Study to Determine the Maximum Tolerated Dose of BIBW 2992 (Afatinib) When Combined With Cisplatin/Paclitaxel or Cisplatin/5-FU in Patients With Advanced Solid Tumours

Study Overview
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Brief Summary
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Study to determine the maximum tolerated dose of BIBW 2992 when combined with backbone chemotherapies consisting in cisplatin plus paclitaxel or cisplatin plus 5 FU. The overall safety, the pharmacokinetics and the anti-tumour efficacy will also be assessed.

Official Title
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A Phase Ib Open Label Study to Assess the Safety, Tolerability and Pharmacokinetics of Continuous Dosing With BIBW 2992 Combined With Two Different Regimens of Backbone Chemotherapy: Cisplatin Combined With 5 Fluorouracil and Cisplatin Combined With Paclitaxel in Patients With Advanced Solid Tumors.

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: BIBW 2992
* Drug: BIBW 2992


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with histologically or cytologically confirmed diagnosis of non resectable and / or metastatic cancer, preferably squamous cell carcinomas of head and neck, oesophagus, lung or cervix Indication for a standard treatment with either cisplatin plus paclitaxel or cisplatin plus 5 FU as judged by the investigator Age 18 years or older. Life expectancy of at least three (3) months. Written informed consent that is consistent with ICH-GCP guidelines. Eastern Cooperative Oncology Group (ECOG) performance score less or equal 2. Patients must have recovered from any therapy-related toxicity from previous chemo-, hormone-, immuno-, or radiotherapies. Patients recovered from previous surgery. Exclusion criteria: Active infectious disease. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhoea. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol. 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 four (4) weeks, no history of cerebral oedema or bleeding in the past four (4) weeks and no requirement for steroids or anti-epileptic therapy. Cardiac left ventricular function with resting ejection fraction less than 50% Absolute neutrophil count (ANC) less than 1500 / mm3. Platelets count less than 100 000/mm3. Bilirubin more than 1.5 x upper limit of institutional norm. Aspartate amino transferase (AST) or alanine amino transferase (ALT) more than 3 x upper limit of institutional norm. Serum creatinine more than 1.5 x upper limit of institutional norm. Women and men sexually active and unwilling to use a medically acceptable method of contraception. Pregnancy or breast-feeding. Treatment with other investigational drugs; chemotherapy, immunotherapy, or radiotherapy or participation in another clinical study with anti-cancer therapy within the past 4 weeks before start of therapy or concomitantly with this study. Treatment with an EGFR- or HER2 inhibiting drug within the past four weeks before start of therapy or concomitantly with this study (2 weeks for trastuzumab). Patients unable to comply with the protocol. Active alcohol or drug abuse.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A. BIBW 2992-cisplatin-paclitaxel<br>daily oral dose of BIBW 2992 combined with 3-weekly infusion of cisplatin-paclitaxel | Drug: BIBW 2992<br>* low to high dose, daily<br>|
| Experimental: B. BIBW 2992-cisplatin-5FU<br>daily oral dose of BIBW 2992 combined with 3-weekly infusion of cisplatin-5FU | Drug: BIBW 2992<br>* In each arm, BIBW 2992 dose will be escalated to determine MTD. Starting dose will be 20mg daily followed by 40 mg (with the option of an intermediary dose of 30 mg) then 50mg daily. Dose escalation will stop at 50 mg. No intra patient dose escalation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLT) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | Number of participants with DLT in the first cycle (21 days) for the determination of the MTD. | 21 days | 
| Maximum Tolerated Dose (MTD) for Regimen A and Regimen B | The MTD was determined using a standard 3 +3 dose escalation cohort design. The sample size and the number of patients who receive each dose in this design depends on the frequency of DLT at each dose level in cycle 1. | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Objective Response | Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.0. Objective response is defined as complete response (CR) and partial response (PR). | Tumor assessment were performed at screening and every 2nd cycle until end of follow up (=end of treatment + 30 days +/- 7 days) | 
| Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) | Cmax,ss represents the maximum concentration of afatinib in plasma at steady state | 0.05hours (h) before administration and 1h, 2h, 2h 55 minutes (min), 4h, 4h 30min, 5h, 6h, 8h, 10h, 24h, 48h, 216h, 480h after administration |