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

Time frame: 3 weeks

Population: Treated Set (TS)

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

Time frame: PK samples were taken at hours; 167:55, 479:55, 481:05, 482:05, 483:05, 485:05, 487:05 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

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

Time frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

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

Time frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

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.

Time frame: From first drug administration until 28 days after last drug administration, up to 717 days.

Population: TS

Maximum concentration of docetaxel in plasma.

Time frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

Maximum concentration of Gemcitabine in plasma.

Time frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

Maximum concentration of Afatinib in plasma at steady state.

Time frame: PK samples were taken at hours; 167:55, 479:55, 481:05, 482:05, 483:05, 485:05, 487:05 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

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.

Time frame: From first drug administration until 28 days after last drug administration, up to 717 days.

Population: TS

Duration of disease control according to RECIST v1.1.

Time frame: From the first administration of study medication to the time of disease progression or death

Population: TS for patients who experienced disease control.

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

Time frame: From the first documented complete response or partial response to the time of disease progression or death

Population: TS for patients who experienced objective response.

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.

Time frame: From first drug administration until 28 days after last drug administration, up to 717 days.

Population: TS

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

Time frame: From the first administration of study medication to the time of death

Population: TS, MTD cohort

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.

Time frame: From the first administration of study medication to the time of disease progression or death

Population: TS, MTD cohort

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).

Time frame: From first drug administration until 28 days after last drug administration, up to 717 days.

Population: TS

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.

Time frame: 6 weeks, 12 weeks and 24 weeks

Population: TS

Total Clearance (CL) of Docetaxel from plasma.

Time frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

Total Clearance (CL) of Gemcitabine from plasma.

Time frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

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

Time frame: PK samples were taken on day 1 at hours; -0:05, 1, 2, 3, 5, 7, 23:55 and on day 22 at hours; -0:10, 1, 2, 3, 5, 7, 23:55

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.

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

Time frame: PK samples were taken on day 1 at hours; -0:05, 0:30, 1, 1:30, 2, 3 and on day 22 at hours; -0:10, 0:30, 1, 1:30, 2, 3

Population: The Pharmacokinetic Set (PKS) was a subset of the Treated Set that included all patients who had taken at least 1 dose of study medication and for whom at least 1 valid plasma concentration was available.