BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

A Randomised, Open-label, Phase III Study of BIBW 2992 Versus Chemotherapy as First-line Treatment for Patients With Stage IIIB or IV Adenocarcinoma of the Lung Harbouring an EGFR Activating Mutation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00949650
• Other study ID #: 1200.32
• Secondary ID: 2008-005615-18
• Status: Completed
• Phase: Phase 3
• First received: July 29, 2009
• Last updated: March 9, 2018
• Start date: August 14, 2009
• Est. completion date: March 16, 2017

Study information

• Verified date: March 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomised, open label phase III trial will be performed in patients with adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. The objectives of the trial are to compare the efficacy of single agent BIBW 2992, Arm A, with Pemetrexed/Cisplatin chemotherapy, Arm B, as first line treatment for this group of patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 345
• Est. completion date: March 16, 2017
• Est. primary completion date: February 9, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage IV adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology.

• Epidermal Growth Factor Receptor mutation detected by central laboratory analysis of tumour biopsy material.

• Measurable disease according to RECIST 1.1.

• Eastern Cooperative Oncology Group score of 0 or 1.

• Age >/= 18 years.

• Life expectancy of at least three months.

• Written informed consent that is consistent with International Conference on Harmonisation-Good Clinical Practice guidelines.

Exclusion criteria:

• Prior chemotherapy for relapsed and/or metastatic NSCLC. Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and randomisation.

• Prior treatment with Epidermal Growth Factor Receptor targeting small molecules or antibodies.

• Radiotherapy or surgery (other than biopsy) within 4 weeks prior to randomisation.

• Active brain metastases

• Any other current malignancy or malignancy diagnosed within the past five years

• Known pre-existing interstitial lung disease.

• Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom.

• History or presence of clinically relevant cardiovascular abnormalities.

• Any other concomitant serious illness or organ system dysfunction.

• Adequate absolute neutrophil count and platelet count

• Adequate liver and kidney function

• Active hepatitis B infection, active hepatitis C infection or known HIV carrier.

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma, Non-Small-Cell Lung

Intervention

Drug:
• Pemetrexed
Pemetrexed IV given once every 3 weeks for up to 6 cycles
• BIBW 2992
BIBW 2992 once daily until progression
• Cisplatin
Cisplatin IV given once every 3 weeks for up to 6 cycles

Locations

Country	Name	City	State
Argentina	Instituto de Medicina Nuclear de Bahía Blanca	Bahía Blanca
Argentina	Hospital Alemán	Capital Federal
Argentina	Hospital Militar Central	Capital Federal
Argentina	IMAI Research	Capital Federal
Argentina	Imcaba S.R.L.	Capital Federal
Argentina	Instituto Alexander Fleming	Capital Federal
Argentina	PALIAR	Capital Federal
Argentina	Centro Oncológico de Rosario	Rosario
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Lifehouse	Camperdown	New South Wales
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	St. Vincents Hospital (MEL)	Fitzroy	Victoria
Australia	Mount Medical Centre	Perth	Western Australia
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	The Burnside War Memorial Hospital	Toorak Gardens	South Australia
Australia	Calvary Mater Newcastle Hospital	Waratah	New South Wales
Austria	KH d. Elisabethinen Linz	Linz
Austria	Klinikum Wels - Grieskirchen GmbH	Wels
Austria	SMZ Baumgartner Hoehe Otto Wagner Spital	Wien
Belgium	Brussels - UNIV St-Pierre	Bruxelles
Belgium	UNIV UZ Gent	Gent
Belgium	Brussels - UNIV UZ Brussel	Jette
Belgium	UZ Leuven	Leuven
Belgium	Centre Hospitalier Universitaire de Liège	Liège
Brazil	Centro de Pesquisa do Hospital Lifecenter	Belo Horizonte
Brazil	Centro de Pesquisas Clínicas em Oncología	Cachoeiro de Itapemirim
Brazil	Insituto de Oncologia do Paraná	Curitiba
Brazil	Hospital São Lucas da Pontifícia Universidade Católica	Porto Alegre
Brazil	UNIFESP Departamento de Medicina de Pneumologia	Sao Paulo
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute (University of Alberta)	Edmonton	Alberta
Canada	Charles LeMoyne Hospital	Greenfield Park	Migration Data
Canada	Hematologiste et oncologue medical CHUM - Hopital Notre-Dame	Montreal	Migration Data
Canada	McGill University, Department of Oncology	Montreal	Migration Data
Chile	Hospital Dirección de Previsión de Carabineros	Los Condes
Chile	Instituto Oncológico Limitada Viña del Mar	Reñaca
Chile	Instituto Clínico Oncológico del Sur - ICOS	Temuco
France	HOP d'Angers	Angers
France	HOP Côte de Nacre	Caen Cedex 5
France	HOP Nord Michallon	La Tronche
France	HOP Croix Rousse, Pneumo, Lyon	Lyon Cedex 4
France	INS Curie	Paris Cedex 05
France	CTR René Gauducheau	Saint Herblain
France	HOP Sud-Réunion, Pneumo, Saint Pierre	Saint Pierre - La Réunion
France	HOP - HIA Sainte Anne	Toulon
France	HOP, Pneumo, Villefranche sur Saône	Villefranche Sur Saône
Germany	Universitätsklinikum Benjamin Franklin, Berlin	Berlin
Germany	Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH	Essen
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Lungenklinik Hemer	Hemer
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Germany	Universitätsklinikum Münster	Münster
Germany	Pius-Hospital, Oldenburg	Oldenburg
Germany	National Taiwan University Hospital	Taipei
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Prince of Wales Hospital	Shatin
Hungary	Szent György Hospital, Szekesfehervar	Szekesfehervar
Hungary	Markusovszky County Hospital, Szombathely	Szombathely
Hungary	Zala County Hospital, Zalaegerszeg	Zalaegerszeg
Ireland	St James's Hospital	Dublin 8
Italy	Ospedale San Donato di Arezzo	Arezzo
Italy	Az. USL 4 di Prato	Prato
Italy	Azienda Ospedaliera Sant'Andrea-Università di Roma La Sapienza	Roma
Italy	Osp. Silvestrin	Sant'Andrea Delle Fratte (PG)
Japan	Aichi Cancer Center Hospital	Aichi, Nagoya
Japan	National Hospital Organization Nagoya Medical Center	Aichi, Nagoya
Japan	National Cancer Center Hospital East	Chiba, Kashiwa
Japan	National Hospital Organization Shikoku Cancer Center	Ehime, Matsuyama
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka, Fukuoka
Japan	Hokkaido University Hospital	Hokkaido, Sapporo
Japan	Institute of Biomedical Research and Innovation Hospital	Hyogo, Kobe
Japan	Kanazawa University Hospital	Ishikawa, Kanazawa
Japan	Kanagawa Cardiovascular and Respiratory Center	Kanagawa, Yokohama
Japan	Niigata Cancer Center Hospital	Niigata, Niigata
Japan	Kurashiki Central Hospital	Okayama, Kurashiki
Japan	Okayama University Hospital	Okayama, Okayama
Japan	Osaka City Hospital Organization Osaka City General Hospital	Osaka, Osaka
Japan	Kindai University Hospital	Osaka, Osaka-Sayama
Japan	National Hospital Organization Kinki-Chuo Chest Medical Center	Sakai, Osaka
Japan	Shizuoka Cancer Center	Shizuoka, Sunto-gun
Korea, Republic of	Chungbuk National University Hospital	Cheongju
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Malaysia	Hospital Pulau Pinang	Palau Pinang
Malaysia	Pusat Perubatan University Kebangsaan Malaysia	Wilayah Persekutuan
Malaysia	University Malaya Medical Centre	Wilayah Persekutuan
Peru	Hospital Nacional Guillermo Almenara Irigoyen	La Victoria
Peru	Clínica Anglo Americana	San Isidro
Peru	Instituto Nacional de Enfermedades Neoplásicas	Surquillo
Philippines	Perpetual Succour Hospital (Cebu)	Cebu City
Philippines	Makati Medical Center	Makati City
Philippines	St. Luke Medical Centre	Quezon
Romania	Institutul Oncologic "Prof. Dr. Ion Chiricuta"	Cluj Napoca
Romania	ONCOLAB SRL, Craiova	Craiova
Russian Federation	Republic Clinical Oncology Dispensary, Dept. Chemotherapy	Kazan
Russian Federation	FSBSI "N.N Blokhin Medical Research Center of Oncology"	Moscow
Russian Federation	Medical Radiology Science Centre	Obninsk
Russian Federation	First Pavlov State Medical University Saint Petersburg	St. Petersburg
Russian Federation	FSBI "N.N. Petrov National Medical Research Center of Oncology" of MoH of RF	St. Petersburg
Russian Federation	SPb SBIH "City Clinical Oncological Dispensary"	St. Petersburg
Taiwan	Chang Gung Memorial Hospital Kaohsiung	Kaohsiung
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	NCKUH	Tainan
Taiwan	Taipe Veterans General Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital(TaoYuan)	Taoyuan
Thailand	Ramathibodi Hospital	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai
Thailand	Srinagarind Hospital	Khonkaen
Thailand	Songklanagarind Hospital	Songkla
Ukraine	City Clinical Hospital #4, Dnipropetrovsk State Medical Academy	Dnipropetrovsk
Ukraine	Donetsk Regional Antitumor Centre	Donetsk
Ukraine	Kharkiv Regional Clinical Oncology Center	Kharkiv
Ukraine	Lviv State Oncological Regional Treatment & Diagnostic CTR	Lviv
United Kingdom	Royal Devon and Exeter Hospital	Exeter
United Kingdom	Royal Surrey County Hospital	Guildford
United Kingdom	The Royal Marsden Hospital	London
United Kingdom	Maidstone Hospital, Kent Oncology Centre	Maidstone
United Kingdom	Scunthorpe General Hospital, Oncology	Scunthorpe
United Kingdom	The Royal Marsden Hospital	Sutton
United Kingdom	Royal Cornwall Hospital	Truro
United States	Lehigh Valley Hospital / Lehigh Valley Health Network	Allentown	Pennsylvania
United States	South Texas Institute of Cancer, Northwest Cancer Center	Corpus Christi	Texas
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Crescent City Research Consortiom	Marrero	Louisiana
United States	Innovative Medical Research of South Florida	Miami	Florida
United States	Clinical Trials and Research Associates Inc	Montebello	California
United States	Interlakes Foundation, Incorporated	Rochester	New York

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  France,  Germany,  Hong Kong,  Hungary,  Ireland,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Peru,  Philippines,  Romania,  Russian Federation,  Taiwan,  Thailand,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS) Time	PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates.	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Secondary	Percentage of Patients With Objective Response (OR)	OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1.	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Secondary	Percentage of Participants With Disease Control (DC)	DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1.	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Secondary	Overall Survival (OS) Time	OS was defined as time from randomisation to death.	From randomisation to cut-off date (17MAR2017).
Secondary	Tumour Shrinkage	Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race.	Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
Secondary	Change From Baseline in Body Weight	Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm.	Baseline and throughout the trial until progression (every 3 weeks), up to 28 months.
Secondary	Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)	ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction.; Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work.; Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities.; Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours.; Completely disabled, cannot carry on any self-care, totally confined to bed or chair.; Dead.	Throughout the trial until progression (every 3 weeks), up to 28 months.
Secondary	Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing	HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.	Throughout the trial until progression (every 3 weeks).
Secondary	HRQOL: Time to Deterioration in Dyspnoea	HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.	Throughout the trial until progression (every 3 weeks).
Secondary	HRQOL: Time to Deterioration in Pain	HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.	Throughout the trial until progression (every 3 weeks).
Secondary	Trough Plasma Concentrations of Afatinib at Day 22	Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.	Day 22.
Secondary	Trough Plasma Concentrations of Afatinib at Day 29	Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.	Day 29.
Secondary	Trough Plasma Concentrations of Afatinib at Day 43	Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.	Day 43.

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