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S1403, Afatinib Dimaleate With or Without Cetuximab in Treating Patients With Newly Diagnosed Stage IV or Recurrent, EGFR Mutation Positive Non-small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02438722
Recruitment Status : Active, not recruiting
First Posted : May 8, 2015
Results First Posted : March 17, 2021
Last Update Posted : May 6, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
SWOG Cancer Research Network

Study Description
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Brief Summary:
This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

Condition or disease Intervention/treatment Phase
Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Drug: Afatinib Dimaleate Biological: Cetuximab Other: Laboratory Biomarker Analysis Phase 2 Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 174 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)
Actual Study Start Date : May 7, 2015
Actual Primary Completion Date : September 25, 2018
Estimated Study Completion Date : June 15, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (afatinib dimaleate, cetuximab)
Patients receive afatinib dimaleate PO QD on days 1-28 and cetuximab IV over 2 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 Drug: Afatinib Dimaleate
Given PO
Other Names:
  • (2E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(((3S)-tetrahydrofuran-3-yl)oxy)quinazolin- 6-yl)-4-(dimethylamino)but-2-enamide bis(hydrogen (2Z)-but-2-enedioate)
  • BIBW 2992MA2
  • BIBW2992 MA2
  • Gilotrif

Biological: Cetuximab
Given IV
Other Names:
  • Chimeric Anti-EGFR Monoclonal Antibody
  • Chimeric MoAb C225
  • Chimeric Monoclonal Antibody C225
  • Erbitux
  • IMC-C225

Other: Laboratory Biomarker Analysis
Correlative studies
Active Comparator: Arm II (afatinib dimaleate)
Patients receive afatinib dimaleate as in Arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 Drug: Afatinib Dimaleate
Given PO
Other Names:
  • (2E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(((3S)-tetrahydrofuran-3-yl)oxy)quinazolin- 6-yl)-4-(dimethylamino)but-2-enamide bis(hydrogen (2Z)-but-2-enedioate)
  • BIBW 2992MA2
  • BIBW2992 MA2
  • Gilotrif

Other: Laboratory Biomarker Analysis
Correlative studies


Outcome Measures
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Primary Outcome Measures :
  1. 2-year Overall Survival Rate [ Time Frame: Up to 3 years post registration ]

    Percentage of participants still alive 2 years post registration.

    KM estimate at 2 years is presented, Overall Survival assessed for a total of 3 years in order to calculate value.


  2. Progression-Free Survival [ Time Frame: up to 3 years post registration ]

    From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause.

    Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed, as well as an absolute increase of at least 0.5 cm. Unequivocal progression of non-measurable disease in the opinion of treating physician. Appearance of any new lesion/site. Death due to disease without prior documentation of progression and without symptomatic deterioration.



Secondary Outcome Measures :
  1. Response Rates [ Time Frame: Up to 3 years ]

    Percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1).

    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of appropriate diameters of all target measurable lesions; Overall Response (OR) = CR + PR.


  2. Time to Treatment Discontinuation [ Time Frame: up to 3 years post-registration ]
    From date of registration to date of discontinuation of treatment or death due to any cause

  3. Time to Treatment Failure [ Time Frame: assessed up to 3 years post registration ]
    From date of registration to date of first documentation of progression or symptomatic deterioration, early discontinuation of treatment, or death due to any cause.

  4. Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Duration of treatment and follow up until death or 3 years post registration ]
    Routine Adverse Events are reported by CTCAE4.0. For serious adverse event reporting, we updated from CTCAE4.0 to CTCAE5.0. . Only adverse events that are possibly, probably or definitely related to study drug are reported.


Other Outcome Measures:
  1. Change in Copy Number Alterations in MET, EGFR, and HER2, Analyzed Using Fluorescence in Situ Hybridization [ Time Frame: Baseline up to 3 years (after disease progression) ]
    For each of these markers, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the absolute difference between the copy number after progression and the copy number in the pre-treatment specimen (or an appropriate transformation of the difference, determined after exploratory data analysis) is not equal to zero.

  2. Change in the Ratio of Sensitizing EGFR Mutation to EGFR T790 Mutation [ Time Frame: Baseline up to 3 years (at progression) ]
    To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.

  3. EGFR Immunohistochemistry H-score [ Time Frame: Baseline ]
    To evaluate the hypothesis that H-score positive status at baseline is associated with absolute difference in PFS (and OS) among patients randomized to receive afatinib dimaleate monotherapy a test of interaction will be performed at the 1-sided 20% level.

  4. Levels of Circulating Tumor Markers [ Time Frame: Up to 3 years ]
    Tumor marker levels over time will be evaluated using a linear mixed model for continuous markers and using generalized estimating equations for binary markers. A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.

  5. Presence of de Novo EGFR T790M Mutation or Other Molecular Alterations [ Time Frame: Baseline ]
    To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test..

  6. Ratio of Sensitizing EGFR Mutation to EGFR T790 Mutation [ Time Frame: Up to 3 years ]
    To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). Cox regression will be used to assess the predictive association of the ratio in the afatinib dimaleate monotherapy arm with both OS and PFS


Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC)
  • Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
  • Patients must have tissue available and must agree to submission of tissue and blood; one to two paraffin-embedded tissue blocks or 15-20 unstained slides are requested (a minimum of 12 slides is required); cytology (i.e. fine-needle aspirations, pleural effusion specimens) is acceptable if a cell block or sufficient unstained slides are available; tumor material must be reviewed by a local pathologist who must confirm that at least 100 viable tumor cells are present in the sample and sign the S1403 Pathology Review Form; patients must also be willing to submit blood samples for correlative research at baseline, during treatment and at progression
  • Patients enrolled at sites participating in the Repeat Biopsy Study must agree to submission of tissue obtained by a repeat biopsy performed at the time of disease progression
  • Patients must not have received any prior systemic anticancer therapy for advanced or metastatic disease including chemotherapy or EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, afatinib, or any experimental EGFR tyrosine kinase inhibitors [TKI] agents); prior chemotherapy for non-metastatic disease (i.e. adjuvant therapy or concurrent chemo-radiotherapy) is allowed as long as > 12 months has passed since completion of therapy; adjuvant EGFR-directed therapy is not allowed; local therapy (i.e. palliative radiotherapy) is allowed as long as a period of 7 days has passed since the last dose was received and the patient has recovered from any associated toxicity at the time of registration
  • Patients may have measurable or non-measurable disease documented by computed tomography (CT) or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease; in order to qualify as measurable, measurable disease must be outside previous radiation field; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
  • Patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration; patient must not have symptomatic brain metastases or evidence of leptomeningeal carcinomatosis; patients with asymptomatic brain metastases are eligible if off of steroids for at least 7 days prior to registration without development of symptoms
  • Patients must not have any known clinically active interstitial lung disease
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelets >= 75,000/mcL
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or =< 5 x IULN for patients with known liver metastases)
  • Serum creatinine =< 1.5 x IULN OR measured or calculated creatinine clearance >= 60 mL/min
  • Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, etc)
  • Patients must be able to swallow medication by oral route
  • Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50%
  • Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed
  • Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive
  • Patients must not have any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug
  • Patients must not be planning to receive any other investigational agents during the course of protocol treatment
  • Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab
  • Prestudy history and physical must be obtained with 28 days prior to registration
  • Patients must have Zubrod performance status of 0 - 2
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years
  • Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02438722


Locations
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Sponsors and Collaborators
SWOG Cancer Research Network
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sarah Goldberg SWOG Cancer Research Network
  Study Documents (Full-Text)

Documents provided by SWOG Cancer Research Network:
Study Protocol, Statistical Analysis Plan, and Informed Consent Form  [PDF] July 29, 2020

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: SWOG Cancer Research Network
ClinicalTrials.gov Identifier: NCT02438722    
Other Study ID Numbers: S1403
NCI-2014-02405 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
BI 1200.124
S1403 ( Other Identifier: SWOG )
S1403 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: May 8, 2015    Key Record Dates
Results First Posted: March 17, 2021
Last Update Posted: May 6, 2023
Last Verified: May 2023
Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Antineoplastic Agents, Immunological
 Cetuximab
Afatinib
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action