BIBW 2992 (Afatinib) in Head & Neck Cancer

Head and Neck Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00514943
• Other study ID #: 1200.28
• Secondary ID: 2008-007097-38
• Status: Completed
• Phase: Phase 2
• First received: August 9, 2007
• Last updated: September 30, 2014
• Start date: August 2007
• Est. completion date: July 2013

Study information

• Verified date: September 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Service Public Health, Food Chain Safety and EnvironmentFrance: Agence Francaise de Securite Sanitaire des Produits de SanteSpain: Spanish Agency of MedicinesUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 124
• Est. completion date: July 2013
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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:

1. Progressive disease within 3 months after completion of curative intent treatment for localized/locoregionally advanced disease.

2. 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).

3. More than 2 chemotherapeutic regimens given for recurrent/metastatic disease.

4. 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

5. eliminated per Amendment #1

6. 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.

7. Patients with history of decompensated heart failure.

8. Cardiac left ventricular function with resting ejection fraction <50% or less than the institutional lower limit of normal by MUGA or echocardiogram.

9. Active infectious disease.

10. Gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea.

11. Serious illness, concomitant non-oncological disease or mental problems considered by the investigator to be incompatible with the protocol.

12. Use of alcohol or drugs incompatible with patient participation in the study in the investigator's opinion.

13. Patients unable to comply with the protocol.

14. 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.

15. Absolute neutrophile count (ANC) less than 1000/mm3.

16. Platelet count less than 75,000/mm3.

17. 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.

18. Asparate amino transferase (AST) or alanine amino transferase (ALT) greater than 3 times the upper limit of normal.

19. Serum creatinine greater than 1.5 X upper limit of normal for the institution.

20. Patients who are sexually active and unwilling to use a medically acceptable method of contraception.

21. Pregnancy or breast-feeding.

22. Patients with known pre-existing interstitial lung disease.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Squamous Cell
• Head and Neck Neoplasms

Intervention

Drug:
• BIBW 2992
experimental drug taken once daily orally
• Cetuximab
active comparator administered weekly intravenously

Locations

Country	Name	City	State
Belgium	1200.28.0030 Boehringer Ingelheim Investigational Site	Bruxelles
Belgium	1200.28.0031 Boehringer Ingelheim Investigational Site	Gent
Belgium	1200.28.0032 Boehringer Ingelheim Investigational Site	Leuven
France	1200.28.0062A Boehringer Ingelheim Investigational Site	Ales
France	1200.28.0062B Boehringer Ingelheim Investigational Site	Ales
France	1200.28.0059A Boehringer Ingelheim Investigational Site	Avignon
France	1200.28.0052A Boehringer Ingelheim Investigational Site	Lille
France	1200.28.0051A Boehringer Ingelheim Investigational Site	Lyon
France	1200.28.0050A Boehringer Ingelheim Investigational Site	Montpellier cedex 5
France	1200.28.0058A Boehringer Ingelheim Investigational Site	Nimes cedex 9
France	1200.28.0061A Boehringer Ingelheim Investigational Site	Poitiers
France	1200.28.0055G Boehringer Ingelheim Investigational Site	Rouen
Spain	1200.28.0040 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1200.28.0044 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1200.28.0043 Boehringer Ingelheim Investigational Site	Madrid
Spain	1200.28.0042 Boehringer Ingelheim Investigational Site	Malaga
Spain	1200.28.0045 Boehringer Ingelheim Investigational Site	Santander
Spain	1200.28.0041 Boehringer Ingelheim Investigational Site	Valencia
United States	1200.28.0012 Boehringer Ingelheim Investigational Site	Ann Arbor	Michigan
United States	1200.28.0024 Boehringer Ingelheim Investigational Site	Baltimore	Maryland
United States	1200.28.0017 Boehringer Ingelheim Investigational Site	Chapel Hill	North Carolina
United States	1200.28.0013 Boehringer Ingelheim Investigational Site	Charleston	South Carolina
United States	1200.28.0001 Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	1200.28.0005 Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	1200.28.0011 Boehringer Ingelheim Investigational Site	Harvey	Illinois
United States	1200.28.0007 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1200.28.0022 Boehringer Ingelheim Investigational Site	Indianapolis	Indiana
United States	1200.28.0002 Boehringer Ingelheim Investigational Site	Jackson	Mississippi
United States	1200.28.0009 Boehringer Ingelheim Investigational Site	Madison	Wisconsin
United States	1200.28.0020 Boehringer Ingelheim Investigational Site	Milwaukee	Wisconsin
United States	1200.28.0008 Boehringer Ingelheim Investigational Site	New Hyde Park	New York
United States	1200.28.0006 Boehringer Ingelheim Investigational Site	Omaha	Nebraska
United States	1200.28.0016 Boehringer Ingelheim Investigational Site	Rochester	Minnesota
United States	1200.28.0021 Boehringer Ingelheim Investigational Site	St. Joseph	Michigan
United States	1200.28.0010 Boehringer Ingelheim Investigational Site	Stanford	California
United States	1200.28.0004 Boehringer Ingelheim Investigational Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Belgium,  France,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Secondary	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.	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

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