Testing of Drugs Erlotinib and Docetaxel in Lung Cancer Patients Classified Regarding Their Outlook Using VeriStrat®. (EMPHASIS)

A Randomized Phase III Trial of Erlotinib Versus Docetaxel in Patients With Advanced Squamous Cell Non-small Cell Lung Cancer Who Failed First Line Platinum Based Doublet Chemotherapy Stratified by VeriStrat Good vs VeriStrat Poor

Using a laboratory test (VeriStrat), patients with relapsed squamous cell lung cancer are assigned to two strata, VSG (VeriStrat Good) and VSP (VeriStrat Poor). They are then randomized between an EGFR-TK inhibitor (erlotinib) and chemotherapy (Docetaxel).

It is hypothesized that the VeriStrat test results are able to predict the benefit of treatment with erlotinib vs docetaxel. This would suggest a significant improvement in progression-free survival for VSG patients when treated with Erlotinib, and no significant improvement in VSP patients who receive the same treatment.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Erlotinib; Drug: Docetaxel

Detailed Description

Goals of the study:

1. Explore the predictive ability of the VeriStrat signature, by testing for interaction between treatment arms (Arm A: erlotinib vs Arm B: docetaxel) and VeriStrat status (VSG vs VSP) using as outcome progression free survival.
2. Explore whether treatment with erlotinib provides progression free survival benefit as compared to docetaxel in the VSG group.
3. Compare progression free survival in the two treatment arms (Arm A: erlotinib vs Arm B: docetaxel) in the VSP group.
4. Explore the prognostic ability of the VeriStrat signature by testing for an overall difference in progression free survival between the two VeriStrat groups (in case of no significant interaction).
5. Explore the predictive ability of the VeriStrat signature using the secondary measures of clinical efficacy including overall survival, objective response rate, and disease control rate.
6. Compare overall survival, objective response rate and disease control rate between treatment groups separately in the VSG and VSP groups.
7. Explore the prognostic ability of the VeriStrat signature by testing for an overall difference in overall survival, objective response rate and disease control rate between the two VeriStrat groups (in case of no significant interaction).
8. Assess the safety and the tolerability of the two treatments separately in each VeriStrat group and overall.

Recruitment period: 18 months Sample Size: 500

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria
    • Krankenhaus Hietzing
• Belgium
  • Brussels, Belgium
    • Institut Jules Bordet
• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital
• Greece
  • Heraklion, Greece
    • University Hospital Of Heraklion
• Hungary
  • Budapest, Hungary
    • National Institute of Oncology
• Ireland
  • Dublin, Ireland
    • St James's Hospital
• Israel
  • Petah Tikwa, Israel
    • Institution Rabin MC
  • Tel-Aviv, Israel
    • Tel-Aviv Medical Center
• Italy
  • Naples, Italy
    • Medical Oncology, Second University Naples
  • Vercelli, Italy
    • Vercelli Teaching Hospital
• Netherlands
  • Amsterdam, Netherlands, 1007 MB
    • Free University Medical Center
• Spain
  • Alicante, Spain
    • Hospital General de Alicante
  • Barcelona, Spain, 08036
    • Hospital Clinic Barcelona
  • Barcelona, Spain
    • Institut Català d'Oncologia - L'Hospitalet
  • Ciudad Real, Spain
    • Ciudad Real General University Hospital
  • Cáceres, Spain
    • Hospital San Pedro de Alcantara
  • Donostia, Spain
    • Onkologikoa
  • Leganés, Spain
    • Hospital Severo Ochoa
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
  • Malaga, Spain
    • Carlos Haya Hospital
  • Reus, Spain
    • Hospital Universitari Sant Joan
  • Valencia, Spain
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain
    • Hospital La Fe
  • Valencia, Spain
    • Hospital Arnau Vilanova Valencia
• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel
  • Chur, Switzerland
    • Kantonsspital Graubünden
  • Lausanne, Switzerland, 1011
    • Fondation du centre Pluridisciplinaire d'Oncologie (CePO)
  • Luzern, Switzerland, 6016
    • Kantonsspital Luzern
  • Thun, Switzerland, 3600
    • Onkologiezentrum Berner Oberland
  • Zürich, Switzerland
    • Universitätsspital Zürich
• United Kingdom
  • Manchester, United Kingdom
    • University Hospital South Manchester
  • Sheffield, United Kingdom
    • Weston Park Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced stage IIIB, not amenable to radical radiotherapy, or metastatic stage IV non-small cell lung cancer (NSCLC) of predominant squamous subtype, according to the 7th edition of the TNM classification, including M1a (separate tumor nodule in a contralateral lobe, tumor with pleural nodules or malignant pleural or pericardial effusion) and/or M1b (distant metastasis).
• Progressive disease upon or after previous chemotherapy including at least one line of platinum-based chemotherapy.
• Measurable or evaluable disease according to RECIST v1.1 (Appendix 2).
• ECOG PS 0-2.
• Age ≥ 18 years.
• Adequate organ function, including:
• Adequate bone marrow reserve: ANC > 1.5 x 109/L, platelets > 100 x 109/L.
• Hepatic: bilirubin <1.5 x ULN; AP, ALT < 3.0 x ULN; AP, ALT <5 x ULN is acceptable in case of liver metastasis.
• Renal: calculated creatinine clearance > 40 ml/min based on the Cockroft and Gault formula.
• Signed and dated informed consent form.
• Male and female patients with reproductive potential must use an approved contraceptive method, during the trial and 12 months thereafter. Female patients with reproductive potential must have a negative pregnancy test within 7 days prior to study registration.
• Estimated life expectancy >12 weeks.
• Patient compliance and geographical proximity that allow adequate follow-up.

Exclusion Criteria:

• Evidence of other medical condition which would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease, active infection, uncontrolled diabetes mellitus).
• Previous treatment with any EGFR-TKI or docetaxel.
• Documented brain metastases unless the patient has completed local therapy for central nervous system metastases and has been off corticosteroids for at least 14 days prior to study registration.
• Documented presence of activating EGFR mutations, if the patient was tested for EGFR mutations.
• Previous malignancy within the past 5 years with the exception of adequately treated cervical carcinoma in situ, breast cancer in situ or localized non-melanoma skin cancer.
• Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, or interfering with compliance for oral drug intake.
• Concurrent treatment with experimental drugs or other anti-cancer therapy treatment in a clinical trial within 21 days prior to study registration.
• Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs or any concomitant drugs contraindicated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A: Erlotinib; Erlotinib in standard dose. Until progression (clinical or radiological) or unacceptable toxicity.	Drug: Erlotinib; Erlotinib 150 mg/day p.o. continuously with 21 days cycle.; Other Names: Tarceva (Roche)
Experimental: B: Docetaxel; Docetaxel in standard dose. Until progression (clinical or radiological) or unacceptable toxicity.	Drug: Docetaxel; Docetaxel 75 mg/m2 as an IV infusion every 21 days.; Other Names: Taxotere (Sanofi-Aventis)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Time from the date of randomization until documented progression or death without documented progression. Assessment of Progressive Disease (PD) based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) Target lesions:At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.(Note: the appearance of one or more new lesions is also considered progression). Non-target lesions:Unequivocal progression of existing non-target lesions. (Note:the appearance of one or more new lesions is also considered progression). To achieve 'unequivocal progression', there must be an overall level of substantial worsening in non-target disease such that,even in presence of SD or PR in target disease, the overall tumour burden has increased sufficiently	The combined run in period, treatment and follow-up for PFS is expected to extend the study duration to a total of 24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Defined as time from the date of randomization until death from any cause.	All patients will be followed for survival status every 12 weeks up to 24 months after the last patient is randomized
Objective Response	Objective response is defined as best overall response (CR or PR) across all assessment time-points according to RECIST Criteria 1.1 during the period from randomization to termination of trial treatment.	Same as primary outcome: 24 months
Disease Control	Disease control is defined as achieving objective response or stable disease for at least 6 weeks.	Same as primary outcome: 24 months
Number of Participants With Adverse Events	Adverse events classified according to NCI CTCAE version 4	Same as primary outcome: 24 months

Collaborators and Investigators

• Sponsor: ETOP IBCSG Partners Foundation
• Collaborators: Biodesix, Inc.
• Investigators: Study Chair: Solange Peters, MD-PhD, Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland; Study Chair: Egbert Smit, MD-PhD, Vrije Universiteit VU, Medical Centre, 1007MB Amsterdam, The Netherlands; Study Chair: Rolf Stahel, MD, Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital Zürich, 8044 Zürich, Switzerland

Publications and helpful links

General Publications

• Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. doi: 10.1056/NEJMoa050753.
• Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975 Mar;31(1):103-15.
• Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000 May;18(10):2095-103. doi: 10.1200/JCO.2000.18.10.2095.
• Di Maio M, Chiodini P, Georgoulias V, Hatzidaki D, Takeda K, Wachters FM, Gebbia V, Smit EF, Morabito A, Gallo C, Perrone F, Gridelli C. Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2009 Apr 10;27(11):1836-43. doi: 10.1200/JCO.2008.17.5844. Epub 2009 Mar 9.
• Taguchi F, Solomon B, Gregorc V, Roder H, Gray R, Kasahara K, Nishio M, Brahmer J, Spreafico A, Ludovini V, Massion PP, Dziadziuszko R, Schiller J, Grigorieva J, Tsypin M, Hunsucker SW, Caprioli R, Duncan MW, Hirsch FR, Bunn PA Jr, Carbone DP. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst. 2007 Jun 6;99(11):838-46. doi: 10.1093/jnci/djk195.
• Yildiz PB, Shyr Y, Rahman JS, Wardwell NR, Zimmerman LJ, Shakhtour B, Gray WH, Chen S, Li M, Roder H, Liebler DC, Bigbee WL, Siegfried JM, Weissfeld JL, Gonzalez AL, Ninan M, Johnson DH, Carbone DP, Caprioli RM, Massion PP. Diagnostic accuracy of MALDI mass spectrometric analysis of unfractionated serum in lung cancer. J Thorac Oncol. 2007 Oct;2(10):893-901. doi: 10.1097/JTO.0b013e31814b8be7.
• Sargent DJ, Conley BA, Allegra C, Collette L. Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol. 2005 Mar 20;23(9):2020-7. doi: 10.1200/JCO.2005.01.112.

Helpful Links

• Related information

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: July 26, 2012
• First Submitted That Met QC Criteria: July 26, 2012
• First Posted (Estimate): July 30, 2012

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 23, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Docetaxel; NSCLC; Erlotinib; TKI; squamous cell; VeriStrat; protein signature
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protein Kinase Inhibitors; Docetaxel; Erlotinib Hydrochloride
• Other Study ID Numbers: ETOP3-12; 2012-001896-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO