Clinical Trials /

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

NCT03302247

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Depletion of Myeloid Derived Suppressor Cells to Enhance Anti PD-1 Therapy
  • Official Title: Depletion of Myeloid Derived Suppressor Cells to Enhance Anti PD-1 Therapy

Clinical Trial IDs

  • ORG STUDY ID: TH-113
  • NCT ID: NCT03302247

Conditions

  • Non Small Cell Lung Cancer Stage IIIB

Interventions

DrugSynonymsArms
NivolumabNivolumab+Gemcitabine
Nivolumab+GemcitabineNivolumab+Gemcitabine

Purpose

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.

Detailed Description

      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
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab+GemcitabineExperimentalNivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle
  • Nivolumab
  • Nivolumab+Gemcitabine

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate depletion of MDSC in numbers as a result of treatment with gemcitabine.
Time Frame:2 years
Safety Issue:
Description:Evaluate immunosuppression in terms of number of circulating MDSC in the blood by comparing within each arm reduction in the number of MDSCs after each cycle of treatment

Secondary Outcome Measures

Measure:Evaluate whether these measures result in enhanced T-cell activity
Time Frame:2 years
Safety Issue:
Description:Evaluate if MDSC elimination by gemcitabine results in increase in T-cell activity
Measure:Evaluate whether these measures result in enhanced NK cell function
Time Frame:2 years
Safety Issue:
Description:Evaluate any change in the number of circulating NK cells and cytokines released when the two arms of study are compared
Measure:Determine the tolerability and clinical activity (including response rate and survival) of this approach
Time Frame:2 years
Safety Issue:
Description:Treatment related adverse events would be observed as assessed by CTCAE v4.0
Measure:Correlate MDSC number with tumor PD-L1 expression
Time Frame:2 years
Safety Issue:
Description:Fresh or archived tumor specimen will be analyzed for PD-L1 expression

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fox Chase Cancer Center

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