Clinical Trials /

GRN-1201 With Pembrolizumab in Subjects With Metastatic PD-L1+ NSCLC

NCT03417882

Description:

This is a non-randomized, Phase 2, 2-stage, open-label, multi-center study of GRN-1201/sargramostim + pembrolizumab in subjects with PD-L1+ metastatic NSCLC. All subjects will have newly diagnosed metastatic PD-L1+ (TPS ≥ 50%) NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Subjects with EGFR or ALK genomic tumor aberrations with progression on FDA-approved therapy for these aberrations are eligible

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: GRN-1201 With Pembrolizumab in Subjects With Metastatic PD-L1+ NSCLC
  • Official Title: A Pilot, Open-Label, Multi-Center, Multi-Dose Study of GRN-1201 Added to Pembrolizumab in Subjects With PD-L1+ Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: GRN-1201-002
  • NCT ID: NCT03417882

Conditions

  • Metastatic NSCLC

Interventions

DrugSynonymsArms
GRN-1201 + PembrolizumabPembrolizumabCohort 1

Purpose

This is a non-randomized, Phase 2, 2-cohort, 2-stage, open-label, multi-center study of GRN-1201/sargramostim + pembrolizumab in subjects with PD-L1+ metastatic NSCLC. Both first and second line subjects will be enrolled including: - Cohort 1: Subjects with newly diagnosed, metastatic PD-L1+ (TPS ≥ 50%) NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, or - Cohort 2: Subjects with metastatic PD-L1+ (TPS ≥ 1%) NSCLC with progression on or after first-line platinum-based regimen. Subjects with EGFR or ALK genomic tumor aberrations with progression on FDA-approved therapy for these aberrations are eligible

Detailed Description

      This is a non-randomized, Phase 2, 2-cohort, 2-stage, open-label, multi-center study of
      GRN-1201/sargramostim + pembrolizumab in subjects with metastatic PD-L1+ NSCLC.

      Both first and second line subjects will be enrolled including:

        -  Cohort 1: Subjects with newly diagnosed, metastatic PD-L1+ (TPS ≥ 50%) NSCLC with no
           EGFR or ALK genomic tumor aberrations, or

        -  Cohort 2: Subjects with metastatic PD-L1+ (TPS ≥ 1%) NSCLC with progression on or after
           first-line platinum-based regimen. Subjects with EGFR or ALK genomic tumor aberrations
           with progression on FDA-approved therapy for these aberrations are eligible.

      Each cohort will follow a Simon two-stage design [1] with up to 43 subjects in Cohort 1 and
      47 subjects in Cohort 2 for a total of 90 subjects enrolled if both cohorts enroll both
      stages. All subjects will receive GRN-1201 at 3.0 mg in combination with 75 µg sargramostim
      and 200 mg pembrolizumab.

      GRN-1201 is to be administered once weekly for 4 weeks followed by every 3-week dosing for an
      additional 12 doses (16 total doses of GRN-1201). Each dose of GRN-1201 will be given as 1 mL
      divided into 4 separate 0.25 mL intradermal injections on each day of treatment.
      Pembrolizumab is to be given every 3 weeks for up to a total of 35 doses.

      This study will consist of a screening period of up to 28 days; a treatment period consisting
      of GRN-1201/sargramostim administered weekly for 4 weeks (4 doses) followed by administration
      every 3 weeks for 12 additional doses . Pembrolizumab is to be given every 3 weeks for up to
      a total of 35 doses.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalCohort 1: Subjects with newly diagnosed, metastatic PD-L1+ (TPS ≥ 50%) NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations,
    Cohort 2ExperimentalCohort 1: Subjects with newly diagnosed, metastatic PD-L1+ (TPS ≥ 50%) NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations,

      Eligibility Criteria

              Inclusion Criteria:
      
                1. Be male or female at least 18 years of age (at the time consent is obtained);
      
                2. Be able and willing to provide written informed consent and to comply with all
                   requirements of study participation (including all study procedures);
      
                3. Have histologically- or cytologically-confirmed diagnosis of Stage IV NSCLC and meet
                   the corresponding requirements for the cohort of the study they will enroll into;
      
                4. Be HLA-A*02+ as determined by Central Laboratory;
      
                5. Be able to provide formalin fixed, paraffin-embedded (FFPE) tumor tissue obtained from
                   either a core or excisional tumor biopsy;
      
                6. Have a life expectancy of at least 3 months;
      
                7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
      
                8. Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
                   1.1 as determined by the site study team. Target tumor lesions situated in a
                   previously irradiated area are considered measurable if progression has been
                   demonstrated in such lesions;
      
                9. Has adequate organ function as defined by:
      
                     -  Absolute neutrophil count ≥ 1,500/µL
      
                     -  Platelets ≥ 100,000/µL
      
                     -  Hemoglobin ≥ 9 g/dL (without transfusion for at least one month)
      
                     -  Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) OR
      
                        o glomerular filtration rate (GFR) ≥30mL/min if serum creatinine > 1.5 x ULN,
                        creatinine clearance may be calculated using the institutional/laboratory
                        standard method
      
                     -  Serum total bilirubin ≤ 1.5 x ULN OR
      
                        o Direct bilirubin ≤ ULN for subjects with total bilirubin >1.5 x ULN
      
                     -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN
                        (≤ 5 x ULN for subjects with liver metastases)
      
                     -  Albumin ≥2.5mg/dL
      
                     -  International Normalized Ratio (INR) or PT/aPTT <1.5 x ULN. For subjects
                        receiving anticoagulation therapy, PT/aPTT and INR should not be greater than the
                        recommended range for the intended use of the anticoagulant
      
               10. Have recovered from the effects of any prior radiotherapy or surgery;
      
               11. Female subjects of childbearing potential must have a negative serum human chorionic
                   gonadotropic (hCG) test within 1 week of Day 1 (pregnancy test not required for
                   subjects with bilateral oophorectomy and/or hysterectomy or for those subjects who are
                   >1 year post-menopausal); and
      
               12. All female and male subjects of reproductive potential must agree to use an effective
                   method of contraception, as determined by the Investigator, during and for 4 months
                   after the last dose of study treatment.
      
                   Additional Inclusion Criteria for Cohort 1:
      
               13. Newly diagnosed, metastatic NSCLC with a PD-L1 TPS ≥ 50% (as determined by central lab
                   using the PD-L1 IHC 22C3 pharmDx kit) NOTE: Subjects with documentation of PD-L1 TPS ≥
                   50% by IHC analysis using the 22C3 pharmDx kit will not require repeat PD-L1 testing
                   by central laboratory; and
      
               14. Have had no prior systemic chemotherapy for metastatic disease; at least 6 months
                   since prior adjuvant chemotherapy.
      
                   Additional Inclusion Criteria for Cohort 2:
      
               15. Subjects with progression on or after first-line platinum-based chemotherapy who have
                   a PD-L1 TPS ≥ 1% (as determined by central laboratory using the PD-L1 IHC 22C2 pharmDx
                   kit). Subjects with EGFR or ALK genomic tumor aberrations with progression on
                   FDA-approved therapy for these aberrations are eligible NOTE: Subjects with
                   documentation of PD-L1 TPS ≥ 1% by IHC analysis using the 22C3 pharmDx kit will not
                   require repeat PD-L1 testing by central laboratory;
      
               16. Have had no more than one prior platinum-based regimen for metastatic disease NOTE:
                   Maintenance therapy received after initial chemotherapy will not be considered
                   additional chemotherapy and will be allowed; and
      
               17. Have recovered from the acute effects of any prior systemic therapy.
      
              Exclusion Criteria:
      
                1. Is currently participating in or has participated in a study of an investigational
                   agent or using an investigational device within 14 days of the first dose of
                   treatment;
      
                2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy > 10 mg
                   prednisone or equivalent per day or any other form of immunosuppressive therapy within
                   7 days prior to the first dose of study treatment;
      
                3. Has undergone major surgery within 3 weeks of Study Day 1, Subject must have recovered
                   adequately from any toxicity and/or complications from the intervention prior to
                   starting therapy;
      
                4. Has a known additional malignancy that is progressing or requires systemic treatment.
                   Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
                   skin that has undergone potentially curative therapy or in situ cervical cancer.
      
                5. Has received transfusion of blood products (including platelets or red blood cells) or
                   administration of colony stimulating factors (including granulocyte colony-stimulating
                   factor [G-CSF], GM-CSF or recombinant erythropoietin) within 4 weeks prior to study
                   Day 1;
      
                6. Has known active central nervous system (CNS) metastases NOTE: Subjects with
                   previously treated brain metastases may participate provided they are stable (without
                   evidence of progression by imaging [using the identical imaging modality for each
                   assessment, either magnetic resonance imaging (MRI) or computerized tomography (CT)
                   scan] for at least four weeks prior to the first dose of study treatment and any
                   neurologic symptoms have returned to baseline), have no evidence of new or enlarging
                   brain metastases, and are not using steroids for at least 7 days prior to study
                   treatment;
      
                7. Has carcinomatous meningitis;
      
                8. Has an active autoimmune disease that has required systemic treatment in the past 2
                   years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
                   drugs). Replacement therapy (e.g., thyroxine, insulin or physiologic corticosteroid
                   replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
                   form of systemic treatment NOTE: Subjects with vitiligo or resolved childhood
                   asthma/atopy would be an exception to this rule. Subjects that require intermittent
                   use of bronchodilators or local steroid injections would not be excluded from the
                   study;
      
                9. Has history of interstitial lung disease, or history of (non-infectious) pneumonitis
                   that required steroids, or current pneumonitis;
      
               10. Has an active infection requiring systemic therapy NOTE: Antibiotic therapy must have
                   been completed a minimum of 3 days prior to start of study treatment;
      
               11. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
                   [qualitative] is detected);
      
               12. History of myocardial infarction, unstable angina, cardiac or other vascular stenting,
                   angioplasty, or surgery within 6 months prior to day 1 of study treatment;
      
               13. Has a history or current evidence of any condition, therapy, or laboratory abnormality
                   that might confound the results of the study, interfere with the subject's
                   participation for the full duration of the study, or is not in the best interest of
                   this subject to participate, in the opinion of the treating investigator;
      
               14. Has known psychiatric or substance abuse disorders that would interfere with
                   cooperation with the requirements of the study;
      
               15. Has received a live virus vaccine within 30 days of the planned first dose of study
                   therapy NOTE: seasonal influenza vaccines for injection which are generally
                   inactivated flu vaccines are permitted; however, intranasal influenza vaccines (e.g.,
                   Flu-Mist®) are live attenuated vaccines and are not permitted;
      
               16. Is pregnant, breastfeeding, or expecting to conceive or father a child within the
                   projected duration of the study including 120 days following the last dose of study
                   treatment; or
      
               17. Has any concurrent medical condition that, in the opinion of the Investigator, would
                   complicate or compromise compliance with the study or the well-being of the subject.
      
                   Additional Exclusion Criteria for Cohort 1:
      
               18. Have an EGFR or ALK genomic tumor aberrations for which targeted therapy with an EGFR
                   or ALK inhibitor is indicated.
      
                   Additional Exclusion Criteria for Cohort 2:
      
               19. Has had prior treatment with an anti-PD-1 or anti-PD-L1 antibody, anti-cytotoxic
                   T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab) or any
                   other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
                   pathways;
      
               20. Has had a prior monoclonal antibody (mAb) within 4 weeks prior to Study Day 1 or who
                   has not recovered (i.e. ≤ Grade1 1 or at baseline) from acute adverse events from
                   prior mAb therapy NOTE: Subjects with ≤ Grade 2 neuropathy or Grade 2 alopecia are an
                   exception to this criterion and may qualify for the study. Investigators should
                   discuss individual cases with the Medical Monitor or Sponsor as needed;
      
               21. Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 2
                   weeks prior to Study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline)
                   from adverse events due to a previously administered agent NOTE: Subjects with ≤ Grade
                   2 neuropathy or Grade 2 alopecia are an exception to this criterion and may qualify
                   for the study. Investigators should discuss individual cases with the Medical Monitor
                   or Sponsor as needed; or
      
               22. Has had prior therapy with more than one cytotoxic chemotherapy regimen NOTE:
                   Treatment with maintenance therapy after initial chemotherapy will not be considered a
                   separate regimen and will be allowed.
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Assess the effect, as measured by response rate of the addition of GRN-1201 to Pembrolizumab
      Time Frame:First dose through 16 weeks after last dose of study drug
      Safety Issue:
      Description:Tumor assessment over time using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

      Secondary Outcome Measures

      Measure:Evaluate the adverse event profile for the combination of GRN-1201 and Pembrolizumab as assessed by treatment -related events according to CTCAE version 4
      Time Frame:First dose through 16 weeks after last dose of study drug
      Safety Issue:
      Description:The safety and tolerability of GRN-1201/sargramostim + pembrolizumab will be evaluated by local and systemic signs and symptoms of injection site reactions, and incidence of adverse events including immune related adverse events (irAEs).
      Measure:Host immune response to GRN-1201
      Time Frame:First dose through 16 weeks after last dose of study drug
      Safety Issue:
      Description:Immune responses to GRN-1201 will be monitored to establish proof-of principle for the proposed pharmacological effect and demonstrate immunogenicity of GRN-1201. Immune response to the individual peptides will be assessed by measurement of cytotoxic T lymphocytes (CTLs) (by gamma interferon [IFN-γ] ELISPOT assay) and by measurement of antibodies to each peptide
      Measure:Clinical Benefit response rate (CR + PR + SD >/= 16 weeks)
      Time Frame:First dose through 16 weeks after last dose of study drug
      Safety Issue:
      Description:Tumor assessment over time using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
      Measure:Progression-free survival
      Time Frame:First dose through 2 years after last dose of combination treatment
      Safety Issue:
      Description:Progression-free survival will be determined by tumor assessments or death from any cause
      Measure:Duration of response in responding subjects
      Time Frame:First dose through 16 weeks after last dose of study drug
      Safety Issue:
      Description:The duration of objective response will be assessed
      Measure:Duration of clinical benefit
      Time Frame:First dose through 16 weeks after last dose of study drug
      Safety Issue:
      Description:The duration of clinical benefit response rate will be assessed
      Measure:Overall survival
      Time Frame:First dose through 16 weeks after last dose of study drug
      Safety Issue:
      Description:All subjects will be followed for overall survival after discontinuation of combination treatment

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:BrightPath Biotherapeutics

      Trial Keywords

      • PD-L1+

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