| Eligibility |
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), 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)
- Patient consents to undergo a medically safe tumor biopsy at time of disease
progression for mutation analysis
- 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 =< 1.5 times upper limit of normal (ULN)
- Alkaline phosphatase (ALP) =< 3.0 x ULN
- Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN; for
patients with hepatic metastases, ALT and AST =< 5.0 x ULN are acceptable
* Note: if a patient experiences elevated ALT > 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); postmenopausal status in females under 55 years
of age should be confirmed with a serum follicle-stimulating hormone (FSH) level
within laboratory reference range for postmenopausal women
- 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) =< grade 1 to be eligible
- History of arterial or venous thromboembolism within 3 months prior to study
enrollment; patients with a history of venous thromboembolism beyond 3 months prior to
study enrollment can be enrolled if they are appropriately treated with low molecular
weight heparin
- 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 < 2 weeks prior to starting study treatment
- 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
- Known positive test for hepatitis B, hepatitis C, human immunodeficiency virus (HIV),
or acquired immunodeficiency syndrome (AIDS)
- 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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