Afatinib Dimaleate, Combination Chemotherapy, and Radiation Therapy in Treating Patients with Stage IIIA or Stage IIIB Non-small Cell Lung Cancer
This phase II trial studies how well afatinib dimaleate works when given together with combination chemotherapy and radiation therapy in treating patients with stage IIIA or stage IIIB non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed disodium and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving afatinib dimaleate together with combination chemotherapy and radiation therapy may kill more tumor cells.
Inclusion Criteria
- Participants must have histologically confirmed stage IIIA or IIIB non-squamous non-small cell lung cancer (NSCLC) (American Joint Committee on Cancer [AJCC] 7th edition); patients with a clinical stage of IIIB are allowed only if they are thought to be a candidate for concurrent chemoradiation
- Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with spiral computed tomography (CT) scan
- Participants must have a lung cancer harboring an EGFR mutation
- Pulmonary function tests within 6 months of study enrollment must have forced expiratory volume in 1 second (FEV1) >= 1.2 L and diffusing capacity of the lung for carbon monoxide (DLCO) >= 40% of predicted; patients with FEV1 of < 1.2 L but a predicted value of >= 40% may be eligible after review of the case by the study radiation primary investigator (PI) or his designee
- Positron emission tomography (PET)/CT scan including neck, chest, abdomen, pelvis within 4 weeks of study enrollment documenting the absence of distant metastases
- Brain magnetic resonance imaging (MRI) with gadolinium within 4 weeks of study enrollment demonstrating the absence of brain metastases; if an MRI is medically contraindicated or if the patient refuses, a head CT with IV contrast is acceptable
- Life expectancy of greater than 6 months
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- All patients must be evaluated by a medical oncologist, radiation oncologist, and thoracic surgeon within 4 weeks of enrollment into study to document that they are a candidate for chemoradiation and whether or not they are candidates for consideration of surgical resection (not required to be a surgical candidate)
- Women of child-bearing potential must have a negative pregnancy test during screening; women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Prior EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, or any experimental EGFR tyrosine kinase inhibitor [TKI] agent)
- Prior treatment with radiation to the thoracic region
- Participants may not be receiving any other investigational agents
- Known pre-existing interstitial lung disease
- Significant or recent gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, or complete blood count [CBC] grade >= 2 diarrhea of any etiology)
- History or presence 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 randomization
- 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
- Absolute neutrophil count (ANC) < 1,500/mcL
- Platelets =< 100,000/mcL
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) >= 3 times the upper limit of normal (if related to liver metastases >= 5 times the upper limit of normal)
- Total bilirubin >= 1.5 mg/dL (> 26 mol/L, SI unit equivalent)
- Serum creatinine >= 1.5 times the upper normal limit or calculated/measured creatinine clearance =< 60 mL/min
- Women of childbearing potential, or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnant women are excluded from this study; breastfeeding is not allowed during the course of the study; female patients must have a negative pregnancy test (human chorionic gonadotropin beta subunit [B-HCG] test in urine or serum) prior to commencing study treatment
- Patients unable to comply with the protocol
- Known active hepatitis B infection, active hepatitis C infection or known human immunodeficiency virus (HIV) carrier
- Known or suspected active drug or alcohol use
- Known hypersensitivity to afatinib, cisplatin, or pemetrexed
- Concomitant treatment with strong inhibitor of P-glycoprotein (P-gp)
- Individuals with a history of an active malignancy (other than the current lung cancer diagnosis) within the last 3 years (except non-melanoma skin cancer or a non-invasive/in situ cancer)
Additional locations may be listed on ClinicalTrials.gov for NCT01553942.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To assess the response rate to induction afatinib (afatinib dimaleate).
SECONDARY OBJECTIVES:
I. To estimate the 2-year progression-free survival (PFS) of stage III epidermal growth factor receptor (EGFR) mutation-positive patients treated with this novel regimen of induction afatinib, cisplatin/pemetrexed (pemetrexed disodium) and radiation, with or without surgery, and selected consolidation afatinib.
II. To describe the safety profile of combining induction afatinib therapy with concurrent chemotherapy and radiation.
III. To estimate the proportion of patients with unresectable disease that can be converted to operable cases.
IV. To estimate 2-year locoregional tumor control rates, distant metastasis rates and overall survival rates, as well as median overall survival (OS).
V. To evaluate genomic tumor deoxyribonucleic acid (DNA) for the presence of pre-existing resistance mechanisms such as EGFR T790M mutations or met proto-oncogene (hepatocyte growth factor receptor) (MET) kinase amplifications, and explore correlations of these with response to afatinib and to explore additional predictive biomarkers of tumor response to afatinib and chemoradiation in clinical samples and circulating tumor cells (including chromatin markers and DNA repair proteins).
OUTLINE:
INDUCTION: Patients receive afatinib dimaleate orally (PO) once daily (QD) for 8 weeks.
CHEMORADIATION: Patients receive cisplatin intravenously (IV) over 60 minutes and pemetrexed disodium IV over 10 minutes on day 1, and undergo 35-40 fractions of 4-dimensional (4D) conformal radiation therapy 5 days per week for 7-8 weeks. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
SURGICAL RESECTION: Operable patients undergo surgical resection 4-6 weeks after completion of chemoradiation.
ADJUVANT CHEMOTHERAPY (OPTIONAL): Patients receive cisplatin IV over 60 minutes and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: Patients achieving complete response (CR) or partial response (PR) receive afatinib dimaleate PO QD on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 3 years and then annually for 1 year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorLecia Van Dam Sequist
- Primary ID11-464
- Secondary IDsNCI-2012-01535, 1200.158
- ClinicalTrials.gov IDNCT01553942