An Explorative Study of Afatinib in the Treatment of Advanced Cancer Carrying an EGFR, a HER2 or a HER3 Mutation

Study Overview
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Brief Summary
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Objective(s):To investigate the efficacy and safety of afatinib in EGFR, HER 2 and HER3 mutated cancers, regardless of cancer type, excluding EGFR mutated non-small cell lung cancer. Methodology:Open label, genomic driven trial (basket trial) No. of patients total entered:Optimal Simon two stage design for the three genetic driven cohorts: 10 patients will be enrolled per cancer type in the first stage and an additional 19 in the second stage (maximum total 87 patients) Indication : cancers harbouring an EGFR mutation(excluding non-squamous non- small cell lung cancer, a registered indication), a HER2 mutation or a HER3 mutation Test product(s) : Afatinib At progression paclitaxel will be added for those patients that have no contra-indications dose: Starting dose of afatinib at 40 mg/day. Dose increase to 50 mg in the absence of adverse events. Stepwise dose reduction to 30,20, 10 mg/day according to drug-related adverse events. At progression, addition of paclitaxel 80 mg/m2 weekly 3w/4 to afatinib 40 mg/day . mode of admin. : Oral for afatinib Intravenous for paclitaxel Duration of treatment: Continuous treatment until progression or unacceptable adverse events or withdrawal of consent. At disease progression, add paclitaxel until progression or unacceptable adverse event or withdrawal of consent if no contra-indications. Criteria for efficacy: Primary Endpoint: • Response rate (CR+ PR) via RECIST v1.1 Secondary Endpoints: Disease control rate (CR+PR+SD) Progression free survival Overall survival To correlate tumor response with findings on tumor biopsies To investigate resistance mechanisms response rate (CR+ PR) determined by RECIST and progression free survival on the combination therapy of afatinib and paclitaxel Criteria for safety: Incidence and intensity of adverse events according CTCAE v4.0

Official Title
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An Open Explorative Phase II, Open Label Study of Afatinib in the Treatment of Advanced Cancer Carrying an EGFR, a HER2 or a HER3 Mutation

Conditions
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Cancers Harbouring an EGFR Mutation, (Excluding Non-squamous Non- Small Cell Lung Cancer, a Registered Indication), a HER2 Mutation or a HER3 Mutation

Intervention / Treatment
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* Drug: Afatinib
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and men with locally advanced or metastatic cancers harboring either an activating EGFR mutation or a HER2 mutation or a HER3 mutation Failure of at least one line of standard systemic therapy No eligibility for other open genomic driven phase I, II or III trial available for these tumor genotypes ECOG performance status ≤2 Patient with a life expectancy >3 months Patients able to provide written informed consent prior to enrollment into the clinical trial. Adequate organ function Exclusion Criteria: Non squamous non-small cell lung cancer harbouring an EGFR mutation (registered indication) Chemotherapy, biological therapy or investigational agents within four weeks prior to the start of study treatment Known hypersensitivity to afatinib or the excipients of any of the trial drugs Prior treatment with afatinib

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Open label<br>Afatinib 40 mg/day during Period 1 Afatinib 40 mg/day + Paclitaxel 80mg/kg/3w during Period 2 | Drug: Afatinib<br>* Open label<br>Drug: Paclitaxel<br>* Paclitaxel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate |  | 6 weeks | 
| Incidence and intensity of adverse events |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate |  | 6 weeks | 
| Progression free survival |  | 6 weeks | 
| Overall survival |  | 6 weeks |