Male and female patients who were 18 years of age or older, had histologically proven advanced solid tumors for which curative therapy was not available, and were considered eligible for treatment with standard doses of single-agent docetaxel were recruited. All patients provided written and informed consent. Other key inclusion criteria included (a) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (b) resolution of all acute toxic effects of prior chemotherapy, radiotherapy, or surgical procedure to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade ≤ 1; (c) adequate hematologic parameters (absolute neutrophil count [ANC] ≥1,500/μL; platelets ≥100,000/μL; hemoglobin ≥9 g/dL) and hepatic, renal, and cardiac function, including left ventricular ejection fraction (LVEF) ≥50% without the support of cardiotropic agents.
Exclusion criteria included (a) prior treatment with high-dose chemotherapy requiring stem cell rescue or prior irradiation to ≥25% of the bone marrow; (b) surgery, systemic therapy or any investigational agent within 4 weeks prior to starting study treatment; (c) extensive prior anthracycline or anthracenedione exposure (i.e. cumulative doxorubicin exposure >300 mg/m2, epirubicin exposure >900 mg/m2, mitoxanthrone exposure >120 mg/m2, doxorubicin liposome injection exposure >550 mg/m2); (d) centrally located lung lesions (unless irradiated with ≥30 Gy >2 weeks prior to starting study treatment); (e) NCI CTCAE grade 3 hemorrhage within 4 weeks of study entry, significant hemoptysis, or grade ≥ 2 neuropathy or edema; (f) diagnosis of a second malignancy within the last 5 years, except for adequately treated basal or squamous cell skin cancer, localized prostate cancer, or in situ bladder or cervical cancer; (g) known brain metastases, spinal cord compression or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease; (h) severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within 12 months of study entry or ongoing cardiac dysrhythmias (grade ≥ 2), atrial fibrillation or QTc interval prolongation; (i) history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80. Patients who were pregnant or breastfeeding were also excluded.
Study design and treatment
In this phase I, open-label, multicenter, non-randomized, dose-finding study, successive cohorts of patients received IV docetaxel q21d in combination with escalating daily doses of oral sunitinib.
Sunitinib was administered using one of two dosing schedules over approximately 18 weeks: 4 consecutive weeks of once-daily treatment followed by 2 weeks off treatment (Schedule 4/2) in three repeated 6-week cycles, or 2 consecutive weeks of once-daily treatment followed by 1-week off treatment (Schedule 2/1) in six repeated 3-week cycles. To enable sampling for PK profiles, on Schedule 4/2, patients were administered sunitinib once daily on days 4–31 in cycle 1. Patients were administered sunitinib daily on days 1–28 in subsequent cycles. On Schedule 2/1, patients were administered sunitinib daily on days 1–14 with the exception of patients undergoing full-profile PK assessments; these patients were administered sunitinib on days 3–16. In subsequent cycles, sunitinib was administered daily on days 1–14. To ensure patient safety, the starting dose level was sunitinib at 25 mg/day (50% of its previously determined maximum tolerated dose [MTD] as monotherapy on Schedule 4/2) with docetaxel at 60 mg/m2 q21d (the lowest dose recommended in the United States package insert). MTD was defined as the highest dose at which 0/3 or 1/6 patients experienced a DLT (protocol-defined as grade 3 or 4 non-hematologic toxicity lasting ≥7 days, or grade 4 neutropenia ≥7 days, febrile neutropenia [fever >38.5°C for ≥24 h], neutropenic infection, and/or grade ≥ 3 thrombocytopenia with bleeding or lasting ≥7 days) during the first 31 or 21 days of cycle 1 (Schedules 4/2 and 2/1, respectively), with the next highest dose having ≥2/3 or ≥2/6 patients experiencing a DLT. Additional patients were enrolled at the MTD to further characterize safety and tolerability at this dose level.
Escalating doses of sunitinib and docetaxel were first studied on Schedule 4/2, starting at dose level 0 (Table ). Following determination of Schedule 4/2 MTD, subsequent patients were enrolled onto Schedule 2/1, starting at the Schedule 4/2 MTD. Dose escalation and de-escalation occurred as detailed in Table in order to determine the MTD on Schedule 2/1. Initial cohorts of 3 patients were enrolled onto Schedule 4/2, and any cohort was expanded to 6 patients if a DLT was observed. An additional 3 patients could be included at specific dose levels to further explore the observed toxicity profile.
Sunitinib and docetaxel dosing schedules, and dose-limiting toxicities
Patients were treated for the entire study period unless there was disease progression, lack of tolerance, or withdrawal of consent. Dose reductions by one or two dose levels of either or both study drugs were permitted after completion of the DLT observation period. After completing the study period, patients who were receiving clinical benefit were offered participation in an extended-use protocol of single-agent sunitinib.
The study was performed with institutional ethics committee approval, and in accordance with International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki (1996 Version), and applicable local regulatory requirements and laws.
Study endpoints and assessments
The primary objective of this trial was to assess the MTD and overall safety of sunitinib in combination with docetaxel when sunitinib was administered on Schedule 4/2 or 2/1 in patients with solid tumors. Secondary objectives were to evaluate PK profiles and the efficacy of this treatment combination.
Safety was assessed by recording adverse events (AEs) documented from the first day of study medication (docetaxel or sunitinib) and graded using NCI CTCAE, version 3.0. Other safety assessments included urinalysis at screening, hematology and blood chemistry parameters, and physical examinations. Twelve-lead electrocardiograms (ECG) and multigated acquisition (MUGA) scans were performed at screening and during treatment (cycles 1 and 3, respectively for Schedule 4/2, and cycles 2 and 6, respectively for Schedule 2/1).
Objective tumor response was assessed in patients with measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) [23
]. Radiologic tumor assessments were performed at screening, during treatment (during cycles 1 and 2 for Schedule 4/2, and cycles 2 and 4 for Schedule 2/1), at the end of the dosing period (if not performed within the previous 6 weeks), whenever disease progression was suspected and to confirm response (at least 4 weeks after initial evidence of response).
Full PK profiles for docetaxel and sunitinib were obtained for all patients on Schedule 4/2 and those patients enrolled on the MTD expansion cohort on Schedule 2/1. PK parameters for sunitinib, its primary metabolite (SU12662), total drug (sunitinib + SU12662), and docetaxel are reported as well as trough levels. Full PK profiles for docetaxel were obtained on days 1 and 22 of cycle 1 on Schedule 4/2 and on day 1 of cycles 1 and 2 on Schedule 2/1, using blood samples collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h post-docetaxel dose. Docetaxel PK parameters were analyzed at Covance Laboratories (Madison, WI) using a validated liquid chromatographic–tandem mass spectrometric method in accordance with Covance’s SOPs. Full PK profiles for sunitinib and SU12662 were obtained on days 18 and 22 on Schedule 4/2 and on day 3 of cycle 1, and day 1 of cycle 2 on Schedule 2/1. Blood samples were collected pre-dose, and 1, 2, 4, 6, 8, 12, and 24 h post-sunitinib dose. Additional trough blood samples were collected for patients on Schedule 4/2 on cycles 2/3 days 1 and 28 (day 31 of cycle 1 only) and on Schedule 2/1 on cycles 1–6 day 1 and day 14 of cycle 1. Sunitinib PK parameters were analyzed at Bioanalytical Systems Inc (BASi, West Lafayette, IN) using a validated liquid chromatographic–tandem mass spectrometric method in accordance with BASi’s standard operating procedures (SOPs).
Maximum enrollment into the trial was dependent upon the observed safety profile, which determined the number of patients per dose level and number of dose escalations. The populations for safety analyses included all patients who had taken at least one dose of study medication. Efficacy analyses were performed on patients with measurable disease at baseline who received at least one dose of sunitinib and had a response assessment made by the investigator.
Descriptive statistics were used to summarize all patient characteristics, safety parameters, efficacy endpoints, and PK parameters. PK parameters were calculated for each subject by noncompartmental analysis using WinNonlin Version 4.1a. Samples below the limit of quantitation were included as zero. If pre-dose concentrations of a study drug or metabolite for an individual were >5% of Cmax, a dose correction was made. Only patients with paired observations at each dose level were included in descriptive statistics for PK profiles of sunitinib, SU12662, total drug, and docetaxel, and for comparison of PK parameters when sunitinib or docetaxel was administered alone or in combination. Trough data are reported for all patients with trough observations.