Study of Erlotinib With or Without Investigational Drug (U3-1287) in Subjects With Advanced Non-small Cell Lung Cancer

This is a Phase 1b/2 study. In Phase 1b, subjects will know the treatment they are receiving. Subjects will receive Erlotinib + U3-1287. The Phase 1b portion will determine if adding U3-1287 to Erlotinib will be safe in subjects with advanced non-small cell lung cancer who fail prior treatment. In the Phase 2 portion, subjects will be blinded to the treatments they are receiving. Subjects will receive either Erlotinib alone or Erlotinib + U3-1287.

The Phase 2 portion will determine if adding U3-1287 to Erlotinib will be safe and improve survival in subjects with advanced non-small cell lung cancer who failed the first treatment.


Eligibility Criteria:
Inclusion Criteria:

* ≥ 18 years of age.
* Histologically or cytologically confirmed stage IIIB not amenable to surgery or curative intent or stage IV NSCLC.
* Disease progression or recurrence following treatment after last chemotherapy or chemoradiation regimen (completed within the previous 12 months) documented by radiographic assessment.
* Measurable disease by Response Evaluation Criteria for Solid Tumors v1.1 (RECIST v1.1).
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate bone marrow, renal, and hepatic function.
* Prothrombin time and partial thromboplastin time ≤1.5 x upper limit of normal (ULN).
* Availability of recent (before treatment start) or archival tumor specimens (Phase 2 participants only).
* For female participants, must be postmenopausal, surgically sterile, or must use maximally effective birth control during the period of therapy, and must be willing to use effective contraception up to 6 months after the last dose of study drug and had a negative urine or serum pregnancy test before entry into the study if female participants were of childbearing potential.
* For male participants, must be surgically sterile or willing to use a double barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose
* Written informed consent.

Exclusion Criteria:

* Left ventricular ejection fraction (LVEF) \< 45%.
* Prior epidermal growth factor receptor (EGFR)-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy.
* More than 2 prior chemotherapy regimens for NSCLC (Phase 2 participants only).
* History of other malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years.
* History of corneal disease.
* History of interstitial lung disease.
* Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that were no longer symptomatic and required no treatment with steroids could be included in the study if they had recovered from the acute toxic effect of radiotherapy.
* Uncontrolled hypertension (diastolic \> 100 mmHg or systolic \> 140 mmHg).
* Clinically significant electrocardiogram changes that obscured the ability to assess the respiratory rate, pulse rate, QT, QTc, and QRS intervals.
* Ascites or pleural effusion requiring chronic medical intervention.
* Myocardial infarction within 1 year before enrollment, symptomatic congestive heart failure (New York Heart Association \> Class II), unstable angina, or unstable cardiac arrhythmia requiring medication.
* Treatment with anticancer therapy, antibody based therapy, retinoid therapy, or hormonal therapy within 4 weeks before study treatment or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment or treatment with small molecule tyrosine kinase inhibitors (TKIs) within 2 weeks before study drug treatment. Prior and concurrent use of hormone replacement therapy was permitted.
* Therapeutic radiation or major surgery within 4 weeks before study treatment or palliative radiation therapy within 2 weeks before study drug treatment.
* Participated in clinical drug trials within 4 weeks (2 weeks for small molecule TKIs) before study drug treatment. Current participation in other investigational procedures.
* Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
* History of hypersensitivity to any of the study drugs or to any excipients.
* Concurrent use of CYP3A4 inducers or inhibitors.
* Any known pre-existing condition including substance abuse that could interfere with participant's participation in and completion of the protocol.