Depletion of Myeloid Derived Suppressor Cells to Enhance Anti PD-1 Therapy

Primary Objective

• The primary objective of this proposal is to evaluate gemcitabine as a method of MDSC
depletion.

Secondary Objectives

- Evaluate whether these measures result in enhanced T-cell activity and/or NK cell
function and number.

- Determine the tolerability and clinical activity (including response rate and survival)
of this approach.

- Correlate MDSC number with tumor PD-L1 expression

Inclusion Criteria:

1. Histologically confirmed diagnosis of non-small cell lung cancer (NSCLC). Patients
should have stage IV disease (AJCC 7th edition), stage IIIb disease that is not
amenable to potentially curative treatment (e.g. chemoradiotherapy) or unequivocal
progression in a prior irradiated field. Measurable or evaluable disease is required.

2. Fresh/ archived tumor tissue available for molecular marker testing is required for
entry. A tumor block or at least 5 unstained slides must be available. As an
alternative FFPE cell block that is sufficient for histologic analysis is acceptable.
If a patient has had PD-L1 status previously determined with and FDA approved assay,
they have met this requirement. Tissue is still requested (but not required) for
further analysis

3. Age > 18 years.

4. ECOG performance status 0 or 1

5. Patients must have normal organ and marrow functions as defined below:

White blood cells (WBC) >2,000/mcL; Platelets >100,000/mcL; Hb ≥9g/dl; Absolute
neutrophil count (ANC) >1,500/mcL; Serum creatinine ≤1.5 x ULN, or

Creatinine clearance (CrCl) ≥50 ml/min (if using Cockcroft Gault formula below):

Female CrCl= ((140 - age in years)/(72 x serum creatinine in mg/dL)) x weight in kg x
0.85; Male CrCl= ((140 - age in years)/(72 x serum creatinine in mg/dL) x weight in kg
x 1.0; AST/SGOT ≤ 3 x ULN

Total bilirubin:

If no known liver metastasis: total bilirubin ≤ 1.5 x institutional upper limit (ULN)
(except, subjects with Gilbert Syndrome who may have total bilirubin < 3.0 mg/dl; If
known metastasis: total bilirubin ≤ 5 ULN

6. Negative serum pregnancy test result in Women os Child -bearing Potential (WOCBP)

7. Prior therapies:

- Patients without activating mutations and gene rearrangements should have
received at least one prior chemotherapy regimen. Any number of prior therapies
is allowed except for immunotherapy (e.g. anti PD-1, PD-L1, vaccines, CTLA-4
etc.),

- Patients with activating mutations with known documented benefit from tyrosine
kinase inhibitors should have received and demonstrated progression with that
inhibitor (e.g. EGFR del 19 mutation should have been treated with gefitinib,
erlotinib or afatanib etc). ALK rearrangements should have been treated with an
ALK inhibitor. Patients who have progressed on these agents should be assessed,
if appropriate, for resistance mutations susceptible to approved agents and
treated with that agent.

- No prior gemcitabine treatment

8. Ability to understand and willingness to sign a written informed consent and HIPAA
consent document

Exclusion Criteria:

1. Patients with active, known or suspected autoimmune disease. Subjects are permitted to
enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
autoimmune condition only requiring hormone replacement, psoriasis not requiring
systemic treatment, or conditions not expected to recur in the absence of an external
trigger

2. Patients requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days of study
drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg
daily prednisone equivalents are permitted in the absence of active autoimmune
disease. Subjects are permitted to use topical, ocular, intra-articular, intranasal,
and inhalational corticosteroids (with minimal systemic absorption). Physiologic
replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day
prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg,
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type
hypersensitivity reaction caused by contact allergen) is permitted.

3. As there is a potential for hepatic toxicity with nivolumab, drugs with predisposition
to hepatotoxicity should be used with caution in patients treated with
nivolumab-containing regimen.

4. Patients are excluded if they have active brain metastases or leptomeningeal
metastases. Subjects with brain metastases are eligible if metastases have been
treated without clinical or radiologic evidence of progression for 14 days prior to
initiation of treatment. An MRI within 14 days of commencing therapy is required for
patients with a history of brain metastases.

5. There must be no requirement for immunosuppressive doses of systemic corticosteroids
(>10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug
administration.

6. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab.

7. Uncontrolled inter-current illness that would increase the risk of toxicity or limit
compliance with study requirements. This includes but is not limited to, uncontrolled
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness or social situations that would limit compliance
with study requirements.

8. Known HIV-positive patients on combination antiretroviral therapy are ineligible
because of the abnormal immune response that results from HIV disease.

9. Patients should be excluded if they are positive test for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection

10. Patients who have had systemic (IV) cytotoxic chemotherapy or any other
investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior
to entering the study or those who have not recovered from adverse events due to
agents administered more than 4 weeks earlier. If a patient received an oral agent,
treatment on study can not commence at least five half-lives of the agent have
elapsed.

11. Subjects with previous malignancies (except non-melanoma skin cancers, and in situ
cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma,
or breast) are excluded unless a complete remission was achieved at least 2 years
prior to study entry and no additional therapy is required or anticipated to be
required during the study period.

12. Other active malignancy requiring concurrent intervention.

13. Subjects with any history of interstitial lung disease.

14. Pregnant or breast feeding.