Study of Glembatumumab Vedotin in gpNMB-Expressing, Advanced or Metastatic SCC of the Lung

Lung cancer is the most frequent cancer in the world, with annual cases worldwide currently
estimated at one million and increasing to 10 million by the year 2025. In the United States,
despite the declining incidence in white males in recent years, lung cancer is still the
second most frequent cancer in both men (next to prostate) and women (next to breast cancer).

This is an open-label, single arm study of glembatumumab vedotin, a fully-human IgG2
monoclonal antibody. The activity of glembatumumab vedotin may be greatest in patients who
overexpress the target, gpNMB.

This study will include a dose-escalation phase to determine the maximum safe and tolerated
dose. This will be followed by a 2-stage Phase II expansion. During Phase II Stage 1,
approximately 20 eligible, treated patients will be enrolled. If ≥ 2 patients achieve a tumor
response [Partial Response (PR) or Complete Response (CR)]; an additional 15 eligible,
treated patients will be enrolled in Stage 2, for a maximum total of 35 eligible, treated
patients.

Glembatumumab vedotin will be administered once every 3 weeks, as a 90-minute intravenous
(IV) infusion.

Patients will continue treatment until disease progression or intolerance. Tumor assessments
will be performed every six (±1) weeks for six months, and every nine (±2) weeks thereafter,
until progression.

A tumor tissue sample (i.e., obtained during a previous procedure or biopsy) will be sent to
a central laboratory and tested for gpNMB. Research blood samples will also be required.

Inclusion Criteria:

1. Read, understood, and provided written informed consent and Health Insurance
Portability and Accountability Act (HIPAA) authorization after the nature of the study
has been fully explained and must be willing to comply with all study requirements and
procedures.

2. Male or female patients with metastatic, histologically- or cytologically-confirmed
unresectable Stage IIIB or IV non-small cell lung cancer (NSCLC) of squamous histology
(Staging per American Joint Committee on Cancer [AJCC], Edition 7). Mixed histology
adenosquamous NSCLC will also be permitted.

3. Experienced progression/recurrence of disease during or subsequent to the most recent
anti-cancer regimen.

4. Any number of prior lines of systemic therapy may have been received for advanced
(recurrent, locally advanced, or metastatic) SCC of the lung, but at least one must
have been a platinum-based chemotherapy regimen. Platinum therapy may be given
on-label or as part of a clinical trial.

5. Lung cancer confirmed to express gpNMB, as assessed by immunohistochemistry at a
central lab (using expression in ≥ 5% of tumor epithelial cells as a cut-off for
positivity). This can be tested on archived tissue if available, although preferred
tumor specimen is a biopsy after the most recent therapy.

6. Age ≥ 18 years.

7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.

8. Measurable disease by RECIST 1.1 criteria. Target lesions selected for tumor
measurements should be those where surgical resection or radiation are not indicated
or anticipated.

9. Resolution of all toxicities related to prior therapies to ≤ NCI-CTCAE Grade 1
severity, except for alopecia, vitiligo, or endocrinopathies on replacement therapy.

10. Adequate bone marrow function as assessed by absolute neutrophil count (ANC) ≥
1500/mm3; hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3.

11. Adequate renal function as assessed by serum creatinine ≤ 2.0 mg/dL; or calculated or
24-hour urine creatinine clearance >40 mL/min.

12. Serum albumin ≥ 3 g/dL.

13. Adequate liver function as assessed by total bilirubin ≤ 1.5x upper limit of normal
(ULN), and alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5x ULN (≤
5.0x ULN in the case of liver metastases). Patients with known Gilbert's syndrome may
be enrolled with total bilirubin ≤ 3.0 mg/dL.

14. Both male and female patients of childbearing potential enrolled in this trial must
use adequate birth control measures during the course of the trial and for at least
one month after discontinuing study drug.

15. Willing to provide blood samples for research purposes.

Exclusion Criteria:

1. Received glembatumumab vedotin (CR011-vcMMAE; CDX-011) or other MMAE-containing agents
previously.

2. Chemotherapy within 21 days or at least 5 half-lives prior to the planned start of
study treatment; radiation outside the thorax within 14 days prior to the planned
start of study treatment or thoracic radiation; antibody based therapy or
investigational therapy within 28 days prior to the planned start of study treatment.

3. Neuropathy >NCI-CTCAE Grade 1.

4. Subjects with a history of allergic reactions attributed to compounds of similar
composition to dolastatin or auristatin. Compounds of similar composition include
Auristatin PHE as an anti-fungal agent, Auristatin PE (TZT-1027, Soblidotin,
NSC-654663) as an anti-tumor agent and Symplostatin 1 as an anti-tumor agent.

5. Known brain metastases, unless previously treated and patients are neurologically
returned to baseline except for residual signs and symptoms related to Central Nervous
System (CNS) treatment and CNS lesions are not progressive in size and number for 4
weeks.

6. Significant cardiovascular disease including unstable angina pectoris, uncontrolled
hypertension, and congestive heart failure related to primary cardiac disease, a
history of a serious uncontrollable arrhythmia despite treatment, ischemic or severe
valvular heart disease, or a myocardial infarction within 6 months prior to the trial
entry.

7. Active systemic infection requiring treatment. Infection controlled by oral therapy
will not be exclusionary.

8. Subjects on immunosuppressive medications such as azathioprine, mycophenolate mofetil,
cyclosporine or require chronic corticosteroid use (defined as ≥ 3 months of
prednisone dose equivalent of ≥ 10 mg).

9. The MMAE component of glembatumumab vedotin is primarily metabolized by CYP3A.
Patients taking strong CYP3A inhibitor and inducers are excluded in Phase I (the dose
escalation portion), to minimize the effect of these modulators on exposure,
tolerability and dose selection.

10. History of other malignancy except for adequately treated basal or squamous cell skin
cancer, curatively treated in situ disease, or any other cancer from which the patient
has been disease-free for ≥ 2 years.

11. Pregnant or breast-feeding women.

12. Subjects must not be on home oxygen therapy (intermittent or continuous).

13. Any underlying medical condition that, in the Investigator's opinion, will make the
administration of study treatment hazardous to the patient, or would obscure the
interpretation of adverse events.