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Clinical Cancer Research 13, 3293, June 1, 2007. doi: 10.1158/1078-0432.CCR-06-2496
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Phase I and Pharmacokinetic Study of AI-850, A Novel Microparticle Hydrophobic Drug Delivery System for Paclitaxel

Alain C. Mita1, Anthony J. Olszanski2, Richard C. Walovitch3, Raymond P. Perez2, Kathleen MacKay2, David P. Tuck4, Cecilia Simmons1, Susan Hammond2, Monica M. Mita1, Muralidhar Beeram1, Anne J. Stone3, Eric K. Rowinsky1 and Lionel D. Lewis2

Authors' Affiliations: 1 Institute for Drug Development, Cancer Therapy and Research Center and University of Texas Health Science Center, San Antonio, Texas; 2 Sections of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, Dartmouth Medical School and Norris Cotton Cancer Center at Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire; 3 Acusphere, Inc., Watertown, Massachusetts; and 4 Yale Cancer Center, New Haven, Connecticut

Requests for reprints: Lionel D. Lewis, Section of Clinical Pharmacology, Department of Medicine, Dartmouth Medical School and Dartmouth Hitchcock Medical Center, Lebanon, NH 03756. Phone: 603-650-7811; Fax: 603-650-6841; E-mail: Lionel.Lewis{at}Dartmouth.edu.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacokinetics of paclitaxel in this new formulation, and seek evidence of anticancer activity.

Experimental Design: This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concentrations were measured by liquid chromatography-tandem mass spectrometry.

Results: Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m2. Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m2 AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas.

Conclusions: The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m2. The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.

Although paclitaxel, a natural product isolated from the Pacific yew tree Taxus brevifolia, is one of the most active and useful anticancer agents (1–5), its chemical structure, consisting of a bulky tetracyclic core baccatin III ring with an attached amide tail and many hydrophobic elements, confers poor aqueous solubility and difficulties in drug formulation (6, 7). After investigation of several excipients to enable parenteral administration, a viable option was found in Taxol (Bristol-Myers Squibb, Princeton, NJ), one of the currently marketed formulations of paclitaxel, in which paclitaxel is formulated in 50% (v/v) polyoxyethylated castor oil (PCO; Cremophor EL) and 50% dehydrated ethanol. However, this formulation portends several toxicologic, pharmacologic, and pharmaceutical disadvantages, including severe hypersensitivity reactions related to PCO, protracted infusion times, the requirement for non–polyvinyl chloride infusion systems with in-line filtration to prevent precipitation, and postulated PCO-enhanced taxane-induced neurotoxicity (2–4, 8–10). Therefore, alternative formulations of paclitaxel were actively sought.

AI-850 (Acusphere, Inc., Watertown, MA) is a PCO-free formulation of paclitaxel designed to reduce the incidence of hypersensitivity reactions and to eliminate the requirement for premedication, reduce the administration time, and potentially provide superior therapeutic indices compared with PCO-formulated paclitaxel (11, 12). In AI-850, the limited water solubility of paclitaxel is addressed by a unique hydrophobic drug delivery system using porous microsphere manufacturing techniques to produce a rapidly dissolving formulation of paclitaxel as shown in Fig. 1A and B . The manufacturing process for AI-850 involved spray drying a solution of paclitaxel plus a water-soluble excipient and a pore-forming agent (i.e., a volatile salt) to form a dry powder of sponge-like, paclitaxel-containing microspheres, which is reconstituted in sterile water for injection (11, 12). The microspheres (<2 µm mass median diameter) consist of the active ingredient paclitaxel in a water-soluble carrier matrix and contain D-mannitol, povidone C-15, and polysorbate 80 as excipients. During reconstitution, the water-soluble excipients dissolve, leaving a suspension of drug microparticles and submicrometer particles that dissolve on further dilution in the plasma. Preclinical toxicology studies conducted in rodents and monkeys have compared AI-850 with the PCO-formulated paclitaxel (11, 12). At equivalent doses, AI-850 produced lower maximum plasma paclitaxel concentrations (Cmax) and paclitaxel was more rapidly cleared from the vascular compartment than the PCO-formulated paclitaxel. However, the acute and subacute tolerability of AI-850 was superior to PCO-formulated paclitaxel, thereby allowing the administration of higher doses of AI-850. Furthermore, AI-850 showed antitumor activity comparable with PCO-formulated paclitaxel at equivalent doses in various human tumor xenograft models, including OVCAR-5 ovarian, MDA-MB-435 breast, and NCI-H460 non–small cell lung carcinomas (11). Moreover, the administration of higher doses of AI-850 resulted in increased efficacy as evidenced by a greater delay in tumor regrowth compared with the maximum tolerated dose (MTD) of PCO-formulated paclitaxel (11, 12). Taken together, these data suggested that higher tissue concentrations of paclitaxel and potentially increased antitumor activity may be achievable after administration of AI-850.


Figure 1
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  		Fig. 1. Hydrophobic drug delivery system (HDDS).

 
We undertook an open-label phase I and pharmacokinetic study designed to evaluate the safety and feasibility of administering AI-850 as a brief (<30 min) i.v. infusion every 3 weeks without premedication in patients with advanced solid malignancies. The principal objectives of this trial were to (a) characterize the safety profile of a brief infusion of AI-850, (b) determine the MTD and recommend a dose of AI-850 for phase II studies of this schedule, (c) determine the plasma paclitaxel concentration-time profile and paclitaxel pharmacokinetic following AI-850 administration, and (d) seek evidence of preliminary antitumor activity.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
The study protocol was approved by the local Institutional Review Board at Dartmouth College (Lebanon, NH) and the Institute for Drug Development (San Antonio, TX).

Patient eligibility. Patients with solid malignancies for whom standard therapeutic options did not exist were eligible for this study. All prior anticancer therapy had to have been completed at least 28 days before study enrollment (42 days for nitrosoureas and mitomycin C). Patients who had been treated with high-dose chemotherapy and autologous stem cell rescue were not eligible. Prior taxane-based therapy was allowed. Additional eligibility criteria included the following: age ≥18 years; an Eastern Cooperative Oncology Group performance status ≤2; adequate hematopoietic (absolute neutrophil count ≥1,500/µL, hemoglobin ≥8.5 g/dL, and platelets ≥100,000/µL), adequate hepatic (total bilirubin ≤1.5 mg/dL and transaminases ≤3 times upper limit of normal), and renal (serum creatinine ≤2 mg/dL) function; recovery from all acute toxicities of prior chemotherapy; no symptomatic or active brain metastases; no serious cardiovascular condition, including uncontrolled congestive heart failure or arrhythmia, or history of myocardial infarction within 6 months of enrollment; and no coexisting medical problem of sufficient severity to limit compliance with the study. Pregnant or lactating women, patients who had experienced a hypersensitivity reaction of at least grade 2 associated with prior taxanes, and patients with preexisting peripheral neuropathy grade ≥2 were ineligible for this trial. Before entering the study, patients signed written informed consent according to federal and institutional guidelines.

AI-850 supply and formulation. AI-850 was supplied by Acusphere as a sterile dry powder in 5 mL vials. AI-850 was formulated with D-mannitol, povidone C-15, and polysorbate 80 and reconstituted before administration with 3 mL of sterile water for injection to form a suspension of paclitaxel microspheres at a paclitaxel concentration of 50 mg/mL. Initially, the AI-850 suspension was administered as an i.v. infusion using a syringe pump at a rate of 50 mg/min. Infusion rates of 12.5, 16.3, and 25 mg/min were used subsequently in the trial.

Dose escalation and AI-850 administration. The starting dose of AI-850 was 36 mg/m2 administered as a <30-min i.v. infusion at a fixed rate of 50 mg/min. Dose escalation was done according to a modified Fibonacci scheme. At least three patients were to be entered at each dose level. If no dose-limiting toxicity (DLT) was noted after the third patient had reached day 15 of the treatment cycle 1, then AI-850 dose was escalated to the next dose level. If one of the first three patients at any dose level experienced a DLT, then up to six patients were to be treated at that dose level. If two of the initial three patients or two of six patients experienced a DLT during the first 3-week treatment cycle, then the MTD was exceeded and three to nine additional patients were to be treated at the next lower dose level. Dose reduction by one level was permitted for patients who developed DLT. If marked differences in the incidence and severity of toxicities were noted between the dose level that exceeds MTD and the previous dose level, an intermediate dose level could be explored. Depending on the nature and severity of the toxicities observed, infusion rates could also be adjusted.

All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. DLT was defined as any of the following: (a) grade 3 or 4 drug-related nonhematologic toxicity, except fatigue, arthralgia, and myalgia, and grade 3 or 4 nausea/vomiting or diarrhea in the absence of optimal preventive and supportive measures; (b) grade 4 neutropenia lasting >5 days and/or associated with fever (≥38.5°C) and/or platelet count <25,000/µL; or (c) treatment delay of >7 days due to any unresolved toxicity in patients who experienced any grade 3 drug-related nonhematologic toxicity. The MTD was to be defined separately for minimally pretreated and heavily pretreated patients if it appeared that heavily pretreated patients were more susceptible to DLT. Heavily pretreated patients were defined a priori as those who had received more than six courses of an alkylating agent-containing regimen (except low-dose cisplatin), more than four courses of carboplatin-containing chemotherapy regimens, more than two courses of nitrosoureas or mitomycin C, or irradiation to ≥30% of bone marrow reserves. Patients not meeting one of these criteria were considered minimally pretreated.

Pretreatment assessment and follow-up studies. Clinical history that included performance status, concurrent medications, and adverse event reporting as well as physical examinations and routine laboratory evaluations were done before treatment and weekly during the first treatment cycle and before AI-850 administration for further cycles. Vital signs and oxygen saturation by pulse oximetry were monitored before treatment and at 15, 30, 60, and 120 min after treatment. Routine laboratory evaluations included complete blood cell counts, chemistries, and urinalyses. Complete blood cell counts were repeated weekly in treatment cycle 1. An electrocardiogram was done before treatment and on days 3 and 22 of treatment cycle 1. Complete blood cell counts and chemistries were assessed every other day if the absolute neutrophil count was <500/µL and platelets were <50,000/µL or if any grade 3 to 4 nonhematologic toxicities were observed, respectively. Radiologic studies for assessment of tumor burden as well as a chest radiogram were conducted before treatment and after every other course.

Pharmacokinetic sampling and assay. Blood samples (7 mL) were collected during treatment cycle 1 from a vein in the contralateral limb to that used to infuse AI-850. Venous blood was collected into prechilled EDTA tubes immediately before the administration of AI-850 and at 0.25, 0.5, 1, 2, 4, 8, 10, 24, and 48 h after the initiation of the infusion on day 1. Samples were inverted for ~2 min on a mechanical rocker and then centrifuged at 1,550 to 1,600 x g for 10 min at 2°C to 8°C. Following centrifugation, two aliquots of the plasma fraction were separated and frozen at –70°C until analysis. All samples were assayed for total and free plasma paclitaxel concentrations using a minor modification of a published and validated liquid chromatography-tandem mass spectrometry method done by LC Resources, Inc. (BAS1 Northwest Laboratory Services, McMinnville, OR; ref. 13). The range of the paclitaxel assay in human plasma and plasma ultrafiltrate was 0.1 to 100 ng/mL, with 0.1 ng/mL as the lower limit of quantification. The intraday variability of the quality control samples from the analysis of human plasma study samples was 2.4% to 10% deviation (accuracy) and 2.5% to 11% coefficient of variation (precision). The intraday variability of the quality control samples from the analysis of human plasma ultrafiltrate study samples was –0.32% to 5% deviation (accuracy) and 1.4 to 6.7% coefficient of variation (precision). Unknown samples that initially yielded paclitaxel concentrations that were above the highest concentration of the standard curve of the assay were appropriately diluted until the measured concentration was in range.

Pharmacokinetic analysis. The total and free plasma paclitaxel concentration-time data following a single i.v. infusion of AI-850 were displayed on a semilogarithmic plot of paclitaxel concentration versus time for each patient. The maximum total and free plasma paclitaxel concentration observed after dose (Cmax) and the time at which the Cmax values occurred (Tmax) were the observed values from the raw paclitaxel concentration-time data. The WinNonlin pharmacokinetic program (Pharsight Corp., Mountain View, CA) was used to estimate standard pharmacokinetic variables. The total and free plasma paclitaxel concentration-time data were analyzed using an open noncompartmental method with a constant infusion. The terminal elimination rate constant (ke) was determined using a linear regression of no less than the terminal five data points. The terminal elimination half-life was estimated from 0.693/ke. The area under the concentration versus time curve (AUC) to the last datum point was estimated using the linear-log trapezoidal rule and extrapolated to infinity by adding the Wagner-Nelson correction (Clast/ke). Total body clearance (CL) was calculated from dose/AUC(0-{infty}). The apparent volume of distribution was estimated from CL/ke.

Statistical methods. The AI-850 toxicity data and pharmacokinetic variables are detailed as descriptive summary data. Differences in pharmacokinetic as a function of dose cohort were assessed using ANOVA. Relationships between pharmacokinetic variables and dose were explored using regression analysis. A P value of <0.05 was considered statistically significant.

Assessment of tumor burden. Tumor burden was determined after every two cycles of treatment and evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines (14). Patients were able to continue treatment in the absence of progressive disease or unacceptable toxicity.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Patients and dose escalation
Twenty-two patients were treated with a total of 56 courses of AI-850 in seven cohorts spanning five dose levels. The relevant demographic characteristics of the patients and the dose escalation scheme are detailed in Tables 1 and 2 , respectively. Five treatment courses involving two patients at the 250 mg/m2 dose level were delayed due to intercurrent events (intractable pain, one course) and scheduling conflicts (four courses).


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  		Table 1. Patient characteristics

 

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  		Table 2. AI-850 dose escalation

 
Three patients each were treated at the dose levels of 36, 72, 144, and 205 mg/m2 of AI-850 infused at a rate of 50 mg/min without DLT. However, a grade 3 infusion reaction was reported in one patient following the second cycle of AI-850 administered at the 205 mg/m2 dose level (cohort 4A) as detailed below. Although this event did not meet the strict criteria for DLT, it was elected to further explore AI-850 at the same dose level at a reduced infusion rate of 12.5 mg/min (cohort 4B). The only patient treated in this cohort experienced DLT, consisting of acute grade 4 infusion reaction as described below. Extensive investigation following this event determined that an apparent nonhomogeneity of the AI-850 suspension had occurred during the prolonged infusion at the reduced rate. Subsequently, the protocol was amended to adopt more conservative administration conditions, which included limiting the duration of the infusion to 30 min and ensuring that dosing was complete within 55 min after the AI-850 suspension was reconstituted. In addition, patients were excluded if their oxygen saturation was <90% breathing room air at rest, and mandatory pulse oximetry monitoring immediately before, during, and following the AI-850 administration was also instituted. Three patients who were subsequently treated with AI-850 at 205 mg/m2 using an infusion rate of 16.67 mg/min (cohort 4C) experienced no DLTs. In the subsequent cohort of six patients treated with 250 mg/m2 AI-850 at an infusion rate of 25 mg/min (cohort 5), dose-limiting hematologic toxicity occurred in two patients, consisting of febrile neutropenia in a minimally pretreated patient and grade 4 neutropenia exceeding >5 days in a heavily pretreated patient. Therefore, this dose level exceeded the MTD and dose escalation was stopped. The 205 mg/m2 dose level of AI-850, which resulted in DLT in one of seven patients, was determined to be the MTD, and this dose was the recommended dose for further evaluation in phase II studies in patients with advanced solid malignancies.

AI-850–related toxicities
Infusion reactions. Four patients developed mild (grade 1; n = 1), moderate (grade 2; n = 1), or severe (grade 3-4; n = 2) acute infusion-related reactions.

A 72-year-old male with metastatic pancreatic cancer was premedicated with 0.5 mg i.v. lorazepam and 100 mg i.v. dolasetron and then received 205 mg/m2 (357 mg) AI-850 at a rate of 16.7 mg/min (0.33 mL/min). Approximately halfway through the infusion, the patient complained of left-sided sacroiliac pain (grade 1). Vital signs were stable apart from a tachycardia of 97 beats/min. There were no electrocardiogram changes and the symptoms improved with local application of hot towels and resolved ~5 min after the end of the infusion. Approximately 36 to 48 h after treatment, he developed erythema and urticaria on his arms and upper chest (grade 2 rash), which was treated with diphenhydramine and improved over a period of 8 to 9 days. In course 2 of treatment, he received 0.5 mg i.v. lorazepam, 100 mg i.v. dolasetron, and 8 mg i.v. dexamethasone as premedication but developed the same sacroiliac pain during the infusion (grade 2 on this occasion); this again was resolved with application of local heat ~5 min after the end of the infusion. In addition, he developed an urticarial maculopopular rash (grade 2) on his upper arms and chest without other features of acute hypersensitivity. He was given tapering course of oral corticosteroids and the rash slowly resolved over the next 2 weeks.

A 56-year-old female with metastatic colorectal cancer to the liver who received 72 mg/m2 (124 mg) AI-850 at a rate of 50 mg/min without premedication complained of a sensation of a metallic taste in her mouth, facial warmth, and flushing of her face and neck, back pain, difficulty breathing, and neck tightness immediately before the end of the 2.5-min infusion. A physical exam revealed upper torso and facial erythema, sinus tachycardia at 110/min; mild hypertension, respiratory rate 20/min, and oxygen saturation were unchanged from baseline and varied from 93% to 95% on room air and no electrocardiographic ischemic changes were evident. These symptoms started to subside within 3 to 4 min of the end of the infusion and had dissipated by 15 min after the end of the infusion without any requirement for medication. This was a grade 2 infusion reaction. A similar, self-limiting, moderately severe (grade 2) episode occurred during the AI-850 infusion on course 2 of treatment. In course 3, although the patient received premedication with 25 mg i.v. diphenhydramine, a reaction similar to that described for course 1 was observed.

A 66-year-old male with a diagnosis of cholangiocarcinoma with liver metastases experienced an acute but brief grade 3 infusion reaction during the second course of AI-850 at the 205 mg/m2 dose level (50 mg/min). Of note, the patient previously experienced a mild (grade 1) infusion reaction, consisting of rigors, 1 h after the first course of AI-850, and therefore, the patient received 100 mg i.v. hydrocortisone and 25 mg oral diphenhydramine before his second course of AI-850. Despite this premedication, 4 min after the start of the AI-850 infusion, he developed facial erythema (flushing), chills, rigors, back pain, nausea, vomiting, as well as transient hypotension (90/50 mm Hg). The patient received 100 mg i.v. dolasetron, 50 mg i.v. diphenhydramine, and 10 mg i.v. dexamethasone and recovered within 15 min with no further recurrence of the symptoms.

A 67-year-old male with malignant melanoma metastatic to lung, liver, and spleen experienced an acute, severe (grade 4) infusion reaction following his first course of AI-850 administered at the 205 mg/m2 dose level (0.25 mL/min). His history was also notable for respiratory impairment with dyspnea on minimal exertion and baseline oxygen saturation of 87% to 90%. Fifty minutes after the initiation of the AI-850 infusion, this patient experienced acute worsening of his dyspnea associated with decreased oxygen saturation at 55% in room air as well as rigors and facial erythema. Physical examination revealed decreased respiratory sounds in both lungs but no wheezing. The patient was acutely medicated with 50 mg i.v. diphenhydramine and 125 mg i.v. methylprednisolone, resulting in minimal symptomatic improvement. He subsequently received 0.3 mg s.c. epinephrine, 30 mg i.v. ranitidine, 5 mg i.v. dexamethasone, and oxygen. Finally, after retreatment with 1 mg i.v. epinephrine, symptomatic recovery occurred within 20 min.

Hematologic toxicity. Neutropenia was the most common toxicity of AI-850 in this study. At the highest dose level, 250 mg/m2, one patient experienced grade 4 neutropenia and fever and another patient had grade 4 neutropenia lasting 6 days. Hematologic toxicities are summarized in Table 3 . At the recommended phase II dose, 205 mg/m2, one of seven (14%) patients experienced grade 4 neutropenia, which lasted <3 days. Overall, severe (grade 3 or 4) neutropenia occurred in 4 of 56 (7%) courses. The median neutrophil nadir occurred on day 8, and there was no evidence of cumulative myelosuppression. Only two patients experienced grade 1 to 2 anemia, and two patients had grade 1 to 2 thrombocytopenia but clinically significant thrombocytopenia was not observed.


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  		Table 3. Hematologic toxicity (cycle 1)

 
Nonhematologic toxicities. The principal nonhematologic toxicities of AI-850 were fatigue [19 patients (86%)]; gastrointestinal symptoms, including nausea [9 patients (41%)], vomiting [7 patients (32%)], anorexia [9 patients (41%)], and diarrhea [6 patients (27%)]; and neuropathy [9 patients (41%)] as shown in Table 4 . Alopecia was common and occurred in 10 (45%) patients. The incidence and severity of these toxicities seemed to increase with AI-850 dose. The AI-850–induced neurotoxicity was similar to paclitaxel-induced neuropathy and was characterized by numbness and tingling in a symmetrical "glove and stocking" distribution and by loss of sensation and diminished deep tendon reflexes. Most of these symptoms were mild to moderate in severity, with the exception of one patient who experienced a severe (grade 3) neuropathy following eight cycles of AI-850 at the 250 mg/m2 dose level. He had received prior therapy with 5-fluorouracil, irinotecan, oxaliplatin, and capecitabine. His neuropathy improved slowly after cessation of AI-850 chemotherapy. The nausea and vomiting related to AI-850 were acute, brief, and generally mild (grade 1), except for one patient who experienced grade 3 symptoms that were managed with prochlorperazine and/or 5-hydroxytryptamine-3 receptor antagonists. Diarrhea was manageable with loperamide administered at standard doses. Other common toxicities of AI-850 included arthralgias in six (27%) patients, myalgias in eight (36%) patients, and edema of the lower extremities in six (27%) patients. These mostly mild to moderate adverse events were generally manageable and fully reversible.


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  		Table 4. Principal nonhematologic toxicities by patient (all cycles, highest grade)

 
Pharmacokinetic data
Sampling for pharmacokinetic studies was done on 19 patients. Representative plasma concentration-time profiles for total and free paclitaxel are shown in Fig. 2 . The Tmax of total and free paclitaxel varied with dosing rate. The plasma total and free paclitaxel concentrations declined in a biphasic fashion. The Cmax and AUC values of paclitaxel increased with dose across the dose levels explored. Plasma paclitaxel was largely protein bound, and based on Cmax data, 3.6% to 4.8% of the total plasma paclitaxel was measured as free drug. This is supported by the ratio of AUC of free paclitaxel/AUC of total paclitaxel, which ranged from 0.045 to 0.079. Mean total and free paclitaxel pharmacokinetic variables as a function of AI-850 dose level are detailed in Table 5A and B . Cmax and AUC values increased as a function of dose for both total paclitaxel (Cmax: P = 0.0037, ANOVA; AUC: P = 0.0003, ANOVA) and free paclitaxel (Cmax: P = 0.006, ANOVA; AUC: P = 0.0008, ANOVA). There was no change in total or free paclitaxel half-life or volume of distribution with dose, as all ANOVA P values ranged from 0.12 to 0.75. Total paclitaxel CL seemed to decrease with dose (P = 0.04, ANOVA), but free paclitaxel CL did not change with dose (P = 0.46, ANOVA).


Figure 2
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  		Fig. 2. Mean plasma concentration-time profiles by dose cohort for total (A) and free (B) paclitaxel.

 

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  		Table 5. Pharmacokinetic variables for total and free plasma paclitaxel

 
Antitumor activity
Of the 22 patients who entered into this study, 17 were evaluable for the antitumor activity of AI-850. One patient with endometrial carcinoma with brain and retroperitoneal lymph node metastases, previously treated with combined chemoradiation of the pelvis as well as brain radiation, had a partial response after four treatment courses. She developed progressive disease in her retroperitoneal lymph nodes after eight courses (250 mg/m2 dose tier). One patient with metastatic squamous cell carcinoma of the tongue carcinoma had clinical and radiographic resolution of his nonmeasurable pleural disease after four courses of AI-850 at the 205 mg/m2. This patient remained disease-free and off chemotherapy for 4 months after finishing treatment with AI-850. Four patients had stable disease for at least two cycles of AI-850 therapy, and 11 patients had progressive disease. Five patients were not evaluable for the effect of AI-850 on tumor burden.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The nonionic surfactant PCO is widely used as a vehicle for the solubilization of paclitaxel and other hydrophobic drugs (e.g., cyclosporine, vitamin K, and lorazepam; ref. 15). However, PCO is a pharmacologically active compound, which is responsible for clinically significant adverse events due to modulation of drug disposition, pharmacokinetics, and pharmacodynamics (16, 17). The acute hypersensitivity reactions associated with the use of i.v. paclitaxel formulated in PCO have been attributed, at least in part, to PCO, which induces complement activation and histamine release in vivo (18–21). Moreover, peripheral neuropathy, one of the toxicities ascribed to PCO, may be due to the presence of ethylene oxide residues, although the precise mechanism is not currently completely elucidated (22–25). In addition, PCO "adversely" modulates the pharmacokinetic of paclitaxel but also of other coadministered drugs, including anthracyclines, etoposide, and the active irinotecan metabolite SN-38. The most commonly proposed mechanism for this pharmacokinetic modulation is the encapsulation of paclitaxel in the hydrophobic interior of PCO micelles that occur in aqueous solutions (26, 27). The entrapment of paclitaxel in circulating micelles decreases free paclitaxel available for tissue distribution, contributes to the apparent nonlinear pharmacokinetics of PCO-formulated paclitaxel, as well as the schedule dependency of paclitaxel pharmacokinetics and pharmacodynamics, and has raised concerns about its tumor tissue bioavailability and cytotoxicity (26–29). Additionally, PCO has shown inhibition of the P-glycoprotein (multidrug resistance-1 gene product) in vitro, although the clinical relevance of this observation is still controversial (22, 30, 31).

The drawbacks of the PCO formulation of paclitaxel have resulted in an extensive effort to develop alternative formulations of the drug. Several strategies have been pursued, including novel solvents, the use of liposomal or emulsion formulations, development of analogues or prodrugs, and nanoparticle or microsphere formulations (32–37). AI-850 provides a PCO-free hydrophobic drug delivery system formulation of paclitaxel, which confers several advantages, which include a potential for decreased risk of hypersensitivity reactions, a more convenient administration schedule without premedication, and potentially improved pharmacologic and cytotoxic properties in animal models, all of which support a rationale for clinical development.

The overall toxicity profile of AI-850 defined in this study was similar to that of PCO-formulated paclitaxel. As expected, neutropenia was the principal DLT of AI-850 in this study. Neutropenia was typically brief, reversible, and uncomplicated. At the recommended dose for phase II studies, 205 mg/m2, only one of seven (14%) patients experienced transient grade 4 neutropenia. In addition, mild to moderate AI-850–induced anemia and thrombocytopenia were infrequently observed and mild to moderate and red cell transfusions were rare. Neurosensory symptoms were common and similar to those noted with other paclitaxel formulations (2, 32, 33, 38). The other nonhematologic toxicities, including nausea and vomiting, diarrhea, myalgias, and arthralgias, were mild to moderate and comparable with those of other taxanes. Although the safety profile of AI-850 did not seem to indicate any definite advantage compared with PCO paclitaxel, the small size and the specific phase I methodology make it impossible to detect potential subtle differences between the two formulations of paclitaxel. It is noteworthy that the small but significant differences in both toxicity (hematologic and neurologic) and efficacy of the novel nanoparticle albumin-bound nab paclitaxel were only clearly established following a randomized phase III trial comparing it with PCO paclitaxel (39).

Four patients developed acute AI-850–related infusion reactions. Of these, one resolved spontaneously and three resolved with medical treatment. Although the precise cause of these reactions is not known, the nonhomogeneity of the AI-850 suspension may have contributed, at least in part, to the reaction experienced by the one patient treated in cohort 4B. In addition, several patients even at the lower dose of AI-850 experienced mild flushing at the end of the infusion. Following the implementation of reduced infusion rates, no additional major infusion reactions were observed. Similar reactions have been described with liposomal and/or other microparticle drug formulations (40). The majority of the clinical manifestations of the AI-850–induced drug reactions we observed are compatible with complement activation-related pseudoallergy. This is a class of drug-induced acute immunologically mediated toxicity previously described with radiocontrast media, particulate drug carriers, synthetic nanoparticles, and liposomes (41, 42). However, hypersensitivity reactions to taxanes independent of the formulation vehicle have been well documented, suggesting that the taxane moiety might also be responsible for hypersensitivity reactions (43). However, the precise etiology of these reactions requires further elucidation.

The pharmacokinetic profile of total and free paclitaxel revealed triphasic decay with a mean terminal elimination half-life of 18 to 32 h for total paclitaxel, similar to that reported for PCO-formulated paclitaxel, and 12 to 16 h for free paclitaxel. In this study, paclitaxel Cmax and AUC values increased over the dose range of AI-850 studied. An analysis of our data (n = 21) suggested that the relationship between AI-850 dose and total paclitaxel Cmax (r2 = 0.46) and AUC (r2 = 0.73) was linear (similarly for free paclitaxel), which contrasts with the well-described nonlinearity for PCO-formulated paclitaxel, and largely attributed to PCO (2, 3, 6, 17). The measurement of free paclitaxel immediately after dosing in all patients is compatible with the interpretation that the in vitro release of paclitaxel from the AI-850 formulation seemed to occur in vivo. Although the total paclitaxel AUC values observed in this study at the phase II recommended dose of AI-850 are comparable with those reported with standard doses of PCO-formulated paclitaxel (44–46), it may be hypothesized that paclitaxel tissue penetration could be improved due to the potential increased bioavailability resulting from the lack of PCO. This hypothesis has some limited support from the relatively larger apparent volume of distribution of paclitaxel following administration of AI-850 (629-875 L/m2) compared with that reported for PCO-formulated paclitaxel (99 L/m2) or nanoparticle albumin-bound paclitaxel (400 L/m2; refs. 2, 32, 33, 43–46). However, the clinical relevance of these pharmacokinetic differences of AI-850 is uncertain and needs to be shown by robust proof of increased antitumor activity in the clinical setting. Antitumor activity was observed in this trial. One patient with endometrial carcinoma experienced a prolonged resolution, and one patient with head and neck carcinoma experienced a prolonged resolution of his nonmeasurable pleural disease.

In conclusion, this study showed that the administration of AI-850 by brief (<30 min) infusion every 3 weeks without premedication is feasible at doses of 205 mg/m2. However, AI-850 did not show robust evidence of pharmacokinetic or pharmacodynamic advantages when compared with the previously published data about other paclitaxel formulations. Nevertheless, this study clearly supports the "proof of concept" that the hydrophobic drug delivery system microparticle formulation is a potential alternative for paclitaxel and possibly other lipophilic compounds.


   Footnotes
 
Grant support: Acusphere, Inc., Watertown, MA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/13/06; accepted 12/14/06.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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