Nanoparticle Albumin-bound Paclitaxel: a Novel Cremphor-EL®-free Formulation of Paclitaxel

Thomas E Stinchcombe

Disclosures

Nanomedicine. 2007;2(4):415-423. 

In This Article

Pharmacodynamics

CrEL may also influence the efficacy of paclitaxel. Some preclinical data have indicated that CrEL may adversely impact the efficacy of paclitaxel by causing cell cycle arrest when administered at therapeutic concentrations, while other research has suggested that CrEL may enhance the efficacy of paclitaxel.[17,18] Previously, the influence of CrEL on paclitaxel efficacy was not investigated owing to the fact that there were no alternative paclitaxel formulations available. With the development of nab-paclitaxel and other novel taxane formulations, the potential influence of the CrEL on efficacy has been an area of active investigation. A recent study compared nab-paclitaxel versus CrEL-paclitaxel in animal models.[6] This study found at an equitoxic dose that the nab-paclitaxel-treated group had more complete regressions, longer time to recurrence, longer doubling time and prolonged survival. Following equal doses of nab- and CrEL-paclitaxel, the intratumor accumulation and the tumor AUC of paclitaxel was significantly higher for nab-paclitaxel than for CrEL-paclitaxel.

Tumoral transportation of albumin may have contributed to the difference in paclitaxel concentration. Transendothelial cell transportation of albumin is mediated by the gp60 receptor and caveolar transport mechanisms.[6,19,20,21,22] Albumin binding to gp60 activates caveolin-1, which results in the formation of caveoli, which transports albumin across the endothelial to the interstitial space.[22] The endothelial binding of paclitaxel increased 9.9-fold (p < 0.0001) and transport of paclitaxel across the endothelial cell monolayer increased 4.2-fold (p < 0.0001) with nab-paclitaxel in comparison with CrEL-paclitaxel. The endothelial transcytosis of nab-paclitaxel was completely suppressed by β-methyl cyclodextrin, an inhibitor of caveolar-mediated transcytosis. The matricellular protein secreted protein, acidic and rich in cysteine (SPARC; osteonectin) that binds albumin may also contribute to the higher intratumoral concentration of nab-paclitaxel.[21] SPARC has been associated with a poor prognosis in multiple tumors, including squamous cell cancer of the head and neck, NSCLC and breast cancer.[23,24,25] The incidence of SPARC overexpression and the role SPARC may have in the increased intratumoral uptake or sequestration of nab-paclitaxel is an area of active investigation in various malignancies.

Within the field of oncology, there has been increasing interest in the development of ‘metronomic chemotherapy', which is generally defined as frequent administration of chemotherapy agents at close regular intervals with no prolonged breaks over long periods of time. This treatment schedule reduces the toxicity of the treatment and may increase the anti-angiogenic activity of the therapy.[26] There is interest in developing paclitaxel-based therapy on a metronomic schedule; however, clinically relevant concentrations of CrEL have previously been reported to nullify the anti-angiogneic activity of paclitaxel.[27] Thus, the CrEL formulation may reduce the efficacy of paclitaxel in metronomic therapy and the nab-paclitaxel formulation may alleviate this problem. The antitumor effects of the metronomic and maximum tolerated dose (MTD) of nab- and CrEL-paclitaxel were evaluated and compared in xenograft animal models.[28] Metronomic nab-paclitaxel, but not CrEL-paclitaxel, significantly suppressed tumor growth in xenograft models. The antitumor effect of the minimally toxic metronomic nab-paclitaxel dose approximated that of the MTD of CrEL-paclitaxel. These preclinical data support the investigation of nab-paclitaxel on a ‘metronomic' schedule.

Clinical Efficacy: Single-agent Clinical Trials

Phase I Trials. A Phase I trial of nab-paclitaxel every 3 weeks was performed in patients with metastatic melanoma and breast cancer.[11] The doses investigated were 135, 200, 300 and 375 mg/m2, and the MTD was 300 mg/m2. The dose-limiting toxicities (DLTs) were sensory neuropathy (n = 3), stomatitis (n = 2) and superficial keratopathy (n = 2). The hematological toxicity was limited and, of the 96 treatment cycles administered, only seven (7.3%) resulted in a grade 4 neutropenia, six of which were at a dose above the MTD. Pharmacokinetic analysis revealed that the Cmaxand the AUC values increased linearly over nab-paclitaxel doses of 135-300 mg/m2.

A Phase I trial of nab-paclitaxel on a weekly schedule of days 1, 8 and 15 every 28 days in 39 patients with multiple different types of tumors was performed.[29] Doses of 80, 100, 125, 150, 175 and 200 mg/m2 were investigated in lightly pretreated and heavily pretreated patients (defined as one or more of the following: at least six cycles of alkylating agent, more than two cycles of carboplatin or mitomycin, irradiation to greater than 25% of the bone marrow, treatment with nitrosoureas, high-dose therapy requiring bone marrow or stem cell support and greater than one cycle of investigational agent known to cause a cumulative toxicity). This trial found the MTD was 100 mg/m2 for heavily pretreated and 150 mg/m2 for lightly pretreated patients. The DLTs were sensory neuropathy and grade 4 neutropenia. Patients did not receive premedications for hypersensitivity on either trial and no episodes of hypersensitivity reactions were observed.

Phase II Trials. A Phase II clinical trial that investigated the activity and toxicity of nab-paclitaxel 300 mg/m2 every 3 weeks was performed in 63 patients with metastatic breast cancer.[30] Patients received a median of six cycles of therapy and the primary toxicities were grade 4 neutropenia (24%), grade 3 sensory neuropathy (11%) and grade 4 febrile neutropenia (5%). The overall response rate was 48% (95% confidence interval [CI]: 35.3-60%) and the response rate for patients receiving first-line therapy was 64% (95% CI: 49.0-79.2%). For patients receiving greater than first-line therapy the response rate was 21% (95% CI: 7.1-42.1%). The median time to disease progression was 26.6 weeks and the median survival was 63.6 weeks. A second Phase II clinical trial investigated the activity of nab-paclitaxel 100 mg/m2 days 1, 8 and 15 every 28 days in 55 patients with taxane-refractory metastatic breast cancer.[31] On interim analysis, 28 patients were evalauble for response and the partial response rate was 18% (95% CI: 6-37%). Responses were seen in patients previously treated with paclitaxel, docetaxel and both agents. The activity of nab-paclitaxel in taxane-refractory breast cancer patients is intriguing.

A Phase II trial investigated the activity of nab-paclitaxel (260 mg/m2) every 3 weeks in advanced NSCLC.[32] A total of 43 patients were enrolled, the overall response rate was 16% (95% CI: 5.24-27.3%) and the overall disease control rate (complete plus partial responses plus stable disease) was 48% (95% CI: 33.9-63.8%). The median time to tumor progression was 6 months and the median survival was 11 months. The treatment was well tolerated; no grade 4 toxicities were observed, and 95% of patients were treated without a dose reduction. Two patients discontinued therapy owing to treatment-related toxicities (sensory neuropathy [n = 1] and fatigue [n = 1]).

A Phase I/II trial in advanced NSCLC investigated nab-paclitaxel on days 1, 8 and 15 every 28 days in patients with advanced NSCLC.[33] In the Phase I part of the study, the MTD was determined to be 125 mg/m2, and an additional 40 patients were enrolled at this dose level. The overall response rate was 38% and the median survival was 10.3 months. These single-agent trials demonstrate significant single-agent activity for nab-paclitaxel in advanced NSCLC.

Phase III Trial. A multinational Phase III clinical trial compared the activity and toxicity of nab- with CrEL-paclitaxel in 454 patients with metastatic breast cancer and measurable disease.[34] Patients were randomized to nab-paclitaxel (260 mg/m2 over 30 min) or CrEL-paclitaxel (175 mg/m2 over 3 h) every 3 weeks. Patients receiving CrEL-paclitaxel received premedication with corticosteroids and antihistamines, while no premedication was administered with the nab-paclitaxel. Patients receiving nab-paclitaxel had a statistically significant higher response rate and time to tumor progression ( Table 1 ). A statistically significant higher response rate was seen across multiple different patient subgroups (e.g., age <65 years, visceral dominant metastases, prior adjuvant and/or metastatic anthracycline therapy, prior anthracycline therapy only in metastatic setting, first-line metastatic patients or at least second-line metastatic patients) on subset analysis. There was no difference in median survival for all patients; however, for patients receiving second-line or greater, the median survival was statistically significantly longer on the nab-paclitaxel treatment arm ( Table 1 ).

No grade 3 or 4 hypersensitivity reactions were seen with nab-paclitaxel, despite the absence of premedication. Grade 3 sensory neuropathy was more common in the nab-paclitaxel than CrEL-paclitaxel arm (10 vs 2%, respectively; p < 0.001). Dose interruption and reduction resulted in a rapid improvement of neuropathy to grade 1 or 2 (median time 22 days) and patients could resume treatment at a lower dose. The rate of grade 4 neutropenia was significantly lower for nab- than CrEL-paclitaxel (9 vs 22%, respectively; p < 0.001), despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (<2%) in both study groups. No differences in patients' quality of life were detected between the two treatment arms.

This trial also confirmed the preclinical studies that the use of the nab-paclitaxel formulation could result in clinically relevant improvements in the toxicity and the efficacy of paclitaxel therapy.

Combination Trials

The combination of carboplatin and CrEL-paclitaxel is a standard therapy for NSCLC, ovarian cancer and metastatic breast cancer.[10,35,36] The combination of nab-paclitaxel and carboplatin may have a lower rate of toxicity and/or improved efficacy than carboplatin and CrEL-paclitaxel. Nab-paclitaxel and CrEL-paclitaxel have significant differences in the toxicity and standard doses, and there is the potential for the combination of nab-paclitaxel and carboplatin to have additive toxicities. Therefore, a Phase I trial was conducted to determine the MTD of nab-paclitaxel on three different treatment schedules in combination with carboplatin.[37] Patients on all three treatment schedules received carboplatin AUC 6 using the Calvert equation[38] on day 1, and patients received nab-paclitaxel on three different schedules:

  • Schedule A: day 1 every 21 days

  • Schedule B: days 1, 8 and 15 every 28

  • Schedule C: days 1 and 8 every 21 days

The MTD of nab-paclitaxel in combination with carboplatin was 300, 100, 125 mg/m2 on schedules A, B and C, respectively. Myelosuppression was the primary DLT.

The activity and toxicity of this combination were investigated in a cohort dose-escalation trial in chemotherapy-naive patients with advanced NSCLC.[39] Four cohorts (25 patients each) received nab-paclitaxel at doses of 220, 260, 300 and 340 mg/m2 in combination with carboplatin AUC 6 every 21 days, and the primary end point was response. The preliminary response rate was 29% and an additional 15% of patients had stable disease. The primary toxicities (any grade) seen were neutropenia (43%), fatigue (37%), sensory neuropathy (37%), nausea (35%), thrombocytopenia (33%), anemia (24%), alopecia (24%) and vomiting (21%). This trial has been expanded to investigate the activity of carboplatin and nab-paclitaxel on a weekly schedule. A second trial in advanced NSCLC investigated the activity and toxicity of carboplatin AUC 6 in combination with nab-paclitaxel 100 mg/m2 on days 1, 8 and 15 every 28 days.[40] At the time of a preliminary report, 51 patients were evaluable and the response rate was 47%. The reported grade 3/4 toxicities consisted of neutropenia (30%), thrombocytopenia (18%) and anemia (7%). Currently, the combination of carboplatin AUC 6 and nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 every 28 days is being investigated in a second cohort. The combination of carboplatin AUC 6 and nab-paclitaxel 100 mg/m2 days 1, 8 and 15 every 28 days is currently being investigated in patients with recurrent platinum-sensitive ovarian or primary peritoneal carcinoma.[41] The planned sample for this trial is 43 patients.

Weekly Versus Every-3-Week Schedule of Nab-Paclitaxel. A randomized trial of 320 patients with metastatic breast cancer compared the activity and toxicity of three different schedules of nab-paclitaxel (nab-paclitaxel 300 mg/m2 every 3 weeks, nab-paclitaxel 100 or 150 mg/m2 on days 1, 8 and 15 every 28 days) with each other and docetaxel 100 mg/m2 every 3 weeks.[42] Patients on this trial were receiving first-line therapy for metastatic disease and the primary efficacy end point was response. An interim analysis revealed that the response rates of nab-paclitaxel and docetaxel-every-3-week arms were comparable, 33 and 36%, respectively. The response rates on weekly nab-paclitaxel arms at 100 and 150 mg/m2 were significantly higher than the docetaxel arm (58 vs 36%; p = 0.004 and 62 vs 36%; p = 0.016, respectively). There was no significant difference in the response rate between the two weekly-nab-paclitaxel arms (p = 0.424). The weekly nab-paclitaxel arms had a significantly higher response rate than the every-3-week nab-paclitaxel arms (p < 0.001 for comparison of each nab-paclitaxel weekly arms versus nab-paclitaxel every 3 weeks). The data on progression-free survival is not mature. Grade 4 neutropenia and febrile neutropenia were less frequent with the nab-paclitaxel than the docetaxel. The rate of grade 3 peripheral neuropathy for the every-3-week nab-paclitaxel arm and the weekly nab-paclitaxel arm at 100 and 150 mg/m2 was 14, 7 and 12%, respectively. The rate of grade 3 peripheral neuropathy on the docetaxel arm was 5%. These data suggest that the weekly therapy may be more effective than every-3-week nab-paclitaxel in metastatic breast cancer. The final results of this trial are eagerly awaited.

Safety & Tolerability. Safety data concerning the use of nab-paclitaxel in patients with renal or hepatic dysfunction is currently lacking. Patients with total bilirubin greater than 1.5 mg/dl or creatinine greater than 2 mg/dl were excluded from the Phase III trial. Patients with elevated liver function tests (generally defined as hepatic transaminases of at least 2.5-times the upper limit of normal) have frequently been excluded from nab-paclitaxel trials. A trial evaluating the safety of nab-paclitaxel in patients with hepatic dysfunction is currently ongoing. Patients enrolled on previous trials were required to have a National Cancer Institute's Common Terminology Criteria for Adverse Event (CTCAE) sensory neuropathy of grade 1 or less. The occurrence of grade 1 or 2 sensory neuropathy generally does not require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2, followed by a dose reduction for all subsequent cycles.

Pharmacoeconomics.Nab-paclitaxel is currently more expensive than CrEL-paclitaxel; however, the improved efficacy, reduced toxicity and more convenient administration may offset the increased expense of the drug. The cost-effectiveness of the use of nab-paclitaxel was recently evaluated in comparison to CrEL-paclitaxel in the treatment of metastatic breast cancer.[43] A decision analytic model evaluated the total cost per course, incremental cost per responder and incremental cost per progression-free month. The cost of premedication, administration, toxicity management and treatment failure were considered, but acquisition costs were not considered since pricing was not available for nab-paclitaxel at the time of this analysis. The conclusion of this analysis was that treatment with nab-paclitaxel was more efficacious and less costly than CrEL-paclitaxel.

Regulatory Status. Nab-paclitaxel is approved for the treatment of metastatic breast cancer after failure of combination chemotherapy or relapse after adjuvant therapy within 6 months in the USA, and in the treatment of metastatic breast cancer in Canada. Applications for approval of nab-paclitaxel have been submitted to China and Russia. The therapeutic combination of carboplatin and nab-paclitaxel for FDA approval of nab-paclitaxel in NSCLC is currently in development.

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