A Phase I Dose Escalation Trial of Afatinib Plus Gemcitabine or Plus Docetaxel

DLT was based on following criterions: 1. Grade 4 uncomplicated (not associated with fever >38.5° C (Celsius)) neutropenia for ≥7 days. 2. Grade 3 or 4 neutropenia concomitant with fever >38.5º C or Grade ≥3 infection. 3. Platelet count of <25x 10^9/L or <50x 10^9/L with bleeding requiring whole blood transfusion. 4. Grade ≥3 non-haematological toxicity (except untreated nausea, untreated vomiting, or untreated diarrhoea). 5. Grade ≥2 decrease in cardiac left ventricular function. 6. Grade ≥2 worsening of renal function as measured by serum creatinine, newly developed proteinuria, or a newly developed decrease in glomerular filtration rate. Toxicity grading was based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0

The incidence and intensity of adverse events with grading according to CTCAE. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

Best overall response (according to Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) was the best response recorded at any time from the date of the first administration of afatinib or gemcitabine/docetaxel to the end of treatment (EOT). Partial response is for patients with measurable disease. Missing categories signifies that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.

Disease control according to RECIST v1.1 Disease control is complete response, partial response or stable disease for measurable patients and complete response or non-CR/non-PD for non-measurable patients. Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.

Objective response according to RECIST v1.1. Objective response is complete response or partial response for patients with measurable disease. Missing categories signify that no tumour imaging has been performed post baseline, and therefore the response status could not be assessed.

Objective response according to RECIST v1.1. Objective response is complete response or partial response for patients with measurable disease. Time to objective response is the time from the start of treatment to the date of first documented complete response or partial response. Descriptive analyses has been performed for the time to objective response (N(%) of patients with first occurrence of objective response at 6, 12 and 24 weeks). Onset of objective response is derived for patient with measurable disease.

Duration of objective response was the time from the first documented complete response or partial response to disease progression or death.

Duration of disease control according to RECIST v1.1.

Progression-free survival was defined as the time from the first administration of study medication to the time of disease progression or death, whichever occurred first.

Overall survival was defined as the time from the first administration of study medication to the time of death from any cause.

Area under the concentration-time curve of Afatinib in plasma over a uniform dosing interval t at steady state.

Maximum concentration of Afatinib in plasma at steady state.

Area under the concentration-time curve of Gemcitabine in plasma over the time interval from 0 up to the last quantifiable data point

Maximum concentration of Gemcitabine in plasma.

Total Clearance (CL) of Gemcitabine from plasma.

Apparent volume of distribution at steady state (Vss) of Gemcitabine.

Area under the concentration-time curve of docetaxel in plasma over the time interval from 0 up to 24 hours

Maximum concentration of docetaxel in plasma.

Total Clearance (CL) of Docetaxel from plasma.

Apparent volume of distribution at steady state (Vss) of Docetaxel.