Clinical Trials /

Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable NSCLC

NCT02259621

Description:

The proposed study will evaluate the safety and feasibility of preoperative administration nivolumab +/- ipilimumab in patients with high-risk resectable NSCLC, and will facilitate a comprehensive exploratory characterization of the tumor immune milieu and circulating immune cells and soluble factors in these patients. Data obtained in this study will provide valuable information for planning further prospective clinical trials of anti-PD-1 and other immunotherapies in NSCLC, both in the peri-operative and advanced disease setting.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable NSCLC
  • Official Title: Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable Non-Small-Cell Lung Cancer.

Clinical Trial IDs

  • ORG STUDY ID: J1414
  • SECONDARY ID: NA_00092076
  • NCT ID: NCT02259621

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
NivolumabBMS-936558 or MDX1106Nivolumab

Purpose

The proposed study will evaluate the safety and feasibility of preoperative administration nivolumab +/- ipilimumab in patients with high-risk resectable NSCLC, and will facilitate a comprehensive exploratory characterization of the tumor immune milieu and circulating immune cells and soluble factors in these patients. Data obtained in this study will provide valuable information for planning further prospective clinical trials of anti-PD-1 and other immunotherapies in NSCLC, both in the peri-operative and advanced disease setting.

Detailed Description

      The proposed study will evaluate the safety and feasibility of preoperative administration
      nivolumab +/- ipilimumab in patients with high-risk resectable NSCLC, and will facilitate a
      comprehensive exploratory characterization of the tumor immune milieu and circulating immune
      cells and soluble factors in these patients. Data obtained in this study will provide
      valuable information for planning further prospective clinical trials of anti-PD-1 and other
      immunotherapies in NSCLC, both in the peri-operative and advanced disease setting.
      Ultimately, it is highly desirable to discover prospective biomarkers of response and
      toxicity to allow patients with NSCLC who are most likely to derive benefit to receive
      anti-PD-1 treatment, and conversely to minimize the risk of toxicity and ineffective
      treatment for patients who are unlikely to benefit.

      In addition, an amendment to this study allows evaluation of the combination of nivolumab and
      the anti-CTLA4 antibody, ipilimumab in the neoadjuvant setting for the treatment of
      resectable NSCLC. In a large, multicohort, phase 1 trial, the ORR to combination ipilimumab
      and nivolumab therapy in patients unselected by PD-L1 status ranged from 39-47%. Incidence of
      grade 3-4 toxicity ranged from 33-37% across the combination ipilimumab and nivolumab cohorts
      which compares favorably with the rates of toxicity due to platinum doublet chemotherapy in
      this disease setting.
    

Trial Arms

NameTypeDescriptionInterventions
NivolumabExperimentalNivolumab administration: Three doses of nivolumab will be administered to enrolled patients on Day -42, Day -28, and Day-14 (+/- two days) prior to planned surgery on Day 0 or up to +10 days.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically proven non-small-cell lung cancer (core biopsy required).

               -  Squamous or non-squamous histology

               -  Diagnostic core biopsy specimens must be reviewed by a faculty pathologist at
                  SKCCC or MSKCC

               -  Either a formalin fixed paraffin block or a minimum of fifteen 5-micron tissue
                  sections (slides) of tumor biopsy sample must be available for biomarker
                  evaluation (study pathologist must review for adequacy of sampling). This can be
                  obtained from archived tissues, or from a new biopsy if needed.

          -  Stage - High risk NSCLC with resection option for potential cure, as assessed by a
             faculty surgeon at SKCCC or MSKCC. This may include clinical stage IB (≥4cm), II and
             IIIA(see Appendix A). Subjects with N3 nodal involvement are not included.

        ECOG performance status 0-1

        -Adequate organ function as follows:

          -  Leukocytes ≥ 2,000/mm3

          -  Absolute neutrophil count (ANC) ≥ 1000/mm3

          -  Platelet count ≥ 100,000/mm3

          -  Hemoglobin ≥ 9 g/dL

          -  Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥40 mL/min (if using the
             Cockcroft-Gault formula below):

        Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL

        Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

          -  Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total
             bilirubin < 3.0 mg/dL)

          -  AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 3 times the upper limit of normal

          -  Subjects must have adequate lung function to permit surgical resection determined by
             pre-enrollment pulmonary function tests to include DLCO

               -  The effects of nivolumab on the developing human fetus are unknown. For this
                  reason, women of child-bearing potential (WOCBP) and men must agree to use
                  adequate contraception (hormonal or barrier method of birth control; abstinence)
                  prior to study entry and for the duration of study participation and for up to 23
                  weeks after the last dose of nivolumab. Should a woman become pregnant or suspect
                  she is pregnant while she or her partner is participating in this study, she
                  should inform her treating physician immediately. Sexually active fertile men
                  must use effective barrier birth control if their partners are WOCBP for up to 31
                  weeks after the last dose of nivolumab. WOCBP must have a negative serum or urine
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
                  two weeks of registration. Women must not be breastfeeding.

               -  Patient understands the study regimen, its requirements, risks and discomforts
                  and is able and willing to sign the informed consent form. Voluntary signed and
                  dated IRB/IEC approved written informed consent form in accordance with
                  regulatory and institutional guidelines must be obtained before the performance
                  of any protocol related procedures that are not part of normal patient care.
                  Subjects must be competent to report AEs, understand the drug dosing schedule and
                  use of medications to control AEs.

        Exclusion Criteria:

          -  Subjects are excluded if they have an 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.

          -  Subjects are excluded if they have a condition 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. As there is potential for
             hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a
             predisposition to hepatoxicity should be used with caution in patients treated with
             nivolumab-containing regimen.

          -  Administration of chemotherapy or any other cancer therapy in the pre-operative
             period.

          -  Subjects with active concurrent malignancies are excluded i.e. cancers other than
             NSCLC (except non melanoma skin cancers, in situ bladder, gastric, breast, colon or
             cervical cancers/dysplasia).

          -  Subjects with brain metastasis are excluded from this study, and all patients should
             have brain imaging (either MRI brain or CT brain with contrast) prior to enrollment.

          -  Subjects with a history of symptomatic interstitial lung disease.

          -  Active systemic infection requiring therapy, positive tests for Hepatitis B surface
             antigen or Hepatitis C ribonucleic acid (RNA).

          -  Known positive history or positive test for Human Immunodeficiency Virus or Acquired
             ImmunoDeficiency Syndrome (AIDS).

          -  History of allergy to study drug components.

          -  Women who are pregnant or nursing.

          -  Men with female partners (WOCBP) that are not willing to use contraception.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or
             any other antibody targeting T cell co-regulatory pathways).

          -  Underlying medical conditions that, in the Investigator's opinion, will make the
             administration of study drug hazardous or obscure the interpretation of toxicity or
             adverse events.

          -  Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for
             treatment of either a psychiatric or physical (e.g. infectious disease) illness.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety as measured by number of participants with Grade 3 and 4 lab abnormalities, as defined by CTCAE v4.03
Time Frame:8 weeks
Safety Issue:
Description:Safety will be measured by drawing safety labs. (CBC and a Chemistry Panel will be drawn at 2 week intervals during Nivolumab administration). Grade 3 and 4 lab abnormalities will be recorded from both participating sites.

Secondary Outcome Measures

Measure:Feasibility as measured by rate of enrollment
Time Frame:8 weeks
Safety Issue:
Description:Rate of enrollment of subjects at all study sites will be measured as average number of participants enrolled at both sites per day.
Measure:Pathologic Response
Time Frame:6 weeks
Safety Issue:
Description:Pathologic response to neoadjuvant nivolumab and nivolumab plus ipilimumab in resected tumor and lymph nodes. The rate of major pathologic response, defined as <10% residual viable tumor cells in the resection specimen will be compared to historic data with neoadjuvant chemotherapy.
Measure:Radiographic Response
Time Frame:5 weeks
Safety Issue:
Description:Radiographic response to neoadjuvant nivolumab and nivolumab plus ipilimumab as defined by RECIST 1.1.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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