NSCLC

Primary: • To evaluate the efficacy of ficlatuzumab plus erlotinib versus placebo plus erlotinib in terms of progression-free survival (PFS) in subjects who have previously untreated metastatic EGFR-mutated NSCLC and a BDX004 Positive Label. Secondary: • To evaluate overall survival (OS) in the 2 treatment groups. • To compare objective response rate (ORR) in the 2 treatment groups. • To evaluate disease control rate (DCR) in the 2 treatment groups. • To evaluate safety and tolerability of ficlatuzumab plus erlotinib versus placebo plus erlotinib in subjects who have previously untreated metastatic EGFR-mutated NSCLC and a BDX004 Positive Label. • To evaluate the pharmacokinetics of ficlatuzumab and erlotinib.

Ficlatuzumab (AV-299),

Ficlatuzumab (AV-299),

Concentrate for solution for infusion

20 mg/kg

cThe primary efficacy endpoint PFS is defined as the time from the date of randomization
to the earliest date of the first objective documentation of radiographic disease
progression or death due to any cause. Progression will be assessed in accordance with
RECIST v.1.1 criteria every 4 weeks for the first 8 cycles, and every 8 weeks thereafter.
If disease progression according to RECIST v.1.1 is documented at any time, no further
disease response assessment will be required. Subjects who are alive with no objective
documentation of disease progression by the data cut-off date for PFS analysis will be
censored at the date of their last evaluable tumor assessment.
Secondary efficacy endpoints include: OS as measured from the date of randomization to
the date of death by any cause; ORR based on subjects that had CR or PR; and DCR
based on subjects that had CR, PR, or SD for at least 4 cycles (16 weeks).
PFS is a reasonable endpoint to evaluate new therapy in subjects with advanced NSCLC
harboring activating EGFR mutations.

1. Male or female and ≥18 years of age.
2. Histologically and/or cytologically confirmed primary diagnosis of Stage IV NSCLC
(according to American Joint Committee on Cancer [AJCC] 7th edition lung cancer
staging criteria).
3. Measurable disease according to RECIST v.1.1.
4. An EGFR exon 19 deletion and/or an exon 21 (L858R) substitution mutation.
5. BDX004 Positive Label.
6. Have received no prior systemic chemotherapy, immunotherapy, targeted therapy, or
biologic therapy for metastatic NSCLC. Subjects may have previously been treated
with postoperative adjuvant chemotherapy for early stage lung cancer or
chemo-radiotherapy for locally advanced disease provided this was completed at least
6 months prior to enrollment. No prior EGFR TKI therapy is allowed for any stage of
NSCLC.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Clinical laboratory values meeting the following criteria prior to randomization:
• Serum creatinine ≤1.5 x upper limit of normal (ULN).
• Total bilirubin ≤1.5 x ULN.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤2.5 x ULN, or AST and ALT ≤5 x ULN if liver metastases.
• Activated partial thromboplastin time (aPTT) ≤1.5 x ULN and prothrombin
time/international normalized ratio (PT/INR) ≤1.5 x ULN if not on
anticoagulation therapy. Subjects receiving anti-coagulation therapy with an
agent such as warfarin or low-molecular weight heparin may be allowed to
participate if the subject is on a stable dose of anticoagulant and coagulation
test results are in the therapeutic range established prior to initiation of study
treatment.
• Hematologic function:
- Absolute neutrophil count (ANC) ≥1,500 cells/μL.
- Hemoglobin ≥9 g/dL or 5.6 mmol/L.
- Platelet count ≥100,000/μL.
9. For female subjects of childbearing potential, documentation of negative serum
pregnancy test prior to randomization.
10. For female subjects of childbearing potential and male subjects whose sexual partners
are of childbearing potential, agreement to use an effective method of contraception
during the study and for at least 30 days after the last dose of study treatment.
Effective birth control includes (a) intrauterine device plus one barrier method; (b)
oral, implantable or injectable contraceptive plus one barrier method; or
(c) two barrier methods. Effective barrier methods are male or female condoms,
diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).
11. Ability to give written informed consent and comply with protocol requirements.

1. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant
proteins or excipients in the investigational agent or erlotinib.
2. History of known brain metastases.
3. Prior treatment with any other investigational drug or biologic agent within
5 half-lives prior to randomization, or any investigational device within 2 weeks prior
to randomization.
4. Any unresolved toxicity from previous radiation therapy.
5. Significant cardiovascular disease, including:
• Echocardiogram (ECHO) or multiple gated acquisition (MUGA) showing left
ventricular ejection fraction of less than 55%.
• Cardiac failure New York Heart Association class III or IV.
• Myocardial infarction, severe or unstable angina within 6 months prior to
randomization.
• History of serious ventricular arrhythmia (ie, ventricular tachycardia or
ventricular fibrillation).
• Significant thrombotic or embolic events within 3 months prior to randomization
(significant thrombotic or embolic events include but are not limited to stroke or
transient ischemic attack). Catheter-related thrombosis is not a cause for
exclusion. Diagnosis of deep vein thrombosis or pulmonary embolism is allowed
if it occurred >3 months prior to randomization.
• Any uncontrolled or severe cardiovascular disease.
6. Any other medical condition (eg, alcohol abuse) or psychiatric condition that, in the
opinion of the Investigator, might interfere with the subject’s participation in the trial
or interfere with the interpretation of trial results.
7. History of prior malignancy within 3 years prior to randomization (except for
adequately treated non-melanoma skin cancer, carcinoma in situ of the breast or
cervix, superficial bladder cancer, or early stage prostate cancer, without evidence of
recurrence).
8. Major surgery within 4 weeks prior to randomization.
9. Serious and/or symptomatic active infection within 14 days prior to first dose of
study drug. Subjects who have asymptomatic or mild infection and are currently
taking a short course of antibiotics (eg, urinary tract infection, bronchitis) may be
allowed after discussion with the Medical Monitor.
10. Known human immunodeficiency virus infection.
11. Radiographic evidence of interstitial lung disease.
12. For female subjects, pregnancy or breast feeding.