Trial Exploring Afatinib (BIBW 2992) + Paclitaxel (Part A), Afatinib + Paclitaxel + Bevacizumab (Part B), Afatinib + Carboplatin (Part C) and Afatinib+ Paclitaxel +Carboplatin(Part D) in Patients With Advanced Solid Tumours

A Phase I Open Label Trial of Continuous Dosing With BIBW 2992 Combined With Paclitaxel and BIBW 2992 Combined With Paclitaxel and Bevacizumab, BIBW 2992 Combined With Carboplatin and BIBW 2992 Combined With Paclitaxel and Carboplatin in Patients With Advanced Solid Tumours

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00809133

Enrollment

Registered

2008-12-17

Start date

2007-05-31

Completion date

2015-02-28

Last updated

2016-03-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms

Brief summary

The main purpose of this study is to assess the optimum dose of the following medications when they are given together: * BIBW 2992 and paclitaxel (Taxol) * BIBW 2992 and paclitaxel and bevacizumab (Avastin) * BIBW 2992 and carboplatin * BIBW 2992 and paclitaxel and carboplatin The effect of the different drug combinations will also be assessed.

Interventions

DRUGPaclitaxel

Part A and B:80mg/m2 given on Day 1, 8 and 15 of 28 Day cycle.

DRUGCarboplatin

AUC6 given on day 1 of 21 day cycle

DRUGBIBW 2992

Escalating dose cohorts

DRUGBIBW2992

MTD dose of part A

DRUGBevacizumab

Escalating dose Cohorts - 5mg / kg, 7.5mg / kg and 10mg / kg given Day 1 and Day 15 of a 28 days cycle

Study design

Allocation

NON_RANDOMIZED

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Male or female patients (patients) with a histologically confirmed diagnosis of malignancy that is now advanced, non-resectable and / or metastatic. 2. Age 18 years old or older. 3. Life expectancy of at least 3 months. 4. Written informed consent that is consistent with ICH-GCP guidelines. 5. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. 6. Patients must have recovered from any previous surgery. 7. Adequate organ function including the following: 8. Cardiac left ventricular function with resting ejection fraction greater than or equal to 50% 9. Absolute neutrophil count of greater than or equal to 1,500/microlitres; greater than 2000/microlitres for carboplatin 10. Platelets greater than or equal to 100,000/microlitres 11. Total bilirubin less than or equal to 1.5 mg/dl (\<26 micromol /L, SI unit equivalent). 12. AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal. 13. Creatinine less than or equal to 1.5 mg/dl (less than or equal to 132 micromol per liter, SI unit equivalent). 14. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment. Breast feeding mothers will be excluded since these agents may be toxic to infants.

Exclusion criteria

1. Active infectious disease 2. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol 3. GI tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease. 4. Significant cardiovascular disease (a history of congestive heart failure requiring therapy, a need for anti-arrhythmic therapy for a ventricular arrhythmia, unstable angina pectoris or myocardial infarction within 6 months prior to trial entry). 5. Patients who require full-dose anticoagulation. 6. Patients not completely recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapies to CTC less than or equal to Grade 1. Prior chemotherapy is allowed if completed at least 4 weeks prior to 1st trial treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from the acute toxicities of that therapy. 7. Patients with untreated or symptomatic brain metastases. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least 8 weeks, no history of cerebral oedema or bleeding in the past 8 weeks and no requirement for steroids or anti-epileptic therapy 8. Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause. 9. Patients on immunosuppressant therapy or with known HIV infection. 10. Treatment with any of the following within 4 weeks of starting trial medication, or during the trial, is not permitted: chemo-, immuno-, radio- (small field palliative radiotherapy is allowed provided this does not represent clear disease progression), biological therapies (including trastuzumab), hormone therapy (excluding LHRH agonists in prostate cancer, or bisphosphonates), or treatment with other investigational drugs. 11. Participation in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial. 12. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2 inhibiting drugs within the past 4 weeks before start of therapy or concomitantly with this trial. 13. Patients with known or suspected hypersensitivity to any of the trial drugs, their excipients or similar compounds. 14. Patients unable to comply with the protocol. 15. Active alcohol or drug abuse. 16. Patients with known pre-existing interstitial lung disease Additional

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)	Cycle 1: 21 days (part C and D) or 28 days (part A and B)	Dose limiting toxicity (DLT) was defined as an Adverse Event (AE) or laboratory abnormality considered as related to study treatment.
Maximum Tolerated Dose (MTD)	Cycle 1: 21 days (part C and D) or 28 days (part A and B)	The MTD of afatinib in selected combination treatments was defined as the highest dose at which no more than 1 out of 6 patients experienced DLTs during the first treatment cycle, i.e. the highest dose with a DLT incidence ≤17%. The MTD was determined separately for Afatinib in combination with Paclitaxel (part A), Afatinib in combination with Paclitaxel and Bevacizumab (part B), Afatinib and Carboplatin (part C), and Afatinib in combination with Paclitaxel and Carboplatin (part D). In part C, dose escalation was not continued beyond the dose level A40C6, due to safety and pharmacokinetic considerations and upon mutual agreement between the investigators and the sponsor. Formally, no MTD was determined, however a recommended phase II dose was determined and is presented here. 0=not maximum tolerated dose, 1=is maximum tolerated dose Note, the depicted order of treatment groups is driven by dose level, not by the actual dosing steps.

Secondary

Measure	Time frame	Description
Part A: Afatinib Cmax,ss on Day 15	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.	Maximum measured concentration of Afatinib in plasma at steady state.
Part A: AUC0-24: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From Zero Extrapolated to 24 Hours on Day 1 and Day 15	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.	AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours.
Part A: Paclitaxel Cmax on Day 1 and Day 15	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.	Maximum measured concentration of Paclitaxel in plasma.
Part B: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. There were no analyzable patients for Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab.	Area under the concentration-time curve of Afatinib in plasma at steady state.
Part B: Afatinib Cmax,ss on Day 15	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.	Maximum measured concentration of Afatinib in plasma at steady state.
Part B: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours on Day 1 and Day 15	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.	AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours.
Part B: Paclitaxel Cmax on Day 1 and Day 15	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.	Maximum measured concentration of Paclitaxel in plasma.
Part B: Bevacizumab Plasma Concentration	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.	Bevacizumab plasma concentration after infusion of Bevacizumab 5mg/kg after end of 1st and 2nd infusion in Cycle 1.
Part C: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State in Cycle 2	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.	AUCt,ss: Area under the concentration-time curve of Afatinib in plasma at steady state.
Part C: Afatinib Cmax,ss in Cycle 2	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.	Maximum measured concentration of Afatinib in plasma at steady state.
Incidence and Intensity of AEs According to the Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade	From first drug administration until the end of treatment cycle 1; 21 days (part C and D) or 28 days (part A and B)	Incidence and Intensity of AEs (Adverse Events) graded according to the maximum CTCAE (Common Toxicity Criteria for Adverse Events) grade based on the number of patients with AEs with CTCAE Grade 1-5.
Part C: Carboplatin Cmax in Cycle 1 and Cycle 2	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00	Maximum measured concentration of Carboplatin in plasma.
Part D: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State.	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.	AUCt,ss: Area under the concentration-time curve of Afatinib at steady state.
Part D: Afatinib Cmax,ss	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.	Maximum measured concentration of Afatinib in plasma at steady state.
Part D: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 23 Hours in Cycle 1 and Cycle 2	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 23:00.	AUC0-23: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 23 hours.
Part D: Paclitaxel Cmax in Cycle 1 and 2	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00	Maximum measured concentration of Paclitaxel in plasma.
Part D: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00	AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours.
Part D: Carboplatin Cmax in Cycle 1 and 2	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.	Maximum measured concentration of Carboplatin in plasma.
Objective Tumour Response (Unconfirmed)	From first drug administration until the last trial drug administration, up to 1156 days.	Number of subjects with objective tumour response (unconfirmed). Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR).
Objective Tumour Response (Confirmed)	From first drug administration until the last trial drug administration, up to 1156 days.	Number of subjects with confirmed objective tumour response. Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR). Objective response was to be confirmed by a second tumour assessment at least 4 weeks after the assessment of CR or PR.
Part C: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00.	AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours.
Part A: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.	Area under the concentration-time curve of Afatinib in plasma at steady state.

Countries

United Kingdom

Participant flow

Recruitment details

This was a phase I open label trial of continuous dosing with BIBW 2992 (Afatinib) combined with Paclitaxel and BIBW 2992 combined with Paclitaxel and Bevacizumab, BIBW 2992 combined with Carboplatin and BIBW 2992 combined with Paclitaxel and Carboplatin in patients with advanced solid tumours.

Pre-assignment details

This was a dose-escalation trial, using a 3+3 rule based design. Patients were eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.

Participants by arm

Arm	Count
Part A: A20P80 (Afatinib + Paclitaxel) Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	3
Part A: A40P80 (Afatinib + Paclitaxel) Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	7
Part A: A50P80 (Afatinib + Paclitaxel) Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	6
Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab) Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	3
Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab) Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	5
Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab) Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	7
Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab) Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	6
Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab) Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	8
Part C: A20C6 (Afatinib + Carboplatin) Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	3
Part C: A40C6 (Afatinib + Carboplatin) Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	9
Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin) Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	6
Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin) Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	8
Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin) Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	5
Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin) Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	7
Total	83

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008	FG009	FG010	FG011	FG012	FG013
Overall Study	Consent withdrawn	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Overall Study	Dose Limiting Toxicity (DLT)	0	0	0	0	0	1	1	1	0	0	0	0	0	2
Overall Study	Lost to Follow-up	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Overall Study	Other adverse event	1	1	1	0	0	3	2	4	0	0	1	1	0	1
Overall Study	Other not mentioned above	0	1	0	0	0	1	0	0	0	0	0	0	0	0
Overall Study	Progressive disease	2	5	5	3	4	1	3	3	3	9	5	7	5	4

Baseline characteristics

Characteristic	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)	Total
Age, Continuous	56.3 Years STANDARD_DEVIATION 12.9	53.6 Years STANDARD_DEVIATION 11.2	56.2 Years STANDARD_DEVIATION 10.5	46.0 Years STANDARD_DEVIATION 11.1	59.0 Years STANDARD_DEVIATION 6.8	52.3 Years STANDARD_DEVIATION 10.4	55.0 Years STANDARD_DEVIATION 20.5	56.6 Years STANDARD_DEVIATION 9	73.3 Years STANDARD_DEVIATION 8.3	54.4 Years STANDARD_DEVIATION 14.7	52.0 Years STANDARD_DEVIATION 9.8	53.1 Years STANDARD_DEVIATION 14.2	62.4 Years STANDARD_DEVIATION 11.1	64.6 Years STANDARD_DEVIATION 8.6	56.3 Years STANDARD_DEVIATION 12.3
Sex: Female, Male Female	2 Participants	3 Participants	5 Participants	3 Participants	3 Participants	4 Participants	5 Participants	2 Participants	0 Participants	4 Participants	3 Participants	7 Participants	1 Participants	2 Participants	44 Participants
Sex: Female, Male Male	1 Participants	4 Participants	1 Participants	0 Participants	2 Participants	3 Participants	1 Participants	6 Participants	3 Participants	5 Participants	3 Participants	1 Participants	4 Participants	5 Participants	39 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk	EG012 affected / at risk	EG013 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	3 / 3	7 / 7	6 / 6	3 / 3	5 / 5	7 / 7	6 / 6	8 / 8	3 / 3	9 / 9	6 / 6	8 / 8	5 / 5	7 / 7
serious Total, serious adverse events	2 / 3	5 / 7	3 / 6	1 / 3	4 / 5	5 / 7	6 / 6	5 / 8	3 / 3	3 / 9	3 / 6	5 / 8	4 / 5	4 / 7

Outcome results

Primary

Maximum Tolerated Dose (MTD)

The MTD of afatinib in selected combination treatments was defined as the highest dose at which no more than 1 out of 6 patients experienced DLTs during the first treatment cycle, i.e. the highest dose with a DLT incidence ≤17%. The MTD was determined separately for Afatinib in combination with Paclitaxel (part A), Afatinib in combination with Paclitaxel and Bevacizumab (part B), Afatinib and Carboplatin (part C), and Afatinib in combination with Paclitaxel and Carboplatin (part D). In part C, dose escalation was not continued beyond the dose level A40C6, due to safety and pharmacokinetic considerations and upon mutual agreement between the investigators and the sponsor. Formally, no MTD was determined, however a recommended phase II dose was determined and is presented here. 0=not maximum tolerated dose, 1=is maximum tolerated dose Note, the depicted order of treatment groups is driven by dose level, not by the actual dosing steps.

Time frame: Cycle 1: 21 days (part C and D) or 28 days (part A and B)