Antineoplastic Agents

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Paclitaxel

Albumin-Bound Paclitaxel

Bevacizumab

Carboplatin

Afatinib

Tubulin Modulators

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Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

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Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

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

BIBW 2992

BIBW2992

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

Boehringer Ingelheim

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.

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

Dose limiting toxicity (DLT) was defined as an Adverse Event (AE) or laboratory abnormality considered as related to study treatment.

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.

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.

Area under the concentration-time curve of Afatinib in plasma at steady state.

Maximum measured concentration of Afatinib in plasma at steady state.

AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours.

Maximum measured concentration of Paclitaxel in plasma.

Bevacizumab plasma concentration after infusion of Bevacizumab 5mg/kg after end of 1st and 2nd infusion in Cycle 1.

AUCt,ss: Area under the concentration-time curve of Afatinib in plasma at steady state.

AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours.

Maximum measured concentration of Carboplatin in plasma.

AUCt,ss: Area under the concentration-time curve of Afatinib at steady state.

AUC0-23: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 23 hours.

Number of subjects with objective tumour response (unconfirmed).

Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR).

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.

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.

Part A: A20P80 (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.

Part A: A40P80 (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.

Part A: A50P80 (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 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.

Part B: A20P80B5 (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.

Part B: A30P80B5 (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.

Part B: A40P80B5 (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.

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 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.

Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)

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.

Part C: A20C6 (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.

Part C: A40C6 (Afatinib + 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.

Part D: A20P175C5 ( 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.

Part D: A30P175C5 (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.

Part D: A40P175C5 (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.

Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)

Total

Age, Continuous

Sex: Female, Male

Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Boehringer Ingelheim Call Center

Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)

Maximum Tolerated Dose (MTD)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Incidence and Intensity of AEs According to the Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade

Part A: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15

Part A: Afatinib Cmax,ss on Day 15

Day 1 (N=3, 6, 5)

Day 15 (N=3, 6, 5)

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

Day 15

Part A: Paclitaxel Cmax on Day 1 and Day 15

Part B: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15

Part B: Afatinib Cmax,ss on Day 15

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

Part B: Paclitaxel Cmax on Day 1 and Day 15

Dose escalation of Bevacizumab administered as intravenous infusion to 5 mg/kg. Bevacizumab administered on Days 1 and 15 of a 28-day cycle.

Part B: End of 1st Infusion of Cycle 1

Part B: End of 2nd Infusion of Cycle 1

Part B: Bevacizumab Plasma Concentration

Part C: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State in Cycle 2

Part C: Afatinib Cmax,ss in Cycle 2

Cycle 1 (N=3, 9)

Cycle 2 (N=3, 6)

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

Part C: Carboplatin Cmax in Cycle 1 and Cycle 2

Part D: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State.

Part D: Afatinib Cmax,ss

Cycle 1 (N=5, 7, 5, 6)

Cycle 2 (N=8, 5, 2, 4)

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

Part D: Paclitaxel Cmax in Cycle 1 and 2

Cycle 1 (N=5, 7, 5, 7)

Cycle 2 (N=8, 5, 2, 5)

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

Spots Global Cancer Trial Database for 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

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