Secondary objectives were to evaluate time to disease progression (TTP), changes in quality of life from baseline, and survival and to assess the antitumor activity of ABI-007 monotherapy in anthracycline-naive versus anthracycline-exposed patients.
PATIENTS AND METHODS
The protocol and all related materials were approved by local institutional review boards or ethics committees. The study was conducted in compliance with Good Clinical Practice, guidelines of the International Conference on Harmonisation, and the Declaration of Helsinki. Written informed consent was required from all patients before participation. Case-report forms were submitted to the sponsor (American BioScience Inc), who reconciled the drug accountability logs with the patients enrolled at each site.
Patient Population
Nonpregnant women ( 18 years of age) were eligible for inclusion in the study. Patients had histologically or cytologically confirmed breast cancer (measurable bidimensionally) with evidence of recurrence or metastasis but no other malignancy except nonmelanoma skin cancer, cervical intraepithelial neoplasia, or in situ cervical cancer. Patients had expected survival of > 8 weeks with adequate hematologic, hepatic, and renal function. Patients were excluded from participation if they had clinical evidence of brain metastasis; serious concurrent illness; an Eastern Cooperative Oncology Group performance status of 2; sensory neuropathy grade 1; or received taxane chemotherapy within the previous 6 months, any other investigational drug within the previous 4 weeks, or anthracycline therapy within the previous 3 weeks. There were no restrictions on enrollment based on the number of prior chemotherapy regimens.
Treatment
ABI-007 was administered on an outpatient basis via 30-minute IV infusion at 300 mg/m2 (paclitaxel dose) without steroid or antihistamine premedication, granulocyte colony-stimulating factor support, specialized IV-infusion sets, or in-line filtration. Treatment was repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Dose reductions of 25% of the original dose (from 300 to 225 mg/m2) were required for grade 4 hematologic toxicity, neutropenic fever or sepsis, or grade 3 or 4 nonhematologic toxicity. If any of these adverse events (AEs) recurred after initial resolution and reinitiation of ABI-007 dosing, a second dose reduction to 50% of the initial dose was recommended for all subsequent cycles. Patients who experienced an additional recurrence of the dose-limiting AEs were withdrawn from the study.
Assessments
Target lesions were measured bidimensionally at baseline, at the end of every other chemotherapy cycle, and within 2 weeks of study discontinuation. The imaging method used for a given tumor at baseline was used consistently for that tumor throughout the study. Imaging for tumor reevaluation was limited to sites of preexisting metastasis identified at baseline or to new sites suspected to contain metastasis.
Target-lesion-response analyses were based on investigator evaluation of radiologically and clinically detected target lesions. Tumor responses were categorized according to WHO guidelines12: complete response (CR) was the disappearance of all clinical evidence of visible tumor; partial response (PR) was a 50% decrease in product of largest perpendicular diameters of measurable lesions; stable disease was not meeting the criteria for response or progressive disease; and progressive disease was unequivocal increase in size of any assessable, measurable lesion or appearance of a new lesion. Responses to treatment were confirmed by restaging 4 weeks after the initial documentation of response for CR and PR and 8 weeks for stable disease. Survival was assessed on a monthly basis for 3 months after study completion and every 3 months thereafter.
AEs were coded by using the Medical Dictionary for Drug Regulatory Affairs and further classified according to National Cancer Institute Common Toxicity Criteria. Because ocular toxicities were reported as dose-limiting toxicities in the phase I study, ophthalmologic examinations were conducted at baseline and after every two treatment cycles.
Statistical Methods
The primary efficacy end point was the percentage of patients in the intent-to-treat population who achieved a confirmed CR or PR. The study design incorporated Simon's optimal two-stage procedure for phase II clinical trials,13 which included an interim review of response rate after the first 12 enrolled patients had completed two treatment cycles. The treatment was to be considered a failure and the study terminated if one or less patient had achieved a CR or PR at this time. In contrast, the treatment was to be considered promising and additional patients were enrolled if two or more patients had achieved a CR or PR at this time. The success/failure criteria for the study were based on response rates of 30% to 40% for paclitaxel4 and another widely used taxane, docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Bridgewater, NJ),14 in anthracycline-treated patients with breast cancer. Based on these reports, a 30% target-lesion-response rate for ABI-007 monotherapy was considered a treatment success for this assessment, and a response rate 10% was considered a failure. All patients who received at least one dose of ABI-007 were included in the response and toxicity analyses. Time to first response, TTP, and survival were summarized by using Kaplan-Meier methods.15
RESULTS
Between October 1999 and May 2001, 63 patients were enrolled at seven sites (four in India, three in the United States). All patients were included in the safety and efficacy analyses. Baseline and disease characteristics are listed in Table 1. Eleven patients (17%) had been treated previously with taxanes: three in the adjuvant setting and eight for metastatic disease. Patients received a median of six cycles of ABI-007 treatment (Tables 2 and 3); 16 patients (25%) had dose reductions, primarily because of hematologic toxicities (see Safety). Of the dosing cycles that were delayed (21 of 321 [7%]), most were delayed 4 to 8 days.
Efficacy
Antitumor activity was noted with an overall response rate of 48% (95% CI, 35.3% to 60.0%; Table 4) and was the same regardless of whether WHO or Response Evaluation Criteria in Solid Tumors criteria were used. Complete responses were reported in two patients, and partial responses were reported in 28 patients. Maximum confirmed responses were observed most often at cycles 2 and 4. Response rates were higher among patients who had not received prior treatment for metastatic disease: 64% for patients who received ABI-007 as first-line therapy, compared with 21% for patients with prior chemotherapy for metastatic disease. Responses also were higher in patients with no prior exposure to anthracyclines compared with those who had been treated with anthracyclines (58% v 41%, respectively). The response rate for patients with dominant lesion sites that were visceral was 40%, whereas the response rate for those with nonvisceral lesions was 68%.
Median TTP was 26.6 weeks for all patients and 48.1 weeks for responding patients (confirmed CR or PR). Median overall survival was 63.6 weeks. The median Eastern Cooperative Oncology Group performance status and the Global Health Status (EORTC QLQ-C30) scores did not change from baseline to the final evaluation.
Safety
The most frequently reported toxicities were those expected for paclitaxel in this patient population. Treatment-related toxicities of any grade that occurred in > 20% of patients were alopecia, anemia, neutropenia, leukopenia, sensory neuropathy, fatigue, nausea, myalgia, infection, vomiting, and stomatitis/pharyngitis (Fig 1). Treatment-related grade 3 and 4 toxicities are listed in Table 5. Grade 4 neutropenia occurred in 24% of patients, primarily during the first treatment cycle, and was managed with dose reduction; febrile neutropenia occurred in three of these patients. Grade 3 neutropenia was noted in 27% of patients. Neutropenia generally was transient, asymptomatic, and isolated.
Grade 2 and 3 sensory neuropathy occurred in 12 (19%) and seven (11%) patients, respectively; no grade 4 neuropathy was reported. Episodes of myalgia typically were worse immediately after dosing, generally resolved before the next dosing, and did not result in premature discontinuation of treatment. No episodes of grade 4 myalgia were reported. No severe hypersensitivity reactions were noted despite the absence of premedication with steroids or antihistamines. Ocular/visual toxicities, which were dose-limiting toxicities in the phase I study, were noted in 15 patients (24%) and were mostly dry eye (eight patients) and blurred vision (six patients); no grade 3 or 4 events were noted. Fluid retention and nail changes were noted in three and two patients, respectively; no grade 3 or 4 events were noted.
Seven patients (11%) discontinued treatment prematurely because of AEs: five for sensory neuropathy (treatment related), one for extremity pain (unlikely related to study drug), and one for massive aspiration into the lung (unrelated to treatment). Sixteen patients (25%) required dose reductions for toxicities; toxicities resulting in a dose reduction for two or more patients were uncomplicated neutropenia (seven patients), sensory neuropathy (four patients), febrile neutropenia (three patients), myalgia (three patients), and fatigue (two patients).
Of the 321 treatment cycles administered, 21 (7%) were delayed in six patients to allow resolution of toxicities (neutropenia and urticaria; thrombocytopenia; thrombocytopenia and jaundice; sensory neuropathy; fever; blurred vision). One patient died as a result of possibly treatment-related cardiac ischemia/infarction, and one patient died as a result of massive aspiration into the lung (unrelated to treatment).
DISCUSSION
Preclinical studies demonstrated that penetration of paclitaxel into tumors was greater with ABI-007 than with solvent-based paclitaxel, resulting in superior antitumor activity for ABI-007 in athymic mice with human breast cancer.16,17 This phase II study confirmed that ABI-007 has significant antitumor activity in patients with MBC. The use of albumin as the carrier rather than polyethoxylated castor oil allows for doses of paclitaxel much higher than those achievable with paclitaxel and avoids the toxicities associated with synthetic solvents, as evidenced by the lack of hypersensitivity reactions in the absence of corticosteroid and antihistamine premedication. This albumin-based particle composition of paclitaxel is the first biologically interactive form of the drug with the potential to exploit a receptor-mediated pathway, allowing increased transport of albumin-bound paclitaxel from blood to tumor.18
The overall response rate (CR + PR) for ABI-007 at 300 mg/m2 on an every-3-weeks regimen was 48%. It is well recognized that patient selection can strongly influence the response rates seen in phase II trials. However, our data compare favorably with response rates reported for paclitaxel 250 mg/m2 administered as a 3-hour infusion (22% to 44%)19-21 or as a 24-hour infusion (54% to 62%).21-23 Of note is the high response rate (64%) in patients who received ABI-007 as first-line therapy for their metastatic disease. By comparison, phase III trials with other taxanes as first-line therapy established response rates to paclitaxel 175 or 200 mg/m2 of 26%24 and 25%,25 respectively, and 48% for Taxotere 100 mg/m2.26 In preclinical models, ABI-007 demonstrated greater antitumor activity than paclitaxel.27 These preclinical data and the demonstrated activity of ABI-007 in this trial were the basis for a randomized, comparative trial of ABI-007 versus paclitaxel in MBC.28
ABI-007-associated adverse effects were less frequent and less severe than would be expected for comparable doses of paclitaxel. In this study of ABI-007 at a dose of 300 mg/m2, the incidence of grades 3 and 4 neutropenia combined was 51%. In contrast, in a phase III study of paclitaxel 250 mg/m2, this incidence was 73% when administered as a 3-hour infusion and 81% when administered as a 24-hour infusion.21 Similarly, the incidence of grade 4 neutropenia in this study was 24%, which is less than half of the 57% seen in a phase III study of 250 mg/m2 paclitaxel19 and is comparable with the 28% incidence observed for the standard 175 mg/m2 dose of paclitaxel.4 The relatively low incidences of grade 4 neutropenia and related complications seen in this study are also striking in comparison with those noted for docetaxel; grade 4 neutropenia, neutropenic sepsis, and septic deaths occurred in 84%, 12%, and 1.5% of patients with MBC treated with a standard 100 mg/m2 dose of docetaxel, respectively.14 Similarly, the 11% incidence of grade 3 sensory neuropathy in this study at a dose of 300 mg/m2 compares favorably with that reported for paclitaxel 250 mg/m2 administered as a 3-hour (26% and 22%)19,21 or 24-hour (13%) infusion.21
Ocular toxicities (superficial keratopathy and blurred vision) were dose limiting in the phase I trial of ABI-007 at doses of 375 mg/m2, but severe ocular events were not observed in the current study despite careful ophthalmologic monitoring. The lack of severe ocular toxicity suggests that this toxicity either occurred by chance in the phase I study or was dose related and therefore problematic only when ABI-007 was administered at doses above the MTD. It has been reported that ocular disturbances were noted with paclitaxel administration at paclitaxel doses of 175 and 225 mg/m2 as a direct effect of the drug itself.29 Other common AEs seen in this study (eg, nausea, vomiting, fatigue, arthralgia, myalgia, alopecia) are well-recognized, taxane-associated toxicities and were usually self-limited or easily managed by using standard approaches. Nail changes and fluid retention were uncommon.
ABI-007 was initially developed to avoid the toxicities associated with polyethoxylated castor oil that limit the paclitaxel dose that may be administered safely. In preclinical studies, ABI-007 could be administered at a paclitaxel dose approximately 50% higher than paclitaxel and did not result in hypersensitivity reactions. Consistent with these findings, the phase I trial of ABI-00711 showed that the MTD of ABI-007 administered every 3 weeks with a 30-minute infusion was 300 mg/m2, approximately 70% higher than that of paclitaxel.4 Hypersensitivity reactions did not occur despite the absence of corticosteroid and antihistamine premedication, and administration occurred over 30 minutes without specialized IV-infusion sets or in-line filters. The phase II study reported here further confirms the advantages of removing polyethoxylated castor oil. In addition, the relatively low incidence of neutropenic toxicities supports the suggestion that polyethoxylated castor oil increases the myelosuppression of chemotherapeutic agents that are MDR1 substrates (eg, paclitaxel) by inhibiting the MDR1 gene product (p-glycoprotein) in hematopoietic cells.30
The significant antitumor activity of ABI-007 and favorable safety profile may be related not only to the absence of polyethylated castor oil but also to the choice of albumin as the formulation vehicle. Albumin is the natural carrier of lipophilic molecules (eg, paclitaxel) in humans. Albumin-bound macromolecules are actively transported across microvascular endothelial cells (transcytosis) and into tumor tissues via a specific pathway that is activated by albumin binding to its specific receptor, gp60 (also known as albondin). Binding of albumin to gp60 on the endothelial-cell membrane triggers the formation of vesicles (caveolae) to initiate the transcytosis pathway.31,32 The master regulator of signaling molecules in caveolae seems to be caveolin-1,33 which shows elevated expression in a variety of neoplasms including breast,34 lung,35 and prostate cancer.34 Transcytosis of paclitaxel is inhibited by polyethoxylated castor oil.18 ABI-007, a polyethoxylated castor oil-free, albumin-bound paclitaxel, thus may optimize drug delivery to tumors via receptor-activated transcytosis in addition to exploiting other differences between tumor and normal tissues such as the increased neovasculature, capillary leakage, and decreased/absent lymphatic drainage that are associated with enhanced penetration and retention of albumin-bound paclitaxel in tumor tissue. This hypothesis is supported by preclinical data showing preferential tumor targeting with ABI-007: selectively increased intratumor paclitaxel levels were achieved with ABI-007 compared with paclitaxel in animal models of breast cancer.18 Higher intratumor drug concentrations would be expected to result in higher efficacy. Indeed, preliminary results of an ongoing phase III trial in women with MBC comparing every-3-weeks regimens of 260 mg/m2 ABI-007 to 175 mg/m2 paclitaxel indicates that ABI-007 has efficacy superior to that of paclitaxel as assessed by tumor response rate and TTP.28
Although additional clinical trials are required to define the role of ABI-007 in the treatment of breast cancer, the study reported here demonstrates that paclitaxel administered in a matrix of albumin without solvents has significant antitumor activity with a favorable safety profile. ABI-007, a novel formulation of albumin-bound paclitaxel, may offer patients a number of advantages over existing taxanes. No premedication with corticosteroids, prolonged infusions, or special IV-infusion sets are required with ABI-007, thereby facilitating drug administration and improving patient acceptance. ABI-007 allows for doses of paclitaxel higher than those achievable with paclitaxel without compromising patients' quality of life. The relatively low incidence of neutropenia makes ABI-007 a candidate for combinations with other chemotherapeutic agents or for use in dose-dense treatment regimens.
Authors' Disclosures of Potential Conflicts of Interest
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.
Acknowledgment
We acknowledge Susan A. Thomas and Aaron Van Etten for assistance in preparing this manuscript.
NOTES
Sponsored by American BioScience, Inc, Santa Monica, CA.
Presented in part at the 25th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 11–14, 2002; and the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–21, 2002.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Lutheran General Cancer Center, Park Ridge, IL
The Center for Cancer and Blood Disorders, Fort Worth, TX
Rajiv Gandhi Cancer Institute, New Delhi, India
Gujarat Cancer Research Institute, Ahmedabad, India
MNJ Institute of Oncology, Hyderabad, India
Regional Cancer Center, Thiruvananthapuram, India
American BioScience Inc, Santa Monica, CA.
ABSTRACT
PURPOSE: ABI-007 is a novel nanoparticle, albumin-bound paclitaxel that is free of solvents. This multicenter phase II study was designed to evaluate the efficacy and safety of ABI-007 for the treatment of metastatic breast cancer (MBC).
PATIENTS AND METHODS: Sixty-three women with histologically confirmed and measurable MBC received 300 mg/m2 ABI-007 by intravenous infusion over 30 minutes every 3 weeks without premedication. Forty-eight patients received prior chemotherapy; 39 patients received no prior treatment for metastatic disease.
RESULTS: Overall response rates (complete or partial responses) were 48% (95% CI, 35.3% to 60.0%) for all patients. For patients who received ABI-007 as first-line and greater than first-line therapy for their metastatic disease, the respective response rates were 64% (95% CI, 49.0% to 79.2%) and 21% (95% CI, 7.1% to 42.1%). Median time to disease progression was 26.6 weeks, and median survival was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included grade 4 neutropenia (24%), grade 3 sensory neuropathy (11%), and grade 4 febrile neutropenia (5%). Patients received a median of six treatment cycles; 16 patients had 25% dose reductions because of toxicities, and two of these patients had subsequent dose reductions.
CONCLUSION: ABI-007, the first biologically interactive albumin-bound form of paclitaxel in the nanoparticle state, uses the natural carrier albumin rather than synthetic solvents to deliver paclitaxel and allows for safe administration of high paclitaxel doses without premedication, resulting in significant antitumor activity in patients with MBC, including those receiving the drug as first-line therapy.
INTRODUCTION
Breast cancer, the most common malignancy in women, continues to be a major health concern. Almost one third of all cancers in women are breast cancer, and the disease is expected to kill an estimated 40,110 women in the United States in 2004.1 Treatments for early-stage disease have improved survival, and improvements in chemotherapies have shown demonstrable benefit for women with metastatic breast cancer (MBC).2,3
Paclitaxel plays a central role in the treatment of MBC.4 However, its use is limited by its poor solubility and the toxicities associated with Cremophor EL (polyethoxylated castor oil), the lipid-based solvent used as a vehicle for Taxol (Bristol-Myers Squibb Co, Princeton, NJ) and its generic equivalents. Polyethoxylated castor oil leaches plasticizers from standard intravenous (IV) tubing and has been associated with histamine release, severe anaphylaxis, hyperlipidemia, abnormal lipoprotein patterns, aggregation of erythrocytes, and prolonged, sometimes irreversible sensory neuropathy.5-7 As a result, the administration of paclitaxel requires a large volume of IV fluid, a long infusion period (1 to 24 hours), special IV-infusion sets, in-line filters, and premedication with steroids and antihistamines to minimize the risk of hypersensitivity reactions.4 Despite these precautions, severe and even fatal hypersensitivity reactions still occur.8 In addition, polyethoxylated castor oil forms micelles in the plasma compartment that entrap paclitaxel, resulting in nonlinear pharmacokinetics for paclitaxel.9
ABI-007 (Abraxane; American BioScience Inc, Santa Monica, CA) is a polyethoxylated castor oil-free, albumin-bound paclitaxel that has been developed to address these limitations. This novel approach delivers paclitaxel as a suspension of albumin particles (average size, approximately 130 nm) in saline that allows for a shorter infusion duration (30 minutes) without special delivery apparatus and without steroid and antihistamine premedication for hypersensitivity reactions. The use of albumin as the delivery vehicle for paclitaxel has the potential to enhance drug transport into tumors by taking advantage of albumin receptor (gp60)-mediated transcytosis across endothelial cells.10
A phase I study of ABI-007, administered IV over 30 minutes every 3 weeks, established 300 mg/m2 as the maximum-tolerated dose (MTD),11 notably higher than the MTD for paclitaxel with the 3-week regimen (175 mg/m2). Dose-limiting toxicities were keratitis, blurred vision, sensory neuropathy, stomatitis, and grade 4 neutropenia. No severe hypersensitivity reactions were observed despite the absence of premedication. Maximum paclitaxel concentration (Cmax) and area under the concentration-time curve from time zero to infinity (AUC0-) increased linearly for the ABI-007 dose range of 135 to 300 mg/m2 administered over 30 minutes. Cmax and AUC0- values for individual patients correlated well with toxicity.
The phase II study reported here explored the efficacy and safety of ABI-007 at the MTD of 300 mg/m2 in patients with MBC. The primary end point was tumor response rate. Secondary objectives were to evaluate time to disease progression (TTP), changes in quality of life from baseline, and survival and to assess the antitumor activity of ABI-007 monotherapy in anthracycline-naive versus anthracycline-exposed patients.
PATIENTS AND METHODS
The protocol and all related materials were approved by local institutional review boards or ethics committees. The study was conducted in compliance with Good Clinical Practice, guidelines of the International Conference on Harmonisation, and the Declaration of Helsinki. Written informed consent was required from all patients before participation. Case-report forms were submitted to the sponsor (American BioScience Inc), who reconciled the drug accountability logs with the patients enrolled at each site.
Patient Population
Nonpregnant women ( 18 years of age) were eligible for inclusion in the study. Patients had histologically or cytologically confirmed breast cancer (measurable bidimensionally) with evidence of recurrence or metastasis but no other malignancy except nonmelanoma skin cancer, cervical intraepithelial neoplasia, or in situ cervical cancer. Patients had expected survival of > 8 weeks with adequate hematologic, hepatic, and renal function. Patients were excluded from participation if they had clinical evidence of brain metastasis; serious concurrent illness; an Eastern Cooperative Oncology Group performance status of 2; sensory neuropathy grade 1; or received taxane chemotherapy within the previous 6 months, any other investigational drug within the previous 4 weeks, or anthracycline therapy within the previous 3 weeks. There were no restrictions on enrollment based on the number of prior chemotherapy regimens.
Treatment
ABI-007 was administered on an outpatient basis via 30-minute IV infusion at 300 mg/m2 (paclitaxel dose) without steroid or antihistamine premedication, granulocyte colony-stimulating factor support, specialized IV-infusion sets, or in-line filtration. Treatment was repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Dose reductions of 25% of the original dose (from 300 to 225 mg/m2) were required for grade 4 hematologic toxicity, neutropenic fever or sepsis, or grade 3 or 4 nonhematologic toxicity. If any of these adverse events (AEs) recurred after initial resolution and reinitiation of ABI-007 dosing, a second dose reduction to 50% of the initial dose was recommended for all subsequent cycles. Patients who experienced an additional recurrence of the dose-limiting AEs were withdrawn from the study.
Assessments
Target lesions were measured bidimensionally at baseline, at the end of every other chemotherapy cycle, and within 2 weeks of study discontinuation. The imaging method used for a given tumor at baseline was used consistently for that tumor throughout the study. Imaging for tumor reevaluation was limited to sites of preexisting metastasis identified at baseline or to new sites suspected to contain metastasis.
Target-lesion-response analyses were based on investigator evaluation of radiologically and clinically detected target lesions. Tumor responses were categorized according to WHO guidelines12: complete response (CR) was the disappearance of all clinical evidence of visible tumor; partial response (PR) was a 50% decrease in product of largest perpendicular diameters of measurable lesions; stable disease was not meeting the criteria for response or progressive disease; and progressive disease was unequivocal increase in size of any assessable, measurable lesion or appearance of a new lesion. Responses to treatment were confirmed by restaging 4 weeks after the initial documentation of response for CR and PR and 8 weeks for stable disease. Survival was assessed on a monthly basis for 3 months after study completion and every 3 months thereafter.
AEs were coded by using the Medical Dictionary for Drug Regulatory Affairs and further classified according to National Cancer Institute Common Toxicity Criteria. Because ocular toxicities were reported as dose-limiting toxicities in the phase I study, ophthalmologic examinations were conducted at baseline and after every two treatment cycles.
Statistical Methods
The primary efficacy end point was the percentage of patients in the intent-to-treat population who achieved a confirmed CR or PR. The study design incorporated Simon's optimal two-stage procedure for phase II clinical trials,13 which included an interim review of response rate after the first 12 enrolled patients had completed two treatment cycles. The treatment was to be considered a failure and the study terminated if one or less patient had achieved a CR or PR at this time. In contrast, the treatment was to be considered promising and additional patients were enrolled if two or more patients had achieved a CR or PR at this time. The success/failure criteria for the study were based on response rates of 30% to 40% for paclitaxel4 and another widely used taxane, docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Bridgewater, NJ),14 in anthracycline-treated patients with breast cancer. Based on these reports, a 30% target-lesion-response rate for ABI-007 monotherapy was considered a treatment success for this assessment, and a response rate 10% was considered a failure. All patients who received at least one dose of ABI-007 were included in the response and toxicity analyses. Time to first response, TTP, and survival were summarized by using Kaplan-Meier methods.15
RESULTS
Between October 1999 and May 2001, 63 patients were enrolled at seven sites (four in India, three in the United States). All patients were included in the safety and efficacy analyses. Baseline and disease characteristics are listed in Table 1. Eleven patients (17%) had been treated previously with taxanes: three in the adjuvant setting and eight for metastatic disease. Patients received a median of six cycles of ABI-007 treatment (Tables 2 and 3); 16 patients (25%) had dose reductions, primarily because of hematologic toxicities (see Safety). Of the dosing cycles that were delayed (21 of 321 [7%]), most were delayed 4 to 8 days.
Efficacy
Antitumor activity was noted with an overall response rate of 48% (95% CI, 35.3% to 60.0%; Table 4) and was the same regardless of whether WHO or Response Evaluation Criteria in Solid Tumors criteria were used. Complete responses were reported in two patients, and partial responses were reported in 28 patients. Maximum confirmed responses were observed most often at cycles 2 and 4. Response rates were higher among patients who had not received prior treatment for metastatic disease: 64% for patients who received ABI-007 as first-line therapy, compared with 21% for patients with prior chemotherapy for metastatic disease. Responses also were higher in patients with no prior exposure to anthracyclines compared with those who had been treated with anthracyclines (58% v 41%, respectively). The response rate for patients with dominant lesion sites that were visceral was 40%, whereas the response rate for those with nonvisceral lesions was 68%.
Median TTP was 26.6 weeks for all patients and 48.1 weeks for responding patients (confirmed CR or PR). Median overall survival was 63.6 weeks. The median Eastern Cooperative Oncology Group performance status and the Global Health Status (EORTC QLQ-C30) scores did not change from baseline to the final evaluation.
Safety
The most frequently reported toxicities were those expected for paclitaxel in this patient population. Treatment-related toxicities of any grade that occurred in > 20% of patients were alopecia, anemia, neutropenia, leukopenia, sensory neuropathy, fatigue, nausea, myalgia, infection, vomiting, and stomatitis/pharyngitis (Fig 1). Treatment-related grade 3 and 4 toxicities are listed in Table 5. Grade 4 neutropenia occurred in 24% of patients, primarily during the first treatment cycle, and was managed with dose reduction; febrile neutropenia occurred in three of these patients. Grade 3 neutropenia was noted in 27% of patients. Neutropenia generally was transient, asymptomatic, and isolated.
Grade 2 and 3 sensory neuropathy occurred in 12 (19%) and seven (11%) patients, respectively; no grade 4 neuropathy was reported. Episodes of myalgia typically were worse immediately after dosing, generally resolved before the next dosing, and did not result in premature discontinuation of treatment. No episodes of grade 4 myalgia were reported. No severe hypersensitivity reactions were noted despite the absence of premedication with steroids or antihistamines. Ocular/visual toxicities, which were dose-limiting toxicities in the phase I study, were noted in 15 patients (24%) and were mostly dry eye (eight patients) and blurred vision (six patients); no grade 3 or 4 events were noted. Fluid retention and nail changes were noted in three and two patients, respectively; no grade 3 or 4 events were noted.
Seven patients (11%) discontinued treatment prematurely because of AEs: five for sensory neuropathy (treatment related), one for extremity pain (unlikely related to study drug), and one for massive aspiration into the lung (unrelated to treatment). Sixteen patients (25%) required dose reductions for toxicities; toxicities resulting in a dose reduction for two or more patients were uncomplicated neutropenia (seven patients), sensory neuropathy (four patients), febrile neutropenia (three patients), myalgia (three patients), and fatigue (two patients).
Of the 321 treatment cycles administered, 21 (7%) were delayed in six patients to allow resolution of toxicities (neutropenia and urticaria; thrombocytopenia; thrombocytopenia and jaundice; sensory neuropathy; fever; blurred vision). One patient died as a result of possibly treatment-related cardiac ischemia/infarction, and one patient died as a result of massive aspiration into the lung (unrelated to treatment).
DISCUSSION
Preclinical studies demonstrated that penetration of paclitaxel into tumors was greater with ABI-007 than with solvent-based paclitaxel, resulting in superior antitumor activity for ABI-007 in athymic mice with human breast cancer.16,17 This phase II study confirmed that ABI-007 has significant antitumor activity in patients with MBC. The use of albumin as the carrier rather than polyethoxylated castor oil allows for doses of paclitaxel much higher than those achievable with paclitaxel and avoids the toxicities associated with synthetic solvents, as evidenced by the lack of hypersensitivity reactions in the absence of corticosteroid and antihistamine premedication. This albumin-based particle composition of paclitaxel is the first biologically interactive form of the drug with the potential to exploit a receptor-mediated pathway, allowing increased transport of albumin-bound paclitaxel from blood to tumor.18
The overall response rate (CR + PR) for ABI-007 at 300 mg/m2 on an every-3-weeks regimen was 48%. It is well recognized that patient selection can strongly influence the response rates seen in phase II trials. However, our data compare favorably with response rates reported for paclitaxel 250 mg/m2 administered as a 3-hour infusion (22% to 44%)19-21 or as a 24-hour infusion (54% to 62%).21-23 Of note is the high response rate (64%) in patients who received ABI-007 as first-line therapy for their metastatic disease. By comparison, phase III trials with other taxanes as first-line therapy established response rates to paclitaxel 175 or 200 mg/m2 of 26%24 and 25%,25 respectively, and 48% for Taxotere 100 mg/m2.26 In preclinical models, ABI-007 demonstrated greater antitumor activity than paclitaxel.27 These preclinical data and the demonstrated activity of ABI-007 in this trial were the basis for a randomized, comparative trial of ABI-007 versus paclitaxel in MBC.28
ABI-007-associated adverse effects were less frequent and less severe than would be expected for comparable doses of paclitaxel. In this study of ABI-007 at a dose of 300 mg/m2, the incidence of grades 3 and 4 neutropenia combined was 51%. In contrast, in a phase III study of paclitaxel 250 mg/m2, this incidence was 73% when administered as a 3-hour infusion and 81% when administered as a 24-hour infusion.21 Similarly, the incidence of grade 4 neutropenia in this study was 24%, which is less than half of the 57% seen in a phase III study of 250 mg/m2 paclitaxel19 and is comparable with the 28% incidence observed for the standard 175 mg/m2 dose of paclitaxel.4 The relatively low incidences of grade 4 neutropenia and related complications seen in this study are also striking in comparison with those noted for docetaxel; grade 4 neutropenia, neutropenic sepsis, and septic deaths occurred in 84%, 12%, and 1.5% of patients with MBC treated with a standard 100 mg/m2 dose of docetaxel, respectively.14 Similarly, the 11% incidence of grade 3 sensory neuropathy in this study at a dose of 300 mg/m2 compares favorably with that reported for paclitaxel 250 mg/m2 administered as a 3-hour (26% and 22%)19,21 or 24-hour (13%) infusion.21
Ocular toxicities (superficial keratopathy and blurred vision) were dose limiting in the phase I trial of ABI-007 at doses of 375 mg/m2, but severe ocular events were not observed in the current study despite careful ophthalmologic monitoring. The lack of severe ocular toxicity suggests that this toxicity either occurred by chance in the phase I study or was dose related and therefore problematic only when ABI-007 was administered at doses above the MTD. It has been reported that ocular disturbances were noted with paclitaxel administration at paclitaxel doses of 175 and 225 mg/m2 as a direct effect of the drug itself.29 Other common AEs seen in this study (eg, nausea, vomiting, fatigue, arthralgia, myalgia, alopecia) are well-recognized, taxane-associated toxicities and were usually self-limited or easily managed by using standard approaches. Nail changes and fluid retention were uncommon.
ABI-007 was initially developed to avoid the toxicities associated with polyethoxylated castor oil that limit the paclitaxel dose that may be administered safely. In preclinical studies, ABI-007 could be administered at a paclitaxel dose approximately 50% higher than paclitaxel and did not result in hypersensitivity reactions. Consistent with these findings, the phase I trial of ABI-00711 showed that the MTD of ABI-007 administered every 3 weeks with a 30-minute infusion was 300 mg/m2, approximately 70% higher than that of paclitaxel.4 Hypersensitivity reactions did not occur despite the absence of corticosteroid and antihistamine premedication, and administration occurred over 30 minutes without specialized IV-infusion sets or in-line filters. The phase II study reported here further confirms the advantages of removing polyethoxylated castor oil. In addition, the relatively low incidence of neutropenic toxicities supports the suggestion that polyethoxylated castor oil increases the myelosuppression of chemotherapeutic agents that are MDR1 substrates (eg, paclitaxel) by inhibiting the MDR1 gene product (p-glycoprotein) in hematopoietic cells.30
The significant antitumor activity of ABI-007 and favorable safety profile may be related not only to the absence of polyethylated castor oil but also to the choice of albumin as the formulation vehicle. Albumin is the natural carrier of lipophilic molecules (eg, paclitaxel) in humans. Albumin-bound macromolecules are actively transported across microvascular endothelial cells (transcytosis) and into tumor tissues via a specific pathway that is activated by albumin binding to its specific receptor, gp60 (also known as albondin). Binding of albumin to gp60 on the endothelial-cell membrane triggers the formation of vesicles (caveolae) to initiate the transcytosis pathway.31,32 The master regulator of signaling molecules in caveolae seems to be caveolin-1,33 which shows elevated expression in a variety of neoplasms including breast,34 lung,35 and prostate cancer.34 Transcytosis of paclitaxel is inhibited by polyethoxylated castor oil.18 ABI-007, a polyethoxylated castor oil-free, albumin-bound paclitaxel, thus may optimize drug delivery to tumors via receptor-activated transcytosis in addition to exploiting other differences between tumor and normal tissues such as the increased neovasculature, capillary leakage, and decreased/absent lymphatic drainage that are associated with enhanced penetration and retention of albumin-bound paclitaxel in tumor tissue. This hypothesis is supported by preclinical data showing preferential tumor targeting with ABI-007: selectively increased intratumor paclitaxel levels were achieved with ABI-007 compared with paclitaxel in animal models of breast cancer.18 Higher intratumor drug concentrations would be expected to result in higher efficacy. Indeed, preliminary results of an ongoing phase III trial in women with MBC comparing every-3-weeks regimens of 260 mg/m2 ABI-007 to 175 mg/m2 paclitaxel indicates that ABI-007 has efficacy superior to that of paclitaxel as assessed by tumor response rate and TTP.28
Although additional clinical trials are required to define the role of ABI-007 in the treatment of breast cancer, the study reported here demonstrates that paclitaxel administered in a matrix of albumin without solvents has significant antitumor activity with a favorable safety profile. ABI-007, a novel formulation of albumin-bound paclitaxel, may offer patients a number of advantages over existing taxanes. No premedication with corticosteroids, prolonged infusions, or special IV-infusion sets are required with ABI-007, thereby facilitating drug administration and improving patient acceptance. ABI-007 allows for doses of paclitaxel higher than those achievable with paclitaxel without compromising patients' quality of life. The relatively low incidence of neutropenia makes ABI-007 a candidate for combinations with other chemotherapeutic agents or for use in dose-dense treatment regimens.
Authors' Disclosures of Potential Conflicts of Interest
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.
Acknowledgment
We acknowledge Susan A. Thomas and Aaron Van Etten for assistance in preparing this manuscript.
NOTES
Sponsored by American BioScience, Inc, Santa Monica, CA.
Presented in part at the 25th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 11–14, 2002; and the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–21, 2002.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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