Forty-three patients were enrolled into the trial: 25 patients on Schedule 2/1 and 18 patients on the CDD schedule. The median age of patients was 58 years (range: 32–76). Baseline characteristics are summarized in .
Subject evaluation groups
The doses of study treatment evaluated are shown in . The sponsor and investigators agreed to further expand dose level 2 for Schedule 2/1 and dose level B for the CDD schedule to better characterize the safety profile of the combination regimens. Initially, 6 patients were enrolled in the first cohort at dose level 1 on Schedule 2/1 (including 2 patients who were not evaluable for DLT: n = 1 developed a hypersensitivity reaction to paclitaxel; n = 1 experienced disease progression prior to cycle 1 day 1). One DLT (grade 4 papilledema) was observed and this cohort was expanded to 9 patients, resulting in 7 patients evaluable for DLTs. Because no additional DLTs were observed, patients were next enrolled at dose level 2 and, among 3 patients initially enrolled who were evaluable for DLTs (1 further patient discontinued early due to disease progression prior to cycle 1, day 1), one DLT was observed; this cohort was then expanded to 13 patients. While the dose level 2 cohort was being expanded, the protocol was amended to allow concurrent enrollment into Schedule 2/1 and the CDD schedule. Three patients were enrolled onto dose level 3 and no DLTs were observed. Following enrollment into dose level 3, further DLTs were observed in the expanded dose level 2 cohort. On the CDD schedule starting at dose level A, 3 patients were enrolled and no DLTs were observed. Enrollment of the CDD schedule cohorts continued as described in .
A total of 13 patients (30%) completed the study (receiving the 4 planned cycles of study treatment) and 30 patients discontinued before completion. Of the 13 patients who completed, 12 (n = 4 from Schedule 2/1 cohorts, n = 8 from CDD cohorts) enrolled in a continuation protocol and received sunitinib as a single agent. One additional patient who was discontinued from the study due to AEs after cycle 1 was also enrolled in the continuation protocol. Twenty of the 25 patients (80%) on Schedule 2/1 discontinued treatment early: 11 patients due to insufficient clinical response and 9 due to AEs, including 6 who had AEs that were considered treatment-related (papilledema, gastrointestinal [GI] hemorrhage, syncope, pyrexia, pneumonia, leukopenia, and hemoptysis [all n = 1 each], anemia [n = 3], thrombocytopenia [n = 3], and neutropenia [n = 2]). Ten of the 18 patients (56%) on the CDD schedule discontinued treatment early: 6 patients due to insufficient clinical response; 2 due to AEs (1 patient had AEs considered to be treatment-related: neutropenia, anemia, and thrombocytopenia); 1 patient on the CDD schedule died due to disease progression; and 1 patient withdrew consent.
The number of sunitinib treatment cycles started ranged between 0–4 and 1–5 on Schedule 2/1 and the CDD schedule, respectively. One patient on the CDD schedule received 5 cycles of sunitinib on the study, receiving an additional cycle of treatment while awaiting enrollment in the continuation protocol. In total 11 patients received all three drugs through to the start of cycle 2 without dose reductions, dose delays or dose interruptions (Schedule 2/1 dose level 1, n = 2; dose level 2 n = 2; CDD schedule dose B, n = 5; dose B1, n = 2).
Of the 25 patients on Schedule 2/1, 10 (40%) required sunitinib dose delays and 2 (8%) required dose reductions. Of the 18 patients on the CDD schedule, 8 (44%) required sunitinib dose delays and 3 (17%) required dose reductions. In all but 2 patients, sunitinib dose delays were attributed to neutropenia, thrombocytopenia or leukopenia (all grades). The duration of sunitinib dose delays was most commonly ≥ 3 weeks (n = 18 patients overall).
In the Schedule 2/1 cohorts, 10 patients experienced dose delays for paclitaxel and 10 patients experienced dose delays for carboplatin. Five patients experienced at least one dose reduction of paclitaxel and 1 patient experienced ≥ 2 dose reductions of carboplatin. In the CDD cohorts, 9 and 8 patients experienced dose delays for paclitaxel and carboplatin, respectively, and 3 and 1 patients experienced at least one dose reduction of paclitaxel and carboplatin, respectively.
Determination of MTD
Across all schedules, DLTs occurring in the first treatment cycle were reported in 6 patients (14%; ). All DLTs were reported as serious AEs (SAEs) and considered to be related to sunitinib and/or paclitaxel and carboplatin treatment. On Schedule 2/1, the MTD was determined as sunitinib 25 mg/day plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL. The MTD was not determined for the CDD schedule.
Other safety findings
Treatment-emergent (all-causality) non-hematologic AEs occurring in ≥ 10% of patients across all treatment combinations are shown in . Most nonhematologic AEs were grade 1 or 2 in severity. The most common were fatigue (58%), nausea (44%), alopecia (30%), and dyspnea (28%).
Most common all-causality non-hematologic adverse events (≥ 10% incidence cut-off) in all cohorts
Overall, 35/43 patients (81%) experienced at least one AE (grade ≥ 3) considered related to study treatment. The most common treatment-related AEs were neutropenia (77%; grade 3 [23%] or 4 [42%]), thrombocytopenia (56%; grade 3 [19%] or 4 [14%]), and fatigue (47%; grade 3 [7%]). The frequency of treatment-related AEs was similar for Schedule 2/1 and the CDD schedule, although the incidence of treatment-related thrombocytopenia was higher for patients on the CDD schedule (11/18 subjects, 61%) compared with Schedule 2/1 (13/25 subjects, 52%).
All causality hematologic AEs reported in all cycles and cycle 1 are shown in . Neutropenia (79%) and thrombocytopenia (74%) were the most frequent events. Hematologic laboratory abnormality shifts from grade ≤ 2 to grade ≥ 3 (all patients, both schedules) included neutropenia (70%), leukopenia (49%), thrombocytopenia (40%), lymphopenia (35%), and anemia (23%). No patient experienced grade 4 lymphopenia. One patient experienced a shift to grade 4 anemia.
All-causality hematologic adverse events in all cohorts (occurring in cycle 1 and in all cycles)
Cardiovascular disorders occurred infrequently. Grade 3 thrombosis, grade 1 sinus tachycardia, and grade 1 tachycardia were reported in 1 patient each. None of these AEs was considered related to study treatment. One patient receiving dose level 2 on Schedule 2/1 experienced grade 3 syncope deemed treatment-related by the investigator. There were no clinically significant changes at any timepoints for the mean heart rate, blood pressure, and ECG parameters.
Three patients died on study. Two deaths were attributed to disease progression (bladder cancer [n = 1] and esophageal adenocarcinoma [n = 1]). The third patient, a 59-year-old male patient with pancreatic carcinoma who was receiving treatment on Schedule 2/1 dose level 2, died due to GI hemorrhage and hypotension, which were considered possibly related to study treatment.
Of the 38 patients with measurable disease at baseline and evaluable for response, 4 patients achieved a partial response (PR) for an objective response rate of 10.5% (95% confidence interval [CI]: 2.9%, 24.8%) across all cohorts. Two PRs occurred on Schedule 2/1 (one at dose level 1 and the other at dose level 2). Two PRs occurred on the CDD schedule (one at dose level B and the other at dose level B1). Patients with PRs had the following primary diagnoses: SCLC (n = 1), NSCLC (n = 2), and peritoneal carcinomatosis (n = 1), and 2 patients had received prior chemotherapeutic regimens (carboplatin plus etoposide and topotecan; carboplatin plus paclitaxel; and carboplatin plus gemcitabine).
Across both dosing schedules, stable disease (SD) with duration ≥ 42 days after the first dose of study drug was observed in 12 patients (n = 6 on Schedule 2/1 and n = 6 on the CDD schedule). Twelve patients (32%) experienced progressive disease (PD) as their best response (6 on Schedule 2/1 and 6 on the CDD schedule). Response status could not be determined for 10/38 evaluable patients because post-baseline scans were not available (patients either discontinued early or lesions identified at baseline were not assessed).
AEs prevented many patients from taking sunitinib daily on both schedules. On the CDD schedule, plasma concentration profiles at steady state were collected for only 5 patients (paired observations) at sunitinib 37.5 mg/day plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL (dose level B), and 1 patient at sunitinib 25 mg/day plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL (dose level A). Therefore, PK parameters are presented only for the dose levels on both treatment schedules with a sufficient number of evaluable patients: sunitinib 37.5 mg/day plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL (dose levels 2 and B; ). The data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite SU12662 when sunitinib was given with paclitaxel and carboplatin compared with sunitinib monotherapy (). No notable difference in PK was observed between Schedule 2/1 and the CDD schedule.
Pharmacokinetic parameters (subjects with paired observations only) at sunitinib 37.5 mg/day plus paclitaxel 175 mg/m2 and carboplatin 6 AUC mg•min/mL