BIBW 2992 (Afatinib) in Head & Neck Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to explore the efficacy of BIBW 2992 compared with cetuximab (Erbitux) in patients with metastatic or recurrent head and neck cancer after failure of platinum-containing therapy. In addition, the trial aims to clarify the influence of EGFR genotype on tumor response to the treatment regimens.

Official Title
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A Randomized, Open-label Phase II Study of BIBW 2992 Versus Cetuximab (Erbitux) in Patients With Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) After Failure of Platinum-containing Therapy With a Cross-over Period for Progressing Patients

Conditions
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Head and Neck Neoplasms, Carcinoma, Squamous Cell

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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 1. Metastatic (stage IVc) or recurrent HNSCC 2. Histologically or cytologically confirmed diagnosis of squamous cell of the head and neck. Patients with well-differentiated (keratinizing) nasopharyngeal carcinomas and patients with squamous cell carcinomas metastatic to the neck from an unknown head and neck primary are eligible. 3. Patients must have documented progressive disease (PD) following receipt of prior platinum-based therapy (either as neoadjuvant, adjuvant, concomitant with radiotherapy, or for recurrent/ metastatic disease). 4. Patients must have measurable disease as defined by RECIST criteria. 5. Patients must have recovered from any therapy-related toxicities from previous chemo-, immuno-, or radiotherapies to CTC smaller or equal to Grade 1. 6. Patients must have recovered from previous surgery. 7. Life expectancy of at least three (3) months. 8. Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 or 1. 9. Patients must be eighteen (18) years of age or older. 10. Willingness and ability to give written informed consent consistent with ICH-GCP guidelines. Exclusion criteria: Progressive disease within 3 months after completion of curative intent treatment for localized/locoregionally advanced disease. Prior use of an EGFR or erbB2 inhibitor in the recurrent/metastatic disease setting (treatment with cetuximab (Erbitux®) or other EGFR inhibitor during radiotherapy or chemoradiotherapy is permissible). More than 2 chemotherapeutic regimens given for recurrent/metastatic disease. Treatment with other investigational drugs, other anti-cancer-therapy (e.g., chemotherapy, immunotherapy, radiotherapy), concomitantly with therapy on this study and/or during the last four weeks, prior to the first treatment with the trial drug eliminated per Amendment #1 Patients with history of other malignancy (except for appropriately treated superficial basal cell skin cancer and surgically cured cervical cancer in situ) unless free of disease for at least 3 years. Patients with history of decompensated heart failure. Cardiac left ventricular function with resting ejection fraction <50% or less than the institutional lower limit of normal by MUGA or echocardiogram. Active infectious disease. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea. Serious illness, concomitant non-oncological disease or mental problems considered by the investigator to be incompatible with the protocol. Use of alcohol or drugs incompatible with patient participation in the study in the investigator's opinion. Patients unable to comply with the protocol. Patients with active/symptomatic brain metastases. Patients with a history of treated brain metastases must have stable or normal cerebral MRI scan at screening and be at least three months post-radiation or surgery. Absolute neutrophile count (ANC) less than 1000/mm3. Platelet count less than 75,000/mm3. Bilirubin greater than 1.5 mg/dl/ Higher bilirubin values are acceptable for patients with known Gilbert's disease, approval by the PI and sponsor necessary. Asparate amino transferase (AST) or alanine amino transferase (ALT) greater than 3 times the upper limit of normal. Serum creatinine greater than 1.5 X upper limit of normal for the institution. Patients who are sexually active and unwilling to use a medically acceptable method of contraception. Pregnancy or breast-feeding. Patients with known pre-existing interstitial lung disease.

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: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992<br>once daily taken orally | Drug: BIBW 2992<br>* experimental drug taken once daily orally<br>|
| Active Comparator: Cetuximab<br>once every week by intravenous injection | Drug: Cetuximab<br>* active comparator administered weekly intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Shrinkage Before Crossover (Stage 1) of the Trial as Per Investigator Assessment | Tumor shrinkage before crossover was defined as the change from baseline in the smallest post-randomisation sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after randomisation but before crossover minus SLD at baseline. Baseline was the SLD measured before randomisation. A negative value means the smallest post-randomisation SLD was smaller than baseline (decreased since baseline); a positive value means tumor size increased since baseline. Mean calculated is actually the Adjusted mean. Adjusted mean is obtained from fitting an ANCOVA model including treatment, stratification factor prior chemotherapy for recurrent/metastatic disease and the baseline sum of longest distance of target lesions as covariates. | From randomization until start of Stage 2 treatment, or within 28 days after the termination of Stage 1. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Shrinkage After Crossover (Stage 2) as Per Investigator Assessments | Tumor shrinkage after crossover was defined as the change from baseline in the smallest post-crossover sum of the longest diameters of target lesions (SLD), calculated as the smallest SLD after crossover minus SLD at baseline. Baseline was the SLD measured at the time of crossover, or the closest measurement before the patient started stage 2 treatment. A negative value means the smallest post-crossover SLD was smaller than baseline (decreased after crossover), a positive value means tumor size increased after crossover. | From baseline assessed prior to first dose of Stage 2 study medication to 28 days after termination of Stage 2 treatment. | 
| Best RECIST Assessment as Per Investigator Assessment for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria. | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | 
| Best RECIST Assessment as Per ICR for Stage 1 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment). | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria. | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | 
| Best RECIST Assessment as Per Investigator Assessment for Stage 2 (as as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Objective response ( complete response (CR) or partial response (PR)) assessed by the investigator according to the RECIST 1.0 criteria. | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | 
| Best RECIST Assessment as Per ICR for Stage2 (as Confirmed Disease Control (Clinical Benefit) and Objective Response Are Simply Categories of RECIST Assessment) | Best RECIST Assessment is defined as confirmed Disease control (complete response (CR), partial response (PR) and Stable disease (SD)), Best objective response ( complete response (CR) or partial response (PR)) as assessed by the independent central review (ICR) according to the RECIST 1.0 criteria. | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | 
| Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 1 | Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment for Stage 1. | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | 
| Best RECIST Assessment as Onset of Confirmed Objective Response as as Per ICR for Stage 1 | Best RECIST Assessment as onset of confirmed objective response as per the independent central review (ICR) according to the RECIST 1.0 criteria. | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | 
| Best RECIST Assessment as Onset of Confirmed Objective Response as Per Investigator Assessment for Stage 2 | Best RECIST Assessment as onset of confirmed objective response as per Investigator assessment according to the RECIST 1.0 criteria. | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | 
| Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 1 | Best RECIST Assessment as duration of confirmed objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria. | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | 
| Best RECIST Assessment as Confirmed Duration of Confirmed Objective Response and Disease Control as Per ICR for Stage 1 | Best RECIST Assessment as duration of confirmed objective response and disease control as per the independent central review (ICR) according to the RECIST 1.0 criteria. | Response determined from randomization until patient started Stage 2 or within 28 days after termination of Stage 1 treatment | 
| Best RECIST Assessment as Confirmed Duration of Objective Response and Disease Control as Per Investigator Assessment for Stage 2 | Best RECIST Assessment as confirmed duration of objective response and disease control as per Investigator assessment according to the RECIST 1.0 criteria. | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | 
| Best RECIST Assessment as Confirmed Duration of Disease Control as Per ICR for Stage 2 | Best RECIST Assessment as confirmed duration of disease control as per the independent central review (ICR) assessment according to the RECIST 1.0 criteria. | Response determined during Stage 2 or within 28 days after termination of Stage 2 treatment | 
| Progression Free Survival (PFS) Before Crossover Based on Investigator Assessment | PFS is defined as time from randomisation to until the occurrence of tumor progression or death, whichever occurred first, during Stage 1 of the trial. Median is calculated from the Kaplan-Meier curve for each treatment group. | From randomisation to disease progression in Stage 1 or death whichever occurred first before crossover. | 
| Progression Free Survival (PFS) After Crossover Based on Investigator Assessment | PFS is defined as time from first administration study medication after cross over until the occurrence of tumor progression or death, whichever came first, during Stage 2 of the trial. Median is calculated from the Kaplan-Meier curve for each treatment group. | From first administration of study medication after cross over to disease progression in Stage 2 or death whichever came first after crossover. | 
| Overall Survival (OS) | OS is defined as time from randomisation to death. Median is calculated from the Kaplan-Meier curve for each treatment group. | From randomisation to data cut-off date. | 
| Time to Deterioration in HRQoL - Stage 1 | Health related Quality of Life (HRQoL) for Time to deterioration was assessed using the the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Head and Neck Cancer Module (H&N35). Time to deterioration in HRQoL (defined as a 10-point change towards worsening from the baseline score on a 0-100 point scale) was determined for: global health status (Questions 29 and 30 in EORTC QLQ C30) pain (Questions 9 and 19 in EORTC QLQ C30) swallowing (Questions 35 to 38 in EORTC QLQ-H&N35) | From randomisation to deterioration in HRQoL scores before crossover. | 
| Patients With AEs Resulting in Diarrhea, Skin Rash, Dose Reduction, Treatment Discontinuation and Decreased Cardiac Left Ventricular Function | Patients with adverse events (AEs) resulting in Diarrhea, Skin Rash, dose reduction, treatment discontinuation and decreased cardiac left ventricular function Note: To asses the Decreased Cardiac left ventricular function, Left ventricular ejection fraction (LVEF) was assessed in patients treated with afatinib in Stage 1 and Stage 2 . And no patients in either group had a significant change in LVEF during Stage 1 or Stage 2 of the trial. | First administration of trial medication until 28 days after last drug administration | 
| Incidence and Intensity of Adverse Events With Grading According CTCAE | Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0). | First administration of trial medication until 28 days after last drug administration | 
| Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 15 (Cpre,ss,15) | Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15. Note: At day 15, values for afatinib 40 mg no values reported in stage 1 and stage 2. | Day 15 | 
| Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 29 (Cpre,ss,29) | Cpre,ss,29 represents the pre-dose concentration of afatinib in plasma at steady state on day 29. Note: At day 29, values for afatinib 40 mg no values reported in stage 2. | Day 29 | 
| Pre-dose Concentration of Afatinib in Plasma for Dose 40mg and 50mg at Steady State on Day 57 (Cpre,ss, 57) | Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57. | Day 57 |