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Clinical Cancer Research Vol. 12, 4274-4282, July 15, 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors

Linda L. Garland1, Manuel Hidalgo2, David S. Mendelson3, David P. Ryan4, Banu K. Arun6, Jennifer L. Lovalvo7, Irene A. Eiseman7, Stephen C. Olson7, Peter F. Lenehan7 and Joseph P. Eder5

Authors' Affiliations: 1 Arizona Cancer Center, University of Arizona, Tucson, Arizona; 2 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland; 3 Arizona Cancer Center, University of Arizona, Scottsdale, Arizona; 4 Massachusetts General Hospital, Harvard University; 5 Dana-Farber Cancer Center, Harvard University, Boston, Massachusetts; 6 M.D. Anderson Cancer Center, University of Texas, Houston, Texas; and 7 Pfizer Global Research and Development, Ann Arbor, Michigan

Requests for reprints: Linda L. Garland, Arizona Cancer Center, 1515 North Campbell Avenue, Ste. 1969E, Tucson, AZ 85724. Phone: 520-626-3434; Fax: 520-626-2225; E-mail: lgarland{at}azcc.arizona.edu.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose.

Experimental Design: Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing.

Results: CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics.

Conclusions: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.

Aberrant signaling through the erbB family of receptors, which includes erbB-1 [epidermal growth factor receptor (EGFR)], erbB-2, erbB-3, and erbB-4, plays an important role in the development and progression of a wide range of cancers. The majority of solid tumors express one or more members of the erbB receptor family, especially EGFR and erbB-2 (1, 2); tumor types include breast, ovarian, prostate, gastric, head and neck carcinoma, non–small cell lung carcinoma (NSCLC), and glioblastoma (3–10). Tumors that overexpress these receptors generally have a more aggressive phenotype and a worse clinical prognosis (11, 12).

CI-1033 (canertinib dihydrochloride; Fig. 1 ) is a 4-anilinoquinazoline derivative that acts as a highly selective, irreversible ATP binding site–directed inhibitor of erB-1, erB-2, and erB-4 tyrosine kinases with IC50 values in the low nanomolar/liter concentrations (13). Treatment with CI-1033 completely inhibited EGFR autophosphorylation in A431 human epidermoid carcinoma and MDA-MB-468 human breast cancer cells. Concentration-dependent inhibition of in vitro clone formation has been seen for a wide array of human tumors, including breast, ovary, kidney, liver, pancreas, and prostate. Oral administration of CI-1033 to animals bearing human tumor xenografts delayed growth of H125 (NSCLC) and MB-231 (breast cancer; ref. 14). Moreover, long-term administration (daily gavage, days 1-5 for 10 weeks over a 12-week period) of CI-1033 to mice bearing A431 xenografts caused long-term tumor regression (>9 weeks) without emergence of a drug-resistant population of tumor cells (15). Preclinical studies support an oral continuous daily dosing schedule. The predominant dose-limiting toxicity (DLT) noted in animal toxicology studies is gastrointestinal (diarrhea, emesis, gastrointestinal mucosal erosion, atrophy, and intestinal villus blunting; ref. 16). In vitro combination studies of CI-1033 with cytotoxic chemotherapy agents have shown synergistic activity with topotecan, gemcitabine, cisplatin, and SN-38 (17, 18). In vitro sequencing studies with CI-1033 in combination with docetaxel have shown that antitumor activity is diminished when CI-1033 dosing either precedes or is concurrent with docetaxel dosing.8


Figure 1
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  		Fig. 1. Chemical structure of CI-1033.

 
Phase I studies of CI-1033 as a single oral agent have been conducted in advanced cancer patients using a range of weekly and continuous daily schedules, with CI-1033 doses from 2 to 1,000 mg (19–21). The most commonly reported adverse events have been rash, diarrhea, nausea, vomiting, and asthenia. CI-1033 was given on a 14-day continuous daily dosing schedule every 21 days; the maximum tolerated dose and recommended phase II dose of CI-1033 were both 450 mg/d.

Preliminary evidence of antitumor activity reported in phase I studies of CI-1033 includes a durable complete response in a patient with locally advanced squamous cell carcinoma of the skin and a high frequency of stable disease in patients with NSCLC, squamous cell skin cancer, and breast carcinoma. Pretreatment and posttreatment tumor biopsies from patients treated on phase I studies of CI-1033 showed 40% to 50% inhibition of erbB-1 phosphorylation after 7 days of dosing in a range from 50 to 450 mg/d. Inhibition of phosphorylation was not dose related and was maintained over a 7-day drug-free interval, consistent with preclinical data that show that an irreversible erbB tyrosine kinase inhibitor (TKI), such as CI-1033, is capable of inducing prolonged suppression of receptor kinase activity (22). These biomarker data support using an intermittent CI-1033 dosing regimen as an effective schedule to maintain continued suppression of erbB receptor–mediated cell signaling.

Given the preclinical antitumor activity and preliminary clinical activity of CI-1033, as well as its acceptable safety profile as a single agent, we conducted a dose escalation study of CI-1033 in combination with docetaxel, a taxane with broad anticancer activity in solid tumors. The primary objective was to define the safety profile and pharmacokinetics of CI-1033 in combination with docetaxel, including determination of DLTs and maximum tolerated dose. The secondary objectives were to seek preliminary evidence of antitumor activity and determine the recommended phase II dose for the combination.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient selection. Eligibility criteria included pathologically confirmed advanced-stage nonhematologic malignancies for which docetaxel was a reasonable treatment option, at least 18 years of age, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of >12 weeks, ability to swallow intact CI-1033 capsules, adequate hematopoietic (neutrophil count ≥ 1,500/mL, platelets ≥ 100,000/mL), hepatic [bilirubin ≤ upper limit of normal (ULN) and serum aspartate aminotransferase and alanine aminotransferase ≤ 1.5 times ULN], and renal function (creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft and Gault formula). Treated central nervous system metastases were allowed if patients were neurologically stable for at least 3 months, had discontinued corticosteroid treatment, and had recovered from effects of radiation or surgery. Principal exclusion criteria included more than one prior chemotherapy regimen for the current cancer (prior adjuvant chemotherapy, including taxane-containing regimens, was allowed), known severe hypersensitivity reactions to docetaxel or other drugs formulated in polysorbate 80, grade ≥2 peripheral neuropathy, pregnancy or breastfeeding, and known malabsorption syndrome or other condition that may impair absorption of study medication.

Patient recruitment was undertaken at the Dana-Farber Cancer Institute, the Arizona Cancer Center, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, and the M.D. Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practice. The protocol was approved by local institutional review boards. Written informed consent was obtained from each patient before enrollment on the study.

Study design and treatment plan. This was an open-label, noncomparative, dose-finding, multicenter phase I study dose escalation study. Docetaxel was given on day 1 of each 21-day cycle as a single 1-hour infusion. Oral dexamethasone (8 mg twice daily) was given for 3 days, starting 1 day before docetaxel administration. Starting on day 2, CI-1033 was given as a single oral dose daily for 14 days of each 21-day cycle, with a 6-day drug-free period per cycle.

Adverse events were categorized according to the National Cancer Institute Common Toxicity Criteria, version 2.0 (ctep.cancer.gov/reporting/CTC-3test.html). Patients could continue to receive treatment with study medications if there was no tumor progression, and if patients were tolerating treatment. Patients were withdrawn from the study for progressive disease, global deterioration of health status without objective disease progression, adverse events that remained intolerable, a significant hypersensitivity reaction to docetaxel despite adequate premedication, grade ≥3 peripheral neuropathy, patient refusal to have further treatment with study drugs, or if the principal investigator deemed it would not be in the patient's best interest to continue therapy.

Study medications. CI-1033 was supplied by Pfizer Global Research and Development (Ann Arbor, MI) as gelatin capsules of 5, 25, and 250 mg. An absolute dose was given irrespective of the patient's body surface area and weight based on previous pharmacokinetic studies that did not show a relationship between drug clearance and either body weight or body surface area. The study drug was stored in a closed container and refrigerated at 2°C to 8°C at study sites. Patients stored CI-1033 at room temperature. Patients were instructed to refrain from consuming food and liquid, other than water, for 2 hours before and 2 hours after each dose and to attempt to take the dose at approximately the same time each day. Patients were not to make up a missed dose. A study medication diary was to be completed by each patient for each cycle of treatment. Commercially available docetaxel was supplied by each study institution.

Table 1 shows the general a priori dose escalation scheme for CI-1033 and docetaxel. CI-1033 was given at a starting dose of 50 mg daily, chosen for its equivalence to one tenth the dose that caused severe toxicity or death in rodents on a weekly times four schedule but that did not cause serious, irreversible toxicity in monkeys. This dose was significantly lower than tolerable single agent doses (up to 450 mg/d) reported in multiple-dose studies. The docetaxel starting dose was 75 mg/m2, a dose that is commonly used in single-agent and combination regimens for a range of solid tumors, including NSCLC, bladder, breast, gastric, and prostate cancers (23). The docetaxel was to remain fixed throughout the dose escalation of CI-1033, unless cohort safety analysis warranted further study of CI-1033 with a lower dose of docetaxel, whereby additional cohorts of the CI-1033 maximum tolerated dose with docetaxel 60 mg/m2 could be studied. At least three patients were to be treated at each dose level; if one of three patients experienced a DLT in cycle 1, at least three additional patients were to be enrolled at that same dose level. CI-1033 was to be escalated in 100% increments until the occurrence of two grade 2 treatment-related adverse events during cycle 1, after which dose escalation of CI-1033 would be limited to 50% increments. Upon the first occurrence of a cycle 1 DLT, the cohort was to be expanded, and the dose escalation increment was limited to ≤40% increments. There was no provision for intrapatient dose escalation. Dose reductions were permitted for both CI-1033 and docetaxel to allow continuation of dosing after recovery of absolute neutrophil count to ≥1,500/mL, platelets to ≥100,000/mL, bilurubin to ≤ULN, aspartate aminotransferase and/or alanine aminotransferase to ≤1.5 x ULN, and return of all other toxicities (except tolerable skin rash or alopecia) to grade ≤1, or to baseline toxicity levels if that toxicity was grade >1 at baseline.


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  		Table 1. A priori dose escalation scheme

 
Definitions of DLT and maximum tolerated dose. A DLT was defined as a treatment-emergent adverse event consisting of grade 4 neutropenia lasting ≥14 days (febrile neutropenia and grade ≥3 neutropenia associated with infection requiring hospitalization were not considered DLTs as they were expected adverse events occurring with relatively high frequency with docetaxel administration alone), grade 4 thrombocytopenia, grade 3 prothrombin time/partial thromboplastin time in the absence of anticoagulation therapy, grade ≥3 nonhematologic toxicity (excluding peripheral neuropathy, hypersensitivity reaction on day 1, nausea/vomiting in the absence of optimal antiemetics, diarrhea in the absence of optimal antidiarrheals, asthenia <2 weeks in duration, tolerable skin rash, hyperglycemia temporally related to corticosteroid premedication), and inability to begin a subsequent treatment cycle within 14 days of the scheduled start date at the current dose due to treatment-related toxicity.

The maximum tolerated dose was defined as the highest dose of CI-1033, in combination with docetaxel, that resulted or ≤33% of subjects at a given dose level experiencing DLT within the first treatment cycle, or when the combined adverse event profile across patients suggested that it was not in the best interest of the patients to further dose escalate study drugs.

Pretreatment and follow-up studies. Screening and pretreatment assessments included a medical history, physical examination, assessment of Eastern Cooperative Oncology Group performance status, electrocardiogram, complete blood count with differential and platelet count, routine serum chemistries, prothrombin time, international normalized ratio, activated partial thromboplastin time, urinalysis, concomitant medications recording, and disease assessment with radiographic studies for tumor measurements.

Patient evaluations done on day 1 of each cycle and at the end of the study included physical exam, Eastern Cooperative Oncology Group performance status, complete blood count with WBC differential, routine serum chemistries, urinalysis, and adverse events recording. A complete blood count with WBC differential was also done on days 3 to 5 of cycle 1 and on days 8 and 15 of each treatment cycle. Prothrombin time, international normalized ratio, and activated partial thromboplastin time were assessed on day 15 of each cycle. Radiographic studies for tumor measurements were done after every three cycles to assess response. Pharmacokinetic sampling is described below. All patients were followed for at least 30 days after the last dose of CI-1033. Responding patients were followed every 2 months until progression, death, initiation of new anticancer treatment, or withdrawal from the study.

Pharmacokinetic sampling and assay. Patients had blood samples collected to determine the pharmacokinetics of CI-1033 and docetaxel. For CI-1033, blood samples were drawn on day 15 of cycle 1 immediately before drug dosing and at 2, 4, 6, and 8 hours after dosing. For docetaxel, blood samples were obtained on day 1 of cycles 1 and 2 immediately before drug dosing and at 0.5, 1 (before stopping the infusion), 1.25, 1.75, 4, 8, and 24 hours after dosing.

For each blood sample, 5 mL of whole blood was collected into heparinized, non-separator green top tubes (for docetaxel pharmacokinetics) and EDTA/ascorbic acid red top tubes (for CI-1033) and immediately placed in an ice-water bath for cooling to <4°C. The samples were vortexed at 3,000 rpm for 15 minutes, frozen, and stored at –20°C or below until assayed. CI-1033 was isolated from a 0.2-mL aliquot of plasma using an acetonitrile protein precipitation reaction with an alkene deuterated CI-1033 internal standard. Separation from supernatant and quantitation were done, respectively, by liquid chromatography on a YMC Cyano 3.0 50-mm column (YMC Co., Ltd., Milford, MA) and mass spectroscopic analysis on a SCIEX Triple Quadrupole API 3000 (MDS Sciex, San Francisco, CA). The resulting range of quantitation for CI-1033 was 1.00 to 500 ng/mL. Overall precision (percentage of coefficient of variation) of quality control samples ranged from 5.5% to 7.7%, whereas overall accuracy (percentage of relative error) ranged from –6.2% to –4.2% across 12 sets of quality control samples assayed over 3 days.

Tumor response assessment. Antitumor activity was evaluated for patients with measurable disease at baseline using the Response Evaluation Criteria for Solid Tumors (24). Changes in tumor size were categorized as complete response, partial response, stable disease, and progressive disease; the latter also incorporating the appearance of new lesions. Confirmation of responses by repeat imaging was required to be documented no less than 4 weeks after original response.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics. Twenty-six patients with advanced solid tumors were treated on the study (Table 2 ). Patient median age was 59.5 years (range, 42-80 years); 15 were men and 11 were women. Nine patients (35%) had a performance status of 0, and 17 patients (65%) had a performance status of 1. The most common tumor histologies were renal cell, cervix uteri, pancreatic, and NSCLC. Seventy-three percent of patients in the study had received no more than one prior chemotherapy regimen. Four patients had received a prior paclitaxel-containing regimen.


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  		Table 2. Patient characteristics

 
Dose escalation. Patients were enrolled into four dosing cohorts (Table 3 ). A total of 77 cycles of study drugs were given (range, 1-9 per patient). Five patients were initially enrolled in dosing cohort 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)]; there were no DLTs in cycle 1, and one event of febrile neutropenia was noted. Eight patients were enrolled in cohort 2 [CI-1033 (75 mg/d) + docetaxel (75 mg/m2)], with one DLT (diarrhea) noted; however, 3 of 8 patients (38%) had febrile neutropenia. Because febrile neutropenia was expected with docetaxel alone, it was not defined as a DLT; however, a 38% incidence during cycle 1 was considered by study investigators to be excessive, prompting a dose de-escalation of CI-1033 to 50 mg/d and of docetaxel to 60 mg/m2 for cohort 3. Six patients were enrolled in cohort 3, with two DLTs noted (confusion and neutropenia in one patient; dyspnea, hypoxia, and interstitial pneumonitis in one other patient). Two of six patients (33%) in this cohort had febrile neutropenia. CI-1033 was further dose reduced by 10% to 45 mg/d, a CI-1033 dose that was only slightly below the lowest dose (50 mg) at which, based on a prior study cited above, resulted in significant inhibition of tumor erbB-1 phosphorylation. Seven patients were enrolled onto cohort 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)]. One DLT (hypersensitivity reaction) was noted, and 2 of 7 patients (29%) had febrile neutropenia. A comparison of the safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)] indicated that the two safety profiles were similar in terms of frequency of febrile neutropenia and non-hematologic toxicity, although the DLT profile differed. However, the CI-1033 (50 mg/d) + docetaxel (75 mg/m2) schedule is the more dose intense and was therefore declared the recommended phase II dose of this combination.


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  		Table 3. Cycle 1 DLTs and incidence of febrile neutropenia

 
Toxicity. A study population of 26 patients was evaluable for toxicity. The most common grade 2 to 4 non-hematologic adverse events (see Table 4 ) were asthenia (31%), diarrhea (27%), alopecia (23%), and stomatitis (19%). Nine patients (35%) had grade 1 skin rash (not shown in Table 4); therefore, the overall incidence of skin rash was 50%, with no grade 3 or 4 rashes reported. One patient, a 69-year-old male with emphysema, coronary artery disease, and nasopharyngeal carcinoma with metastases to the lung, lymph nodes, and liver, developed treatment-related interstitial pneumonitis on day 15 of cycle 1 (the end of continuous dosing of CI-1033); the patient was withdrawn from treatment, and he recovered from this event.


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  		Table 4. Grade 2 to 4 nonhematologic toxicities (all cycles, worst grade toxicity by patient)

 
Grade 2 to 4 hematologic adverse events attributed to CI-1033 and docetaxel are listed in Table 5 . The most frequent toxicities were leukopenia and neutropenia (27% and 54%, respectively) and anemia (27%). Ten patients (38%) experienced febrile neutropenia during the study, with eight events occurring during cycle 1 (manifested by days 8-12) and one event each in cycles 2 and 4. These patients were treated with granulocyte colony-stimulating factor with or without a docetaxel dose reduction. No grade 2 to 4 thrombocytopenia was noted.


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  		Table 5. Hematologic toxicity (all cycles, worst grade toxicity by patient)

 
Grade 2 to 4 biochemical toxicities were infrequent, with grade 2 to 3 hyperglycemia the most common, noted in 15% of patients.

Three patients died within 30 days of starting cycle 1 of study treatment: two with progressive disease and one with respiratory failure not related to study treatment. Six patients were withdrawn from the study due to the following treatment-related adverse events: docetaxel-related hypersensitivity reaction (two patients), febrile neutropenia (two patients), interstitial pneumonitis (one patient), and palpitations (one patient).

Five patients required dose reductions of docetaxel, all related to febrile neutropenia. No reductions were made for CI-1033 in the four dosing cohorts.

Antitumor activity. Twenty-one patients had evaluable tumor response data. Best overall response is shown in Table 6 . Two patients had confirmed objective responses. One previously chemotherapy untreated patient with cervix uteri carcinoma metastatic to lung treated with CI-1033 (50 mg/d) + docetaxel (60 mg/m2) achieved a complete response after cycle 6 of treatment with a duration of ≥196 days. One patient with NSCLC metastatic to mediastinal lymph nodes and bony skeleton treated with six cycles of CI-1033 (45 mg/d) + docetaxel (60 mg/m2) had a partial response with a duration of ≥170 days. Additionally, one patient with ureteral cancer metastatic to lung who was treated with CI-1033 (45 mg/d) + docetaxel (60 mg/m2) had stable disease for a duration of 134 days.


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  		Table 6. Antitumor activity: best overall response

 
Pharmacokinetics. Average plasma concentrations of CI-1033 evaluated on day 15 (following administration the 14th dose of CI-1033) for cycle 1 for all 26 patients are summarized in Table 7 , with corresponding relative SD and average values for a 50 and 75 mg dose based on population pharmacokinetics from prior monotherapy trials patients (21, 25). A concentration versus time plot for CI-1033 day 15 pharmacokinetic data is presented in Fig. 2 . Patients exhibited CI-1033 pharmacokinetic profiles that, on average, were ~60% higher than expected, based on experience with similar monotherapy regimens in other phase I studies. Given the considerable variability in these point estimates, with relative SD ranging from 25% to 133%, the differences are not statistically significant. The sparse sampling strategy employed in this study, designed to capture large changes in systemic exposure resulting from a pharmacokinetic interaction between CI-1033 and docetaxel, prevents accurate estimation of a terminal elimination half-life or drug clearance for CI-1033 without relying on Bayesian methods.


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  		Table 7. Day 15 CI-1033 systemic exposure (ng/mL) after 14 days of dosing in cycle 1 and corresponding simulated values using a population pharmacokinetic model of CI-1033 monotherapy

 

Figure 2
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  		Fig. 2. Plasma concentration profile of CI-1033 on day 15.

 
Day 1 docetaxel concentrations for 24 of 26 patients with evaluable pharmacokinetic profiles were generally consistent with expectations based on the docetaxel pharmacokinetic literature (26). Table 8 summarizes docetaxel systemic exposure by dosing cycle and body surface area–normalized dose. The area under the curve [AUC(0-{infty})] and Cmax increased with increasing dose, whereas the dose-normalized AUC(0-{infty}) seemed somewhat independent of dose. Docetaxel pharmacokinetic profiles for 14 patients are available for both cycles 1 and 2; for those patients, there was no consistent trend for exposure to increase or decrease for the dose-normalized AUC(0-{infty}) during cycle 2. In fact, this variable decreased by 5% on average in cycle 2 relative to cycle 1; however, these differences were not statistically significant.


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  		Table 8. Docetaxel systemic exposure following single 1-hour infusions on day 1 (cycle 1) and day 22 (day 1, cycle 2)

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
We have reported the results of a phase I safety and pharmacokinetic study of the pan-erbB TKI, CI-1033, given orally for 14 days of a 21-day cycle in combination with docetaxel given once every 21 days in patients with advanced solid tumors. This study enrolled patients at multiple sites to expedite enrollment. Interest in this combination is based on the finding that many solid tumors that are sensitive to the antitumor activity of docetaxel (i.e., breast, NSCLC, prostate, esophageal, squamous cell of the head and neck, ovarian, and gastric cancers) commonly overexpress erbB family receptors. We showed that two different dose levels of CI-1033 in combination with docetaxel [i.e., CI-1033 (50 mg/d) + docetaxel (75 mg/m2) and CI-1033 (45 mg/d) + docetaxel (60 mg/m2)] had similar toxicity profiles; because the former dose level is more dose intense, it is the preferred dose level for further phase II study.

The study used a 14-day dosing schedule of CI-1033, which began 24 hours after docetaxel and incorporated a 6-day interval between CI-1033 dosing and subsequent docetaxel administration. This schedule design was based on preclinical data showing diminished antitumor activity when CI-1033 was dosed before or concurrently with docetaxel. It has been suggested that G1 arrest induced by EGFR TKI interferes with the cell cycle phase–dependent antitumor activity of chemotherapy (27).

A relatively high incidence of cycle 1 febrile neutropenia (38%) in the second dose escalation cohort [CI-1033 (75 mg/d) + docetaxel (75 mg/m2)] was judged by study investigators to be excessive despite the small sample size, given that patient eligibility limited the number of prior chemotherapies to 0 to 1 (excluding prior adjuvant therapy). In comparison, the incidence of febrile neutropenia reported for single-agent docetaxel (75 mg/m2) given on an 21-day schedule in pretreated NSCLC patients ranged from 1.5% to 12.7% over all treatment cycles (28–30). Because all patients had screening bilirubin ≤ULN and aspartate aminotransferase/alanine aminotransferase ≤1.5 times ULN, it is unlikely that decreased docetaxel clearance, as has been reported with elevated levels of bilirubin and/or transaminases (26), was a factor in this toxicity profile. Furthermore, the pharmacokinetic analysis for docetaxel was generally consistent with expected docetaxel drug exposures.

When the dose of CI-1033 was increased from 50 to 75 mg/d while keeping the dose of docextaxel constant at 75 mg/m2, there was an increased incidence of grade 4 neutropenia (20% versus 63%, respectively), suggesting a dose-response effect for CI-1033. However, it is unlikely that CI-1033 alone contributed to the high incidence of neutropenia seen in this trial as no leukopenia, neutropenia, or febrile neutropenia has been reported in preclinical and phase I studies of single-agent CI-1033 (13, 20) nor in trials using the EGFR TKIs gefitinib and erlotinib (31–34) and lapatinib, a dual erbB-1/erbB-2 TKI (35).

In studies using concurrent dosing of EGFR TKIs and taxane chemotherapy, with or without platinum agents, no unpredictably high rates of neutropenia or febrile neutropenia have been reported. Phase III trials of paclitaxel plus carboplatin in combination with gefitinib or erlotinib in previously treated NSCLC patients have reported neutropenia rates of 8% to 35% and febrile neutropenia rates of 0% to 4%, not significantly different from the chemotherapy-only study arms (36, 37). In a study of gefitinib (250 or 500 mg daily) in combination with docetaxel in first-line or second-line NSCLC, no excessive hematologic toxicity was reported (38). However, in a non–taxane-based phase II trial of gefitinib with irinotecan, 5-fluorouracil, and leucovorin, 62% of patients had grade 3 and 4 neutropenia, a rate that was considered by the study investigators to be excessive. A pharmacokinetic interaction between gefitinib and irinotecan, or an interaction between gefitinib and the multidrug resistance ATP-binding cassette transporter that mediates irinotecan cellular efflux, were invoked as possible explanations (39). It is likely that the higher-than-expected incidence of febrile neutropenia we have reported here is simply a function of random variation and small sample size. However, given its unique irreversible pan-erbB inhibitory mechanism of action, it is still possible that CI-1033 contributed to the relatively high incidence of febrile neutropenia via a pharmacodynamic interaction.

The toxicity profile noted for the CI-1033/docetaxel combination over the four dosing levels was otherwise fairly comparable with reports of other erbB family receptor inhibitors when given in combination with docetaxel (38), with a predominance of skin, constitutional, and gastrointestinal toxicities. Skin rash has been a pharmacodynamic marker of tumor response in some studies of EGFR inhibitors (40, 41). In the current study, skin rash was noted in 50% of patients, although the majority of rashes were mild (grade 1), with no grade 3 or 4 rash noted. Grade 3 skin rash has been reported as a treatment-related event in other studies using doses of CI-1033 of ≥250 mg/d (20, 21).

Like trials with lapatinib, no drug-related cardiac dysfunction, as has been well-documented with the erbB-2 targeted monoclonal antibody trastuzumab, was seen in this study (35, 42). One Caucasian male patient with nasopharyngeal carcinoma metastatic to the lung, lymph nodes, and liver developed treatment-related interstitial pneumonitis during cycle 1. Interstitial lung disease is a well-described, albeit rare, toxicity noted in studies of EGFR TKIs (43) In addition, there are rare reports of docetaxel-associated interstitial pneumonitis (44, 45).

Analysis of CI-1033 pharmacokinetic variables showed that a docetaxel effect on CI-1033 disposition was possible, as CI-1033 plasma concentrations were ~60% higher than expected, although there was a broad range of relative SD around the average concentrations. This interindividual variability in systemic exposure, together with the limited number of patients in each dosing cohort, precludes statistical evaluation of these differences due to lack of power. Any further evaluation of this regimen should include a more rigorous evaluation of the potential effects of docetaxel on CI-1033 pharmacokinetics.

Analysis of docetaxel pharmacokinetic variables indicated that compared with historical data, no significant alteration in the pharmacokinetics of docetaxel was observed. Although docetaxel has a 12-hour half-life, the vast majority of systemic exposure is in the first 24 hours following dosing. Typically, <5% of the AUC is realized beyond 24 hours after dose. In this study, the percentage of AUC extrapolated beyond 24 hours averaged 3.9%, with a range from 1.4% to 8.7%. Assuming CI-1033 had an effect on docetaxel kinetics, one would see this effect only on this last fraction of patient exposure in the current study design, where CI-1033 dosing begins on day 2. It should be noted that the pharmacokinetic sampling scheme used would not capture such an effect because the last docetaxel sample was drawn 24 hours after docetaxel dosing, before the first dose of CI-1033 is given. However, even if there were a profound effect of CI-1033 on docetaxel clearance beyond 24 hours after docetaxel infusion, a clinically significant alteration in docetaxel systemic exposure would be unlikely.

The confirmed objective antitumor activity seen in uteri cervix carcinoma (complete response) and NSCLC (partial response) occurred in dosing cohorts using CI-1033 (45-50 mg/d) + docetaxel (60 mg/m2). The achievable dose range of CI-1033 in the current study is within the range in which CI-1033 inhibits erbB-1 phosphorylation in human tumors (22).

In summary, we report that in advanced solid tumor patients, the irreversible pan-erbB TKI CI-1033 can be combined with docetaxel on an intermittent schedule that avoids concurrent drug dosing, diminishing the risk of antagonism between these agents. A relatively high incidence of febrile neutropenia was noted in this small study population. Future investigations of this combination should rigorously analyze an effect of docetaxel on CI-1033 pharmacokinetics.


   Acknowledgments
 
We thank Meredith Sheeran and Shelly Welch for their expert assistance in providing summarization of the clinical study data.


   Footnotes
 
Grant support: Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, Michigan.

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.

8 Unpublished data. Back

Received 11/15/05; revised 3/ 8/06; accepted 5/ 4/06.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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