A total of 31 patients were accrued (). Sixteen of the 25 patients treated on the original treatment schedule completed at least 1 cycle. Three patients did not complete the first cycle due to early disease progression and 6 patients because of toxicities, 5 of which occurred at the 150 mg daily dasatinib dose and were not considered dose-limiting toxicities (DLT) according to predefined criteria. These non-dose-limiting toxicities included 3 hypersensitivity reactions (2 grade 3 and 1 grade 4), 1 grade 2 headache and 1 grade 3 nausea.. Patients received a median of 2 cycles (range: 1–15). Six patients had dasatinib dose reductions for treatment-related toxicities.
Among the 25 subjects treated on the original schedule, headache was the most common toxicity and was dose-limiting (). Typically, headache started the day of cetuximab loading and lasted 1–3 days (median 2 days). Headache was managed with analgesics, usually narcotics (e.g. oxycodone), and sumatriptan. Two patients required hospitalization for management of headache. Three patients developed DLT: 1 patient at a dasatinib dose of 150 mg/day developed grade 3 headache; 2 patients at 200 mg/day developed grade 3 headache and grade 3 nausea despite antiemetics. One patient developed a grade 4 anaphylatic reaction to dasatinib and another patient a grade 3 infusion reaction to cetuximab, which were not considered dose-limiting. Thus, the MTD was reached at 150 mg/day of dasatinib. Pleural effusion developed after 2–5 months of treatment in 4 patients (grade 2 in 3 patients; grade 3 in 1 patient). Serious adverse events, grade 3 or 4, reported in more than 2 patients included: dyspnea, vomiting, nausea, allergic reactions, headache and anemia ().
Patients with Dose-Limiting Toxicities (DLT)
Drug-Related Toxicities and Serious Adverse Events
Of the 6 patients treated on the altered schedule, 3 experienced headache prior to starting dasatinib (grade 2 in 2 patients; grade 1 in 1 patient) which resolved before starting dasatinib on day 4. Other serious adverse events included hypophosphatemia (n=2) and syncope with QTc prolongation (n=1) (). One patient suffered sudden death at the doctor’s office on cycle 1, day 21; no autopsy was performed, but the event was considered unlikely related to treatment.
The PK parameters (AUC and T-HALF) of dasatinib were comparable when given alone (day 0) or in combination with cetuximab (day 15) (). Dasatinib was rapidly absorbed with a Tmax of 1–2 hours. After the completion of the absorption phase, concentrations of dasatinib declined rapidly with a terminal phase half-life of 5–6 hours. Dasatinib Cmax and AUC parameters were similar for 100 mg and 150 mg dasatinib doses with and without cetuximab ().
Pharmacokinetics of dasatinib
In 23 patients evaluable for response, there were no objective responses; 10 patients with the following tumors had SD as best response: salivary gland cancer (n=3), follicular thyroid carcinoma (1), papillary thyroid carcinoma (1), adenocarcinoma of the esophagus (1), sarcoma (2), adenocarcinoma of unknown primary (1) and NSCLC (1). Median duration of SD was 4.3 months (range 2–22). Patients with previously untreated adenocarcinoma of unknown primary and papillary thyroid carcinoma both had SD lasting 22 months. Data regarding tumor progression prior to study enrollment were not collected.
P-SFK and c-Src levels in PBMC protein lysates were measured (). Compared to baseline levels, P-SFK levels on day 0 tended to be reduced by 4 hours following dasatinib dosing, were significantly reduced by 8 hours and did not differ from baseline levels at 24 hours (). At day 15, P-SFK levels were also significantly decreased by 8 hours from same day pre-dasatinib dosing levels (P=0.03), and P-SFK levels at 24 hours did not differ from pre-dasatinib dosing levels (P=0.18) (data not shown). Therefore, SFK were transiently inhibited in PBMCs following dasatinib dosing. The kinetics of inhibition were not appreciably altered with the co-administration of cetuximab. There was no association between antitumor activity and P-SFK levels.
P-Src levels following dasatinib dosing were transiently decreased in PBMCs and varied in tumor tissues
P-SFK changes in tumor samples were heterogeneous. A NSCLC tumor had markedly reduced P-SFK levels post-treatment, while no appreciable changes in P-SFK levels was observed for the liposarcoma () or parotid tumor (data not shown). The patient with liposarcoma had SD as best response while the other patients with paired tumor biopsies had PD as best response. c-Src was not altered with treatment (data not shown).
We measured plasma EGFR, TGF-α, AR, COX-2 and HGF levels in patients treated on the standard treatment schedule at baseline (n=25) and day 15 (n=16). COX-2 levels were generally below detection limit and were not further evaluated. ICCs for the remaining analytes were 93% to 98%, indicating the assay performed well (data not shown).
AR and TGF-α levels were significantly correlated at baseline and day 15 (ρ= 0.51, P=0.01 and ρ=0.60, P=0.02, respectively). No other analytes tested were correlated. EGFR levels were reduced (P =0.007) and AR and TGF-α levels were increased (P= 0.004 and P=0.007, respectively) after treatment; HGF levels were unaltered. Patients with PD had higher baseline TGF-α levels than patients with SD (P = 0.02). Patients with high baseline TGF-α levels had worse PFS (P= 0.036) (). This association was statistically significantly in univariate proportional hazards models (HR= 2.64; 95% CI= 1.03–6.78) but not after adjusting for patient age and performance status (HR=2.16; 95% CI = 0.80–5.82). No other analyte tested was associated with disease progression ().
Lower plasma TGF-α levels were associated with improved progression-free survival