Phase I Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours.

実験的：BIBW 2992 + BIBF 1120

This is a phase I dose escalation clinical trial and the data obtained shall determine the MTD for the combination of BIBW 2992/BIBF 1120 in 28-day of treatment.

薬：BIBF1120

VEGF阻害剤

薬：BIBW 2992

EGFR inhibitor

Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities

Maximum tolerated dose (MTD) of nintedanib and afatinib based on the Percentage of participants experienced dose limiting toxicities during the dose escalation phase.

Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1

The investigator evaluated whether complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) occurred in a patient.

CR for target lesions: Disappearance of all target lesions. CR for non-target lesions: Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (<10mm short axis).

PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters.

SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study.

PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions

Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0

Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

Changes in Safety Laboratory Parameters

Changes in safety laboratory Parameters reported as adverse events

Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)

Cpre,ss,norm (Dose normalized trough plasma concentration of nintedanib at steady state) are presented for the 2 MTD treatment groups (continuous administered nintedanib at 150 mg b.i.d. concomitantly with continuously administered afatinib 30 mg q.d. or with intermittently administered afatinib 40 mg q.d.)

As nintedanib is given twice daily, samples are taken at Day 8, Day 15, Day 22 and Day 28; the Pharmacokinetic (PK) parameter names will be Cpre,ss,15,norm (Day 8), Cpre,ss,29,norm (Day 15), Cpre,ss,43,norm (Day 22) and Cpre,ss,55,norm (Day 28)

Trough Plasma Concentration of Afatinib at Steady State

C(pre,ss) is defined as pre-dose (trough) concentration of afatinib in plasma at steady state immediately before administration of the next dose.

C24,7 corresponds to the plasma concentration at 24 hours on Day 7. C24,13 corresponds to the plasma concentration at 24 hours on Day 13. C24,27 corresponds to the plasma concentration at 24 hours on Day 27.

Objective Response (OR) During the Expansion Phase

OR is defined as a best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions.

CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be nonpathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters.

Other factors which add to the overall response of an imaging timepoint as PR are as below:

CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; All the above scenarios should also satisfy 'No occurrence of new lesions'.

Disease Control (DC) During the Expansion Phase

DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.

Stable Disease for at Least 12 Weeks During the Expansion Phase

SD: Neither sufficient shrinkage to qualify for PR (Partial response) nor sufficient increase to qualify for PD(Progressive disease), taking as references the smallest sum of diameters SoD while on study.

PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters.

PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions.

Percentage Change in the Tumour Size From Baseline During the Expansion Phase

Percentage change in the tumour size from baseline is expressed as Number of subjects with maximum decrease from baseline in the sum of longest diameters of target lesions.