Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

Eligible patients were aged ≥18 years with a histologically confirmed diagnosis of advanced breast cancer, gastric cancer, non-small cell lung cancer (NSCLC), or RCC and were unsuitable for standard anticancer therapy because of treatment-refractory disease or other reasons. These malignancies were selected as inclusion criteria because they are the most common cancers among the Chinese population [18] and have been shown to respond to everolimus in non-Chinese patient populations with advanced breast cancer, gastric cancer, NSCLC, or RCC [11, 19‐22]. Patients had to have ≥1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) [23]; adequate bone marrow, liver, and renal functions; controlled diabetes (fasting serum glucose ≤1.5 × upper limit of normal); a body weight ≥50 kg and ≤100 kg with a body mass index ≤32 kg/m2; and a World Health Organization performance status of 0-2. Exclusion criteria included primary central nervous system tumors or metastases, uncontrolled infection, seropositive for human immunodeficiency virus or hepatitis B/C, gastrointestinal impairment or disease that could significantly alter the absorption of everolimus, antineoplastic therapy within 30 days (6 weeks for nitrosoureas or mitomycin-C), radiation therapy within 4 weeks, surgery within 3 weeks before starting study drug, or treatment with strong CYP3A inhibitors or inducers within 5 days before starting study drug. All patients gave written informed consent before study entry according to the Good Clinical Practice guidelines of the International Conference on Harmonization and national regulations. The protocol was reviewed and approved by the ethics committee at each participating institution.

In this randomized, open-label, phase I study conducted in 4 clinical centers in China, patients with advanced cancer were randomized 1:1 to receive everolimus 5 mg/day or 10 mg/day (Figure 1). Dose modifications were permitted when patients could not tolerate the protocol-specified dosing schedule. In the event of everolimus-suspected toxicity, the investigator was to follow the study drug modification/interruption guidelines. A patient was kept at the initial dose level (10 mg daily or 5 mg daily) when the toxicity was tolerable. However, if toxicity became intolerable, the study drug was interrupted until recovery to grade ≤1 and then re-introduced at the initial dose or at a lower dose level (reduced to 5 mg daily for the 10 mg/day cohort, or 5 mg every other day for the 5 mg/day cohort) depending on the type of toxicity and its severity. All study drug interruptions or dose modifications were to be documented on the case report/record form. Study drug was provided by Novartis Oncology (Florham Park, NJ), the trial sponsor. Randomization was stratified by center and cancer type, with each center representing 1 cancer type.

Patients continued treatment until tumor progression, unacceptable toxicity, death, or discontinued if the investigator or patient felt it was in the patient's best interest to discontinue participation. Dose modifications were allowed in the event of adverse events grade ≥2. Specific nomograms were followed to manage patients who developed known toxicities of everolimus, such as non-infectious pneumonitis.

Primary end points were PK parameters and safety and tolerability. The secondary end point was objective response. Evaluations were performed within 2 days before the first dose of everolimus (baseline), weekly for the first 4 weeks, every other week for the second and third month, and monthly thereafter. A safety follow-up was conducted 28 days after the last dose of everolimus.

Blood samples for everolimus 24-h PK profile were collected on day 15 pre-dose and at 1, 2, 4, 6, 8, and 24 h post-dose; blood samples for everolimus trough concentration were collected pre-dose on days 2, 8, 16, and 22. Everolimus concentration was determined after liquid extraction by a liquid chromatography-mass spectroscopy method with lower limits of quantification for everolimus of 0.3 ng/mL. PK parameters of everolimus determined for each cohort included the maximum blood concentration (C_max), minimum blood concentration (C_min), time to maximum concentration (T_max), area under the dosing curve (AUC_0-τ), and total body apparent clearance of drug from the blood (CL/F). PK analyses were performed on all patients in the safety population with a sufficient number of evaluable blood samples.

Safety assessments included incidence, severity, and treatment relationship of adverse and serious adverse events and the regular monitoring of hematology, serum and urine chemistry, vital signs, and physical condition. Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3.0 [22]. The safety population consisted of all patients who received ≥1 dose of study drug and had ≥1 post-baseline safety assessment.

Tumor response and progression was assessed locally for all randomized patients using RECIST criteria. A computed tomography scan or magnetic resonance image of the chest, abdomen, and pelvis was performed at screening and every 2 months (±7 days) thereafter. Confirmatory imaging results ≥4 weeks after an initial observation were required for a positive assessment of complete or partial response.

This final analysis was performed after all patients had received 6 months of study drug or had discontinued from the study.

A total of 27 patients were screened for study participation. Of the 24 Chinese patients (6 patients per tumor type) enrolled in the study, 12 received everolimus 5 mg/day and 12 received everolimus 10 mg/day. Patient demographic and baseline characteristics, including treatment history, were similar between the 2 dose cohorts (Table 1). At the time of data cutoff for the final analysis, 2 patients with RCC in the everolimus 5 mg/day cohort and 1 patient with breast cancer in the everolimus 10 mg/day cohort were still receiving treatment. A total of 10 patients in the everolimus 5 mg/day group and 11 patients in the everolimus 10 mg/day group had discontinued. The most common reason for treatment discontinuation was disease progression (Table 2). All 24 patients were included in the full analysis set and in the safety population.

The median durations of exposure to everolimus were 136.5 days in the 5 mg/day cohort and 63.5 days in the 10 mg/day cohort. The patients with RCC in this study remained on treatment the longest with median duration of exposure of 184.5 (range, 65-130) compared with patients with breast cancer (93.0 days; range, 47-243), gastric cancer (88.5 days; range, 46-247), or NSCLC (73.5 days; range, 42-153). For the 3 patients still participating in the study at the time of data cutoff, everolimus exposures were 209 and 230 days for the 2 patients with RCC and 243 days for the patient with breast cancer.

Absorption of everolimus after oral administration was rapid to moderate with a median T_max of 3.0 h in the 5 mg/day cohort and 2.0 h in the 10 mg/day cohort (Figure 2, Table 3). The values for C_min, C_max, and AUC_0-τ with 10 mg/day were approximately 2-fold those at 5 mg/day and increased dose proportionally. After reaching steady state on day 8, mean (± standard deviation) values of CL/F were 16.7 (±5.6) and 18.2 (±7.2) L/h at doses of 5 and 10 mg/day, respectively (Figure 2). The similarity of CL/F between the 5 mg/day and 10 mg/day dose cohorts supports PK linearity.

All 24 patients reported ≥1 adverse event; most were grade 1/2 events that resolved without additional treatment (Table 4). The most common adverse events with a suspected relationship to everolimus in the everolimus 5 mg/day and 10 mg/day dose cohorts were hyperglycemia (16.7% and 41.7%) and fatigue (16.7% and 33.3%, respectively). Three (25%) patients in each dose cohort had grade 3 adverse events suspected to be related to everolimus.

Three deaths (1 breast cancer and 2 NSCLC patients) occurred during the study; 2 were in the 10 mg/day cohort and 1 was in the 5 mg/day cohort. These events were considered unrelated to everolimus. Underlying cause for all 3 patients was disease progression. One patient with NSCLC in the 10 mg/day cohort experienced venous embolism, which led to aggravated condition and death. Another patient with NSCLC in the everolimus 5 mg/day cohort experienced cerebral hemiplegia related to brain metastases from lung cancer. One patient with breast cancer discontinued study treatment on day 47 due to disease progression and died 2 days later.

No complete or partial responses were observed. The best overall tumor response was stable disease for 10 patients (83.3%) in the everolimus 5 mg/day dose cohort and 6 (50.0%) patients in the everolimus 10 mg/day cohort. Median duration of stable disease was 5.03 months (95% confidence interval [CI], 2.89-8.05) for the 5 mg/day dose cohort and 6.08 months (95% CI, 3.58-not reached) for the 10 mg/day dose cohort. Of the patients with stable disease, 3 had breast cancer, 4 had NSCLC, 5 had gastric cancer, and 4 had RCC. Two (16.7%) patients in the 5 mg/day cohort and 5 (41.7%) patients in the 10 mg/day cohort had progressive disease as best overall response. One patient with NSCLC in the 10 mg/day group had a best overall response of unknown (died before first post-baseline tumor assessment).