Clinical Trials /

Radiation and Immune Checkpoints Blockade in Metastatic NSCLC (BMS # CA209-632)

NCT03168464

Description:

NSCLC patients with metastatic disease who have failed at least one prior treatment and have a minimum of two metastatic lesions (at least one measurable), are eligible if they have an ECOG Performance Status of 0-1. Patients will receive on Day 1, ipilimumab (every 6 weeks) concurrently with radiation (6Gy x 5 fractions). Nivolumab (every 2 weeks) will be given in addition to ipilimumab on day 22.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Radiation and Immune Checkpoints Blockade in Metastatic NSCLC (BMS # CA209-632)
  • Official Title: Radiation and Immune Checkpoints Blockade in Metastatic NSCLC (BMS # CA209-632)

Clinical Trial IDs

  • ORG STUDY ID: 1607017434
  • NCT ID: NCT03168464

Conditions

  • Non Small Cell Lung Cancer Metastatic

Interventions

DrugSynonymsArms
Ipilimumab and Radiation therapyYervoyImmunotherapy + Radiation
NivolumabOPDIVOImmunotherapy + Radiation

Purpose

NSCLC patients with metastatic disease who have failed at least one prior treatment and have a minimum of two metastatic lesions (at least one measurable), are eligible if they have an ECOG Performance Status of 0-1. Patients will receive on Day 1, ipilimumab (every 6 weeks) concurrently with radiation (6Gy x 5 fractions). Nivolumab (every 2 weeks) will be given in addition to ipilimumab on day 22.

Detailed Description

      NSCLC patients with metastatic disease who have failed at least one prior treatment and have
      a minimum of two metastatic lesions (at least one measurable), are eligible if they have an
      Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. Patients must be willing
      to undergo a required pre-treatment biopsy prior to enrolling onto the study.

      Non-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy
      treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined
      treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab
      1mg/kg q 6 weeks), and administered until evidence of progression.

      Patients are re-imaged at Week 9 (day 70 ± 7) to evaluate for response (defined as an
      objective response by RECIST of the measurable metastatic sites outside the radiation field).
      This response will be evaluated assessing clinical and positron emission computed tomography
      (PET/CT) responses in the non-irradiated measurable metastatic sites using RECIST 1.1.
    

Trial Arms

NameTypeDescriptionInterventions
Immunotherapy + RadiationExperimentalNon-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab 1mg/kg q 6 weeks), and administered until evidence of progression.
  • Ipilimumab and Radiation therapy
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Ability to understand and the willingness to sign a written informed consent document;

          2. Histologic diagnosis of NSCLC;

          3. Any Kras or epidermal growth factor receptor (EGFR) status is permitted; Patients with
             an EGFR sensitizing mutation must have received an EGFR tyrosine kinase inhibitor
             (either erlotinib, gefitinib or afatinib) and patients with anaplastic lymphoma kinase
             (ALK) translocation must have received anti-ALK therapy.

          4. Patients must have at least two distinct measurable metastatic sites, with one of at
             least 1 cm or larger in its largest diameter. Patients may have additional
             non-measurable metastatic lesions (e.g., bone metastases);

          5. Patients must have prior treatment with at least one line of therapy for metastatic
             NSCLC. Any prior therapy is permitted except prior therapy with ipilimumab, other anti
             cytotoxic T-lymphocyte-associated protein (CTLA) agents or Checkpoint inhibitors;

          6. An interval of 2 weeks from last previous therapy is required;

          7. Patients must have recovered from the toxic effect(s) of the most recent anti-cancer
             treatment to NCI CTCAE Grade 1 or less (except alopecia).

          8. Patients must have adequate organ and marrow function as defined by initial laboratory
             tests:

             white blood cell (WBC) ≥ 2000/uL

               -  absolute neutrophil count (ANC) ≥ 1.5/uL

               -  Platelets ≥ 100 x 103/uL

               -  Hemoglobin ≥ 9 g/dL

               -  Creatinine ≤ 1.5 x upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤
                  5 x ULN if liver metastases are present.

               -  Bilirubin ≤ 1.5 x ULN, (except patients with Gilbert's Syndrome, who must have a
                  total bilirubin ≤ 3.0 mg/dL;

          9. Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 or Karnofsky > 70%;

         10. Men and women, ages > 18 years of age;

         11. Life expectancy > 3 months;

         12. Patients may have brain metastases if these are stable for at least 4 weeks and
             patients are not steroid dependent;

         13. Women of childbearing potential (WOCBP) must be using an adequate method of
             contraception to avoid pregnancy throughout the study and for up to 8 weeks after the
             study.

               -  WOCBP include any female who has experienced menarche and who has not undergone
                  successful surgical sterilization (hysterectomy, bilateral tubal ligation or
                  bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea ≥ 12
                  consecutive months; or women on hormone replacement therapy (HRT) with documented
                  serum follicle stimulating hormone (FSH) level > 35 mIU/mL ]. Even women who are
                  using oral, implanted or injectable contraceptive hormones or mechanical products
                  such as an intrauterine device or barrier methods (diaphragm, condoms,
                  spermicides) to prevent pregnancy or practicing abstinence or where partner is
                  sterile (e.g., vasectomy), should be considered to be of child bearing potential.
                  WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25
                  IU/L or equivalent units of human chorionic gonadotropin (hCG)) within 72 hours
                  prior to the start of study medication.Men should use avoid impregnating women
                  during study and for 7 mos after the study.

        Exclusion Criteria:

          1. Patients having no lesions outside the field of radiation thus nullifying the ability
             to measure an abscopal effect;

          2. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded
             from this study as are patients with a history of symptomatic auto immune disease
             (e.g., rheumatoid arthritis, progressive systemic sclerosis [scleroderma]), systemic
             lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis];

          3. Patients with a history of symptomatic interstitial lung disease OR a history of
             (non-infectious) pneumonitis that required oral or IV steroids or current pneumonitis.

          4. Patients with active HIV infection Patients with Hepatitis B and Hepatitis C
             infection.

          5. Any underlying medical or psychiatric condition, which in the opinion of the
             Investigator, will make the administration of study drug hazardous or obscure the
             interpretation of adverse events (AEs), such as a condition associated with frequent
             diarrhea;

          6. Concomitant therapy with any of the following: IL-2, interferon or other non-study
             immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other
             investigation therapies; or chronic use of systemic corticosteroids; Tyrosine Kinase
             inhibitors such as erlotinib;

          7. Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;

          8. Women and men who are unwilling or unable to use an acceptable method to avoid
             pregnancy for the entire study period and for at least 5mos (women) or 7mos(men) weeks
             after cessation of study drug, or have a positive pregnancy test at baseline, or are
             pregnant or breastfeeding;

          9. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
             treatment of either a psychiatric or physical (e.g., infectious) illness.
      
Maximum Eligible Age:90 Years
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:enhance overall response rate (ORR) to the combination of ipi/nivo in chemo-refractory NSCLC and double the ORR of ipi/RT, from 18% based on intent to treat to 36%.
Time Frame:3 years
Safety Issue:
Description:to enhance the ORR to the combination of Ipi/Nivo in chemo-refractory NSCLC by preceding it with a combination of Ipi/RT to convert the irradiated tumor into an in situ vaccine and to double the ORR of Ipi/RT, from 18% based on intent to treat to 36%.

Secondary Outcome Measures

Measure:changes in T-cell receptor (TCR) repertoire in peripheral blood are associated with response to treatment
Time Frame:4 years
Safety Issue:
Description:changes in T-cell receptor (TCR) repertoire in peripheral blood are associated with response to treatment
Measure:serum markers IFN-b, CXCL11, sMICA, sMICB levels/changes associated with patients' response to the treatment.
Time Frame:4 years
Safety Issue:
Description:serum markers interferon-beta(IFN-B), C-X-C motif chemokine 11(CXCL11), soluble major histocompatibility complex class I-related chain A(sMICA), soluble major histocompatibility complex class I-related chain B (sMICB) levels/changes associated with patients' response to the treatment
Measure:associations of overall response rate (ORR) with changes in the microbiome
Time Frame:4 years
Safety Issue:
Description:associations of ORR with changes in the microbiome
Measure:progression free survival
Time Frame:4 years
Safety Issue:
Description:Patients will be followed for progression free survival.
Measure:Patients' time to progression will be assessed in this study.
Time Frame:3 years
Safety Issue:
Description:Patients' time to progression will be assessed in this study.
Measure:Patients' duration of response (DOR) will be assessed in this study.
Time Frame:3 years
Safety Issue:
Description:Patients' duration of response (DOR) will be assessed in this study.
Measure:Overall survival (OS)
Time Frame:4 years
Safety Issue:
Description:Patients will be followed for overall survival.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Weill Medical College of Cornell University

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