Nimotuzumab and Nivolumab in Treating Patients With Advanced Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicities (DLT) and estimate the maximum tolerated dose
(MTD) of nimotuzumab combined with nivolumab in the therapy of advanced non-small cell lung
cancer (NSCLC) in order to establish the recommended phase II dose (RP2D). (Phase I)

II. To evaluate the 12 month overall survival of nimotuzumab in combination with nivolumab in
patients with advanced NSCLC. (Phase II)

SECONDARY OBJECTIVES:

I. Examine the safety and tolerability profile of nivolumab in combination with nimotuzumab
in NCSLC . (Phase I)

II. To evaluate the safety and the tolerability of nimotuzumab in combination with nivolumab
using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE version 4.0). (Phase I)

III. Determine the immune analysis profile of nivolumab in combination with nimotuzumab.
(Phase I)

IV. Examine the efficacy of the study combination utilizing irRECIST guidelines. (Phase I)

V. Overall response rate (ORR) per the immune-related Response Evaluation Criteria in Solid
Tumors irRECIST. (Phase I)

VI. Progression-free survival (PFS) rate at 1 year. (Phase I)

VII. Progression-free survival (PFS). (Phase I)

VIII. Overall survival (OS). (Phase I)

IX. Disease control rate (DCR) and stable disease (SD). (Phase I)

X. To evaluate the safety profile of Nimotuzaumab in combination with Nivolumab in NCSLC
using the CTCAE V. 4.

XI.To evaluate the efficacy of nimotuzumab in combination with nivolumab in patients with
advanced NSCLC compared to historic outcomes of nivolumab alone, as determined by secondary
measures of efficacy, including: overall response rate (ORR) per irRECIST. (Phase II)

XII. To evaluate the efficacy of nimotuzumab in combination with nivolumab in patients with
advanced NSCLC compared to historic outcomes of nivolumab alone, as determined by secondary
measures of efficacy, including: progression-free survival (PFS) rate at 1 year. (Phase II)

XIII. To evaluate the efficacy of nimotuzumab in combination with nivolumab in patients with
advanced NSCLC compared to historic outcomes of nivolumab alone, as determined by secondary
measures of efficacy, including: progression-free survival (PFS). (Phase II)

XIV. To evaluate the efficacy of nimotuzumab in combination with nivolumab in patients with
advanced NSCLC compared to historic outcomes of nivolumab alone, as determined by secondary
measures of efficacy, including: overall survival (OS). (Phase II)

XV. To evaluate the efficacy of nimotuzumab in combination with nivolumab in patients with
advanced NSCLC compared to historic outcomes of nivolumab alone, as determined by secondary
measures of efficacy, including: disease control rate (DCR) and stable disease (SD). (Phase
II)

TERTIARY OBJECTIVES:

I. Examine the relationship of EGFR expression in tissue to PFS, OS, ORR and adverse events
(AE). (Phase I)

II. Examine the relationship of infiltrating CD4+ and CD8+ T cells and other immune and
genetic markers, and their associated PD-1, CD45RA or CD45RO levels; PD-L1 expression within
both neoplastic and non-neoplastic stromal elements of the tumor microenvironment to PFS, OS,
ORR and AE. (Phase I)

III. Comparison of response assessment criteria for a prospective analysis; irRECIST response
assessment; irRC. (Phase I)

IV. Examine the relationship of EGFR expression in tissue to PFS, OS, ORR and AE. (Phase II)

V. Examine the relationship of infiltrating CD4+ and CD8+ T cells and other immune and
genetic markers, and their associated PD-1, CD45RA or CD45RO levels. (Phase II)

VI. Examine the relationship of PD-L1 expression within both neoplastic and non-neoplastic
stromal elements of the tumor microenvironment to PFS, OS, ORR and AE. (Phase II)

VII. Comparison of response assessment criteria for a prospective analysis; irRECIST response
assessment; irRC. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of nimotuzumab followed by a phase II
study.

Patients receive nivolumab intravenously (IV) over 60 minutes and nimotuzumab IV over 60
minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12
weeks.

Inclusion Criteria:

- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

- Patients with pathologically confirmed non-small cell lung cancer

- Patients must have had progressive NSCLC after first-line platinum-based chemotherapy
for advanced disease

- Have at least 3 months life expectancy

- Have measurable disease per RECIST 1.1 criteria present

- Patients with adenocarcinoma known to have anaplastic lymphoma kinase (ALK)
rearrangements and/or epidermal growth factor receptor (EGFR) mutations that have had
prior EGFR or ALK tyrosine kinase inhibitor therapy and have progressed, will also be
eligible, regardless of line of therapy

- Phase I optional archival tissue/phase II mandatory archival tissue: able to provide
enough biopsy tissue samples including primary diagnostic biopsy (archival), re-biopsy
tissues (archival from time of disease progression/recurrence following first-line
treatment failure) at disease progression to determine PD-L1 and EGFR expression and
other biomarkers

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Hemoglobin >= 9 g/dL

- Serum creatinine =< 1.5 x institution upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 1.5 x ULN or =<
5 x ULN if liver metastases are present

- Total serum bilirubin =< ULN; or total bilirubin =< 3.0 x ULN with direct bilirubin
within normal range in patients with well documented Gilbert's syndrome

- Troponin-I, CK-MB, BNP <= ULN

- LVEF >= LLN

- Participants of child-bearing potential must agree to use adequate contraceptive
methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
entry; should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Active autoimmune disease that has required systemic treatment in past 2 years; use of
inhaled corticosteroids is allowed

- Phase II only: history of other malignancies are allowed as long as the current
disease stage that did not require active treatment with concomitant systemic
cytotoxic chemotherapy, targeted therapy, investigational or biologic therapy (e.g.,
anti-CTLA4 or HER2 monoclonal antibodies) within 12 months prior to study registration
and, is not likely to require systemic therapy in the next 12 months; hormone-related
therapies (e.g., somatostatin analogues, etc.) are allowed on a case-to-case basis
upon discussion with principal investigator

- Active clinically serious infections requiring antibiotics, antiviral or antifungal
agents; participants must be off these agents for at least 28 days prior to the first
dose of the study drug

- Symptomatic brain metastases; uncontrolled pleural effusion, seroperitoneum, or
pericardial effusion

- Has had any major surgery, chemotherapy, or radiotherapy within the previous 4 weeks;
gamma knife radiosurgery for brain metastases within less than 2 weeks

- Receiving other anti-cancer medical treatment during the study outside of the
nimotuzumab or nivolumab

- Clinically significant interstitial pulmonary disease or known diagnosis of
interstitial lung disease (ILD)

- Has known immunosuppressive disease (e.g. human immunodeficiency virus [HIV], acquired
immune deficiency syndrome [AIDS])

- Patient has known hypersensitivity to the components of the study drugs or their
analogs

- Patient with uncontrolled cardiac disease or cardiac dysfunction, including any of the
following:

- History of uncontrolled angina pectoris that does not respond to medical
intervention

- Symptomatic pericarditis or myocardial infarction within 12 months prior to study
entry that did not respond to treatment

- History of documented congestive heart failure (New York Heart Association
functional classification III or IV)

- Documented cardiomyopathy

- Uncontrolled hypertension defined by: systolic blood pressure (SBP) >= 160 mmHg
and/or diastolic blood pressure (DBP) >= 100 mmHg

- Pregnant or nursing female participants

- Unwilling or unable to follow protocol requirements

- Any condition which in the investigator's opinion deems the participant an unsuitable
candidate to receive study drug