Depletion of Myeloid Derived Suppressor Cells to Enhance Anti PD-1 Therapy
Condition: Non Small Cell Lung Cancer Stage IIIB
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Nivolumab; Nivolumab+Gemcitabine
Intervention description: Monoclonal antibody against non small cell lung cancer; Gemcitabine is added to the Nivolumab treatment
Intervention MeSH terms: Gemcitabine; Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Nivolumab 240mg, IV on day 1, 15 + Gemcitabine 1000mg/m2, IV on day 1, 8, 15 of 28 days cycle
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Metastatic non small cell lung cancer can be treated with cytotoxic chemotherapy or using
      recently approved immunotherapy with antibody, Nivolumab. Both the therapies have limitation
      due to development of tolerance or immunosuppression. This trial combines one drug from each
      category, immunotherapeutic Nivolumab and chemotherapeutic gemcitabine as it was reported
      that gemcitabine reduces immunosuppression by killing myeloid derived suppressor cells,
      thereby increasing the efficacy of Nivolumab.
    

Eligibility criteria:

        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.