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Clinical Trials |
Departments of Breast Medical Oncology [N. K. I., R. L. T., E. R., G. N. H.], Melanoma/Sarcoma [S. L., S. E. R., A. B., J. A. E.], and Ophthalmology [B. E.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and American Bioscience, Inc., Santa Monica, California 90403 [N. D., P. S-S.]
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ABSTRACT |
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Experimental Design: ABI-007 was administered in the outpatient setting, as a 30-min infusion without premedications. Doses of ABI-007 ranged from 135 (level 0) to 375 mg/m2 (level 3). Sixteen patients participated in pharmacokinetic studies.
Results: Nineteen patients were treated. No acute hypersensitivity reactions were observed during the infusion period. Hematological toxicity was mild and not cumulative. Dose-limiting toxicity, which occurred in 3 of 6 patients treated at level 3 (375 mg/m2), consisted of sensory neuropathy (3 patients), stomatitis (2 patients), and superficial keratopathy (2 patients). The MTD was thus determined to be 300 mg/m2 (level 2). Pharmacokinetic analyses revealed paclitaxel Cmax and area under the curveinf values to increase linearly over the ABI-007 dose range of 135–300 mg/m2. Cmax and area under the curveinf values for individual patients correlated well with toxicity.
Conclusions: ABI-007 offers several features of clinical interest, including rapid infusion rate, absence of requirement for premedication, and a high paclitaxel MTD. Our results provide support for Phase II trials to determine the antitumor activity of this drug.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The paclitaxel preparation in clinical use (Taxol; Bristol-Myers Squibb, Princeton, NJ) is formulated in the nonionic surfactant Cremophor EL (polyoxyethylated castor oil) and ethanol to enhance drug solubility (7) . Cremophor EL may add to paclitaxel’s toxic effects by producing or contributing to the well-described hypersensitivity reactions that commonly occur during infusion, affecting 25–30% of treated patients (8 , 9) . To minimize the incidence and severity of these reactions, premedication with histamine 1 and 2 blockers, as well as glucocorticoids (usually dexamethasone), has become standard practice (10) . The cumulative side effects of dexamethasone used as a premedication may add to treatment-related morbidity and, in some instances, result in early discontinuation of therapy. Cremaphor EL may also contribute to chronic paclitaxel toxic effects, such as peripheral neuropathy (11) . An additional problem arising from the Cremophor and ethanol solvent is the leaching of plasticizers from PVC bags and infusion sets in routine clinical use (12) . Consequently, Taxol must be prepared and administered in either glass bottles or non-PVC infusion systems and with in-line filtration. These problematic issues have spurred interest in the development of taxanes with improved solubility in aqueous solutions (13) .
ABI-007 is a novel Cremophor-free formulation of paclitaxel (14) . It is prepared by high-pressure homogenization of paclitaxel in the presence of human serum albumin, resulting in a nanoparticle colloidal suspension. Like Taxol, ABI-007 dosage is determined by the paclitaxel content of the formulation, making direct comparison of the two drugs possible. ABI-007 can be reconstituted in normal saline at concentrations of 2–10 mg/ml, compared with 0.3–1.2 mg/ml for Taxol. Thus, the volume and time required for administration is reduced. In the absence of Cremophor EL, the risk of hypersensitivity reactions should decrease significantly, and patients receiving ABI-007 might thus avoid premedication. Moreover, there is no danger of leaching plasticizers from infusion bags or tubing, and conventional PVC infusion systems may be safely used.
To explore the potential clinical utility of ABI-007, we have conducted a Phase I study of this drug for patients with advanced solid tumors. The objectives of this trial were to determine the toxic effects, MTD, and pharmacokinetic profile of this unique paclitaxel preparation.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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9 g/dl, ANC 1,500/mm3, platelet count 100,000/mm3, serum creatinine < 2 mg/dl, and serum bilirubin < 1.5 mg/dl. Patients with prior exposure to taxanes were eligible for the study. Pretreatment evaluations included a complete blood count with differential and platelet count, serum chemistry profile, chest radiograph, and electrocardiogram. Baseline imaging studies and serum tumor marker levels were obtained at the discretion of the treating physician. Brain imaging by computerized tomography or magnetic resonance imaging was required for patients with symptoms suggestive of central nervous system involvement. Evaluations performed during the study included a complete blood count with differential and platelet count at least once weekly and a chemistry profile prior to each course. Restaging was performed after every 2nd or 3rd cycle of therapy. Patients were removed from the study for progression of disease, unacceptable toxicity, or at the patient’s request.
Study Design.
This Phase I study was conducted at The University of Texas M. D. Anderson Cancer Center and was approved by the M. D. Anderson Institutional Review Board. Informed consent was obtained from all subjects. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria. Dose levels of ABI-007 are shown in Table 1
. Dose escalation followed the standard "3 + 3" rule. Briefly, 3 patients were accrued at the starting dose level. If no toxic effects greater than grade 2 were observed, 3 patients were entered at the next dose level. If, at any level, one of the first 3 patients experienced a grade 3 or 4 toxic effect, 3 additional patients were entered at that dose level. The MTD was defined as one dose level below that at which 2 patients experienced grade 3 or 4 toxic effects. Six patients were to be treated at the MTD. Patients were permitted to escalate to the next higher dose level if no significant toxic effects were observed after the first 2 cycles of therapy. Patients with toxicity greater than grade 2 were permitted to reduce dosage by one dose level and remain on therapy at the discretion of the treating physician.
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Pharmacokinetic Studies.
Pharmacokinetic studies were performed in 16 patients, with at least 3 patients representing each dose level. Whole blood samples of 5 ml each were taken to determine the pharmacokinetics of ABI-007 at 13 time points: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24, and 48 h. Paclitaxel was extracted from whole blood samples using protein precipitation with acetonitrile, followed by solid phase extraction. The sample extracts were analyzed for paclitaxel using liquid chromatography atmospheric pressure ionization tandem mass spectrometry. The limit of quantitation for paclitaxel is 5 ng/ml, and the range of reliable response is 5–1000 ng/ml.
Pharmacokinetic parameters were determined from each patient’s whole blood/plasma paclitaxel concentration profile. Analysis was performed by the noncompartmental routine using WinNonlin software (Pharsight Corp., Mountain View, CA). The peak or maximum paclitaxel concentration (Cmax) and the corresponding peak time (tmax) were observed values. The elimination constant (
12z) was obtained by log-linear regression analysis of the terminal phase of the whole blood/plasma concentration versus time profile. The elimination half-life (T1/2) was determined by taking the ratio of natural log of 2 and 12z. The AUC from time 0 to time infinity (AUCinf) was obtained by summation of AUClast (AUC from time 0 to last measurable concentration, calculated by the linear trapezoidal rule) and AUCext (extrapolated area, estimated by taking the ratio between the last measurable concentration and 12z). The dose area relationship (i.e., total ABI-007 dose divided by AUCinf) was used to determine total body CL. The volume of distribution (Vz) was determined by taking the ratio between CL and 12z.
Descriptive statistics (mean, median, SD, coefficient of variation, maximum, and minimum) were computed for pertinent pharmacokinetic parameters by ABI-007 dose. Regression analysis of mean AUCinf versus dose was performed to gain an appreciation of pharmacokinetic linearity, if evident, for the dose range evaluated in this trial. Differences in the means of Cmax and AUCinf between groups of patients were analyzed for significance using a two-tailed, two-sample t test. Pearson’s correlation coefficient was used to examine the correlation between degree of myelosuppression and Cmax or AUCinf.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Three patients were entered initially at level 0, receiving 135 mg/m2 over 3 h. One of these experienced progression of disease over the next several weeks, with rapid clinical deterioration, making it difficult to ascertain toxic effects of ABI-007 in this individual. To verify toxicity data at this dose level and ascertain the safety of administering the drug over a short infusion period, a 4th patient was entered at level 0 and was the first patient to receive drugs over 30 min. There were no instances of grade 3 or 4 toxicity observed at dose levels 0 or 1 (200 mg/m2). At dose level 2 (300 mg/m2), 1 of the first 3 patients developed grade 3 sensory neuropathy. Three more patients were accrued at this level, with no additional observations of dose-limiting toxicity. At dose level 3 (375 mg/m2), during the 1st cycle of treatment, one of the first 3 patients experienced grade 3 sensory neuropathy, grade 3 stomatitis, and a visual disturbance diagnosed as superficial keratopathy, also grade 3. An additional 3 patients were accrued at level 3. One patient from this second cohort experienced a similar spectrum of grade 3 toxic effects, including sensory neuropathy, stomatitis, and superficial keratopathy; this patient developed grade 3 vomiting and diarrhea and thrombocytopenia as well. An additional case of sensory neuropathy, this time as an isolated grade 3 toxic effect, was observed in a 3rd patient at level 3. The study was thus terminated. The MTD for ABI-007 administered as a 30-min infusion every 21 days, as determined by this study, was 300 mg/m2. The dose-limiting toxic effects were sensory neuropathy, stomatitis, and superficial keratopathy. Specific toxic effects are described below.
Hematological Toxicity.
Hematological toxicity was dose dependent but remained modest throughout the study (Table 3)
. Of the 96 treatment cycles administered, only 7 (7.3%) resulted in an ANC nadir < 500/mm3, 6 of which occurred above the MTD at dose level 3. There was one hospital admission for febrile neutropenia. In only one case did the platelet count drop below 75,000/mm3. The patient, who was found to have a platelet nadir of 25,000/mm3 during her 1st cycle of therapy at level 3, also developed a constellation of grade 3 nonhematological toxic effects. This was the only individual who required a platelet transfusion during the study. No patients received growth factors for granulocyte support.
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summarizes the nonhematological toxic effects observed during the first 2 cycles of therapy at each dose level. The majority of these were grades 1 and 2; no patient manifested grade 4 toxicity. Nausea, vomiting, and muscle and joint aches were common but mild. Skin toxicity was also mild, consisting of dry skin or localized vesicular or pustular rash. Alopecia was universal. Peripheral neuropathy, absent at the lower dose levels, was common with higher doses, appearing in 11 of 12 patients treated at levels 2 and 3. The neuropathy occurred in a typical stocking/glove distribution and was manifested by numbness or pain. Six patients with peripheral neuropathy developed peri-oral numbness as well. As described above, the most severe nonhematological adverse effects occurred in 2 patients at dose level 3, consisting of a complex of peripheral neuropathy, stomatitis, and superficial keratopathy, all grade 3.
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Occurrences of new types of toxic effects after the first 2 cycles of therapy were rare. Furthermore, it was uncommon for toxic effects to increase in grade after the first 2 treatment cycles. Therefore, cumulative toxicity did not appear to be a significant problem.
Response.
Partial responses were observed in two breast cancer patients, both of whom had prior exposure to Taxol. The first patient, entered at dose level 2, experienced a 68% decrease in the size of pulmonary metastases. This response lasted a total of 15 months, including 9 months after discontinuation of therapy for toxicity. The 2nd patient, who was also treated at dose level 2, had significant improvement in soft tissue disease involving the chest wall. Because of toxic effects, she was taken off treatment on the date of her response. Disease progression was noted 6 weeks later.
Pharmacokinetic Studies.
Sixteen of the 19 patients entered into the study contributed analyzable pharmacokinetic profiles. Three of these received ABI-007 as a 180-min infusion; the remaining 13 were treated over 30 min. A semilog plot of the mean values of the whole blood paclitaxel concentration for each dose level versus time is shown in Fig. 1
. The maximum paclitaxel concentrations were observed at the termination of ABI-007 infusion; the decline from maximum was biphasic.
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. The pharmacokinetics of ABI-007 administered over 30 min appeared to be linear across the three lower dose levels, which included the MTD (Fig. 2)
. Calculations from the data in Table 5
reveal a 2.2-fold increase in Cmax and a 2.7-fold increase in AUCinf over the 2.2-fold increase in dose from 135 to 300 mg/m2. The decline in CL estimates over this range is 0.8-fold (16.1%). If the highest dose level of 375 mg/m2 is included, nonlinearity becomes evident (Fig. 2)
. Individual Cmax and AUCinf values versus dose are shown in Fig. 3, a and b
, respectively.
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. The differences in mean Cmax and mean AUCinf between the two groups were significant (P = 0.034 and 0.007, respectively). The effect of ABI-007 exposure on myelosuppression was also examined in this group of patients. The percentage of decrease in ANC from baseline to nadir was found to correlate positively with both Cmax (r = 0.610, P = 0.027) and AUCinf (r = 0.614, P = 0.025).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It must be pointed out that, although the absence of Cremophor is clearly desirable with respect to toxicity, this same compound has been proposed to enhance the efficacy of cytotoxic drugs through reversal of the multidrug resistance phenotype (15) . Plasma concentrations of Cremophor attainable during Taxol infusions are sufficient to inhibit P-glycoprotein effects in vitro (16) . However, there have been questions raised as to whether these Cremophor concentrations are relevant to solid tumors, as pharmacokinetic studies demonstrate the compound’s distribution to be limited to the central plasma compartment (17) . This issue should be clarified with the completion of ongoing Phase II trials of ABI-007. If the response rate of ABI-007 is not less than that of Taxol and if responses are seen in patients who are previous taxane failures, the therapeutic contribution of Cremophor to paclitaxel can be considered negligible.
In terms of treatment-related toxicity, a lower incidence of myelosuppression was observed than that which we anticipated based on the dose of paclitaxel administered. In this regard, hematological toxicity was mild and played virtually no role in dose and treatment decisions made in this trial. Although direct comparisons to Taxol administered at this dose range and schedule are not possible, the myelosuppression induced by ABI-007 appeared to be similar to or less severe than that reported for 1-h Taxol infusions at lower doses (18) . Otherwise, the spectrum of toxic effects produced by ABI-007 resembled that of high-dose short-infusion Taxol reported in early Phase I trials, with sensory neuropathy and mucositis becoming dose limiting (19 , 20) . A third dose-limiting toxic effect, superficial keratopathy, was also observed. We were unable to find any prior report of superficial keratopathy as a consequence of paclitaxel administration. In our Phase I trial, this side effect appeared to be related to dose and presented at the level of grade 3 only above the MTD, at a dose of 375 mg/m2. Superficial keratopathy secondary to ABI-007 was similar to that most commonly recognized in association with 1-ß-D-arabinofuranosylcytosine, although any type of ocular surface irritation, including dry eye syndrome, can result in similar corneal findings (21) . Other ocular complications of taxane therapy have been reported. The most common adverse ocular effects of Taxol are photopsia and blurred vision, usually reported by patients during the infusion period (22 , 23) . Cases of optic nerve disturbances have also been documented (24) . Cases of grade 2 conjunctivitis necessitating dose reduction and treatment delay have been reported during weekly therapy with docetaxel (25) . Similar to our findings, reported ocular effects from paclitaxel have been noted only at higher doses and are usually transient. Although all cases of keratopathy in this study resolved completely and without permanent sequellae, in the ensuing Phase II trial, patients will be aggressively monitored for the development of ophthalmologic abnormalities.
Pharmacokinetic analysis of ABI-007 revealed interesting similarities and differences relative to Taxol, based on published data. Disappearance from the blood is biphasic for both drugs (19) . ABI-007 displays linear pharmacokinetics over the clinically relevant dose range of 135–300 mg/m2; over a similar dose range, Taxol AUCinf is nonlinear (26, 27, 28) . In comparing the AUCinf values of ABI-007 infused over 30 min to those reported for Taxol infused over 1 or 3 h, ABI-007 in general showed lower AUCinf values over a similar range of doses (26, 27, 28) . Although several explanations are possible for the differences in AUCinf, it is reasonable to hypothesize that ABI-007 may be distributed more rapidly out of the vascular compartment, a suggestion supported by the difference in formulation between the two drugs. A substantial amount of solvent (Cremophor/ethanol) is infused with Taxol, and the partition of paclitaxel from the vascular compartment to the tissues may thus be relatively slow. In contrast, ABI-007 is formulated with human serum albumin at a concentration of 3–4%, similar to the concentration of albumin in the blood. Because paclitaxel has a very limited solubility in an aqueous albumin solution (<30 µg/ml), it may partition more efficiently into the tissues in the case of ABI-007. Furthermore, lipid, macromolecular, and nanoparticle drug carriers have been known to preferentially accumulate in tumor beds and tissues in what is known as enhanced permeation and retention effect (29) . These factors may facilitate the partition of ABI-007 into tissues.
The MTD of ABI-007 was found in this study to be 300 mg/m2 when given as a short infusion on a 21-day cycle. Although the usual dose range for Taxol is 135–200 mg/m2, doses as high as 250 mg/m2 are occasionally administered. Therefore, the MTD established by this trial represents a moderate increase over that of Taxol. The issue of whether one can achieve uniform and repeated dosing of ABI-007 at the MTD will need to be addressed in Phase II trials.
In conclusion, ABI-007 appears to represent an improvement in paclitaxel formulation in that it can be administered rapidly and safely without the risk of hypersensitivity reactions, eliminating the need for steroid and antihistamine premedication. Furthermore, the increased MTD and favorable toxicity profile of ABI-007 may ultimately prove advantageous in terms of rate and quality of response. Although several interesting pharmacokinetic properties were noted for ABI-007, the small number of patients in this study renders comparisons with Taxol preliminary, and additional studies will need to be conducted to fully appreciate differences in pharmacokinetic behavior. The partial responses seen in 2 patients with prior exposure to Taxol are encouraging and support a continued effort to explore the spectrum of activity for this drug. We are currently conducting a Phase II trial of ABI-007 for patients with metastatic breast cancer to establish the antitumor activity of this novel paclitaxel formulation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by American Bioscience, Inc., Santa Monica, CA. 
2 To whom requests for reprints should be addressed, at Department of Molecular and Cellular Oncology, Box 79, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-8990; Fax: (713) 794-0209; E-mail: jaellerh{at}mail.mdanderson.org
3 The abbreviations used are: MTD, maximum tolerated dose; ANC, absolute neutrophil count; AUC, area under the curve; CL, clearance; PVC, polyvinyl chloride.
Received 9/25/01; revised 1/23/02; accepted 2/ 1/02.
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) represent 2 patients with multiple grade 3 toxicities, whereas the open circle (
) represents the patient with only grade 3 neuropathy.