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Afatinib and Necitumumab in Treating Patients with EGFR Mutation Positive Advanced or Metastatic Non-small Cell Lung Cancer

This phase I trial studies the side effects and best dose of afatinib and necitumumab and to see how well they work in treating patients with EGFR mutation positive non-small cell lung cancer that has spread to other places in the body. Afatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as necitumumab, may interfere with the ability of tumor cells to grow and spread. Giving afatinib and necitumumab may work better in treating patients with EGFR mutation positive non-small cell lung cancer.
Lung, Non Small Cell
Phase I
Mol. targeted/Immunotherapy/Biologics
Afatinib, Necitumumab
Horn, Leora
CITY OF HOPE NATIONAL MEDICAL CENTER, Stanford University, University of California, San Diego, Vanderbilt University


18 Years
Inclusion Criteria:

Signed and dated written informed consent

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Histologically or cytologically-confirmed advanced or metastatic non-small cell lung cancer (NSCLC) that is EGFR mutation positive; rare sensitizing mutations allowed

Progression on a first generation EGFR TKI (T790M negative), progression on first-line osimertinib, or progression on a third generation TKI (if T790M positive at time of progression on a first or second generation TKI)

At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 that can be followed by computed tomography (CT) or magnetic resonance imaging (MRI)

Tumor tissue from biopsy following progression on the most recent TKI available for mutation analysis; if tissue is inadequate for exploratory research testing, patient may enroll with permission of principal investigator

Leukocytes >= 3,000/uL

Absolute neutrophil count (ANC) >= 1,500/uL

Platelets >= 100,000/uL

Hemoglobin >= 9 g/dL

Serum albumin >= 2.5 g/dL

Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula)

Total bilirubin =
Alkaline phosphatase (ALP) =
Alanine aminotransferase (ALT) and aspartate transaminase (AST) = 5 x ULN and elevated total bilirubin > 2 x ULN, clinical and laboratory monitoring should be initiated by the investigator; for patients entering the study with ALT > 3 x ULN, monitoring should be triggered at ALT > 2 x baseline

Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of study medication; and additionally agree to use at least two methods of birth control or abstain from heterosexual intercourse from the time of signing consent, and until 6 months after patient’s last dose of study drug * WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 24 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential)

WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy

Men able to father children who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy; men able to father children are defined as those who are not surgically sterile (i.e. patient has not had a vasectomy)

Exclusion Criteria:

Prior treatment against NSCLC with an EGFR monoclonal antibody

Prior afatinib therapy, unless patient received an intervening third generation EGFR TKI after concluding prior afatinib and before enrollment on this clinical study

Less than 3 days from prior treatment with EGFR TKI; patients with adverse events related to prior EGFR TKI must recover to Common Terminology Criteria for Adverse Events (CTCAE) =
Subjects with a history of interstitial lung disease (e.g., sarcoidosis) that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity; subjects with chronic obstructive pulmonary disease (COPD) whose disease is controlled at study entry are allowed

Symptomatic brain metastases; stable and treated central nervous system (CNS) disease allowed; patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least two (2) weeks prior to initiating study treatment; anticonvulsant therapy will be allowed if patient is on a stable or decreasing dose of anticonvulsant treatment for at least two (2) weeks prior to initiating study treatment

Subjects with carcinomatous meningitis

Prior radiotherapy or radiosurgery
Current symptomatic congestive heart failure (New York Heart Association classification >= grade III), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100 mmHg); or any of the following occurring within 6 months (180 days) prior to first dose of study treatment: myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack; use of antihypertensive medication to control blood pressure is allowed

Patient is pregnant or breastfeeding, or plans to become pregnant or father children from time of signing consent and lasting until 6 months after the last dose of trial treatment

Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured AND no additional therapy is ongoing and required during the study period with the exception of bisphosphonates and anti-androgens and/or gonadorelin analogues for the treatment of prostate cancer are permitted; subjects with other active malignancy requiring concurrent intervention are excluded

Requiring treatment with any of the prohibited concomitant medications listed that cannot be stopped for the duration of trial participation

Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, chronic diarrhea, malabsorption)

Recent (within 30 days before enrollment) or concurrent yellow fever vaccination

All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to grade 1 (National Cancer Institute [NCI] CTCAE version 4) or baseline before administration of study drug

The patient has any ongoing or active infection, including active tuberculosis; Note: a urinary tract infection controlled with oral antibiotics initiated at least 7 days prior to study entry is acceptable

Patients who are immunosuppressed (including known human immunodeficiency virus [HIV] infection); patients with active hepatitis B or C are excluded; patients with controlled hepatitis C, in the investigator’s opinion, are allowed

The patient has a known allergy/history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab, or any other contraindication to one of the administered treatments

Known hypersensitivity to afatinib or the excipients of any of the trial drugs

History of severe hypersensitivity reactions to other monoclonal antibodies

Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness

Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject’s ability to comply with the study requirements, substantially increase risk to the subject, or impact the interpretability of study results

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