Clinical Trials /

Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer (NSCLC)

NCT03285321

Description:

This study is an open label, multicenter, randomized phase II trial of consolidation immunotherapy with either nivolumab alone or the combination of nivolumab and ipilimumab following concurrent chemoradiation in patients with unresectable stage III NSCLC.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer (NSCLC)
  • Official Title: Phase II Study of Consolidation Immunotherapy With Nivolumab and Ipilimumab or Nivolumab Alone Following Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer (NSCLC): BTCRC-LUN16-081

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-LUN16-081
  • NCT ID: NCT03285321

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
NivolumabOPDIVOArm 1
NivolumabOPDIVOArm 2
IpilimumabYervoyArm 2

Purpose

This study is an open label, multicenter, randomized phase II trial of consolidation immunotherapy with either nivolumab alone or the combination of nivolumab and ipilimumab following concurrent chemoradiation in patients with unresectable stage III NSCLC.

Detailed Description

      Patients with unresectable stage IIIA or IIIB NSCLC (unresectable as defined by treating
      physician) will be treated outside this study with concurrent chemoradiation with one of
      three chemotherapy regimens (cisplatin/etoposide, cisplatin/pemetrexed, or weekly
      carboplatin/paclitaxel) in addition to standard dose radiation (dosing can range from 59.4 Gy
      to 66.6 Gy). If repeat imaging between 28-56 days following completion of chemoradiation
      shows no progressive or metastatic disease, the patients will be eligible for enrollment on
      the study.

      Randomization and Stratification:

      At the time of enrollment, patients will be randomized in a 1:1 fashion to receive either
      nivolumab 480mg IV every 4 weeks or the combination of nivolumab 3mg/kg IV every 2 weeks with
      ipilimumab 1mg/kg IV every 6 weeks. Consolidation immunotherapy will be continued until
      progression or unacceptable toxicity for up to a total of 24 weeks.

      Subjects will be stratified by stage (IIIA vs. IIIB) and histology (squamous vs.
      non-squamous).

      Dose Calculations:

      Arm 1: The dose of nivolumab will be a fixed dose (not based on subject's weight) at 480mg.

      Arm 2: The dose of nivolumab will be weight-based at 3mg/kg. The dose of ipilimumab will be
      weight-based at 1mg/kg.

      Nivolumab Alone (Arm 1):

      Arm 1: Nivolumab Administration:

      Nivolumab 480 mg will be administered as a 60 minute IV infusion on Day 1 of each 28 day
      cycle. Sites should make every effort to target infusion timing to be as close to 60 minutes
      as possible. However, given the variability of infusion pumps from site to site, a window of
      -five minutes and +10 minutes is permitted (i.e., infusion time is 60 minutes: -5 min/+10
      min). Treatment will continue for up to 6 cycles, in the absence of prohibitive toxicities or
      disease progression.

      Nivolumab Plus Ipilimumab (Arm 2):

      Arm 2: Nivolumb Administration:

      Nivolumab 3mg/kg will be administered as a 60 minute IV infusion on Day 1, 15, and 29 of each
      42 day cycle. Nivolumab should not be given any earlier than 12 days from the previous dose.
      Sites should make every effort to target infusion timing to be as close to 60 minutes as
      possible. However, given the variability of infusion pumps from site to site, a window of
      -five minutes and +10 minutes is permitted (i.e., infusion time is 60 minutes: -5 min/+10
      min). Treatment will continue for up to 4 cycles, in the absence of prohibitive toxicities or
      disease progression.

      Arm 2: Ipilimumab Administration:

      Ipilimumab 1mg/kg will be administered as a 90 minute IV infusion on Day 1 of each 42 day
      cycle. Sites should make every effort to target infusion timing to be as close to 90 minutes
      as possible. However, given the variability of infusion pumps from site to site, a window of
      -five minutes and +10 minutes is permitted (i.e., infusion time is 60 minutes: -5 min/+10
      min). Treatment will continue for up to 4 cycles, in the absence of prohibitive toxicities or
      disease progression.

      On day 1 of cycle 1, nivolumab will be given first, followed by 30 minutes of monitoring, and
      then ipilimumab given second, followed by 30 minutes of monitoring. If the subject does not
      have an infusion reaction during the first cycle, the post-ipilimumab monitoring may be
      discontinued for subsequent cycles at the discretion of the treating physician. Day 1
      monitoring between the nivolumab/ipilimumab infusions will continue throughout all 4 cycles.
      Post nivolumab monitoring on days 15 and 29 is not mandatory and should follow the guidelines
      of the local infusion center.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalNivolumab 480mg IV every 4 weeks for up to 6 cycles
  • Nivolumab
Arm 2ExperimentalNivolumab 3mg/kg IV every 2 weeks PLUS Ipilimumab 1mg/kg IV every 6 weeks for up to 4 cycles (12 doses Nivolumab and 4 doses of Ipilimumab)
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

        Subject must meet all of the following applicable inclusion criteria to participate in this
        study:

          -  Written informed consent and HIPAA authorization for release of personal health
             information.

          -  Age ≥ 18 years at the time of consent.

          -  ECOG Performance Status of 0 or 1 within 14 days prior to registration.

          -  Histological or cytological confirmation of NSCLC. A pathology report confirming the
             diagnosis of NSCLC must be obtained and reviewed by the treating physician prior to
             registration to study.

          -  Must have unresectable or inoperable stage IIIA or IIIB disease. Subjects must be
             considered unresectable or inoperable based on the judgment of the treating physician.

          -  Subjects may have completed concurrent chemoradiation with a standard chemotherapy
             regimen (Cisplatin/Etoposide, Carboplatin/Paclitaxel or Cisplatin/Pemetrexed
             [non-squamous only]) and a dose of radiation ranging from 59.4-66.6 Gy. Subjects must
             have stable disease or disease response as evidenced on CT or PET scan evaluation. For
             those eligible, protocol therapy should begin a minimum of 28 days and a maximum 56
             days following the completion of chemoradiation OR Subjects may have completed up to 2
             cycles of consolidation therapy started within 4 weeks of completion of radiation.
             After completion of consolidation chemotherapy, subjects must have stable disease or
             disease response as evidenced by CT or PET scan evaluation. For those eligible,
             protocol therapy should begin 3-4 weeks after the last cycle of chemotherapy.

          -  Prior cancer treatment must be completed at least 28 days prior to registration and
             the subject must have recovered from all reversible acute toxic effects of the regimen
             (other than alopecia) to ≤Grade 1 or baseline.

          -  Demonstrate adequate organ function, all screening labs to be obtained within 14 days
             prior to registration:

        Hematological:

          -  Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm^3

          -  Hemoglobin (Hgb) ≥ 9 g/dL

          -  Platelets ≥100,000/mcl

        Renal:

          -  Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used
             in place of creatinine or CrCl) ≤ 1.5 x upper limit of normal (ULN) OR ≥ 60 mL/min for
             subjects with creatinine levels >1.5 x institutional ULN

        Hepatic:

          -  Bilirubin ≤ 1.5 × ULN OR Direct bilirubin of ≤ ULN for subjects with total bilirubin
             levels of >1.5x ULN

          -  Aspartate aminotransferase (AST) ≤ 2.5 × ULN

          -  Alanine aminotransferase (ALT) ≤ 2.5 × ULN

        Coagulation:

          -  International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial
             Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant
             therapy as long as PT/INR/PTT is within therapeutic range of intended use of
             anticoagulants

               -  Women of childbearing potential (WOCBP) must have a negative serum or urine
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7
                  days prior to registration. NOTE: Women are considered of childbearing potential
                  unless they are surgically sterile (have undergone a hysterectomy, bilateral
                  tubal ligation, or bilateral oophorectomy) or are post-menopausal. Menopause is
                  defined clinically as 12 months of amenorrhea in a woman over 45 in the absence
                  of other biological or physiological causes. In addition, women under the age of
                  62 must have a documented serum follicle stimulating hormone (FSH) level less
                  than 40 mIU/mL.

               -  Women of childbearing potential must be willing to abstain from heterosexual
                  activity or use an effective method of contraception from the time of informed
                  consent until 23 weeks after treatment discontinuation.

               -  Men who are sexually active with women of childbearing potential (WOCBP) must use
                  any contraceptive method with a failure rate of less than 1% per year. Men
                  receiving study drug and who are sexually active with WOCBP will be instructed to
                  adhere to contraception for a period of 31 weeks after the last dose of
                  investigational product.

               -  As determined by the enrolling physician or protocol designee, ability of the
                  subject to understand and comply with study procedures for the entire length of
                  the study.

        Exclusion Criteria:

        Subjects meeting any of the criteria below may not participate in the study:

          -  Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 23 weeks (female) or 31 weeks (male) after the last dose of trial treatment.

          -  Active central nervous system (CNS) metastases. Subjects must undergo a head computed
             tomography (CT) scan or brain MRI within 28 days prior to registration for protocol
             therapy to exclude brain metastases if symptomatic or without prior brain imaging.

          -  Treatment with any investigational agent within 28 days prior to registration for
             protocol therapy.

          -  Prior chemotherapy, adjuvant therapy, or radiotherapy for lung cancer other than
             standard concurrent chemoradiation or up to 2 cycles of consolidation.

          -  Prior therapy with a PD-1, PD-L1, PD-L2 or CTLA-4 inhibitor or a lung cancer-specific
             vaccine therapy.

          -  Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be
             evaluated with a CT or PET scan prior to registration for protocol therapy to exclude
             metastatic disease.

          -  Active second cancers.

          -  Evidence of active autoimmune disease requiring systemic treatment within the past 90
             days or a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids or immunosuppressive agents. 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. Subjects with hypothyroidism stable on hormone replacement or
             Sjogren's syndrome will not be excluded from the study.

          -  Interstitial lung disease or history of pneumonitis requiring treatment with
             corticosteroids.

          -  Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy
             or other immunosuppressive therapy (excludes inhaled corticosteroids) within 7 days of
             first dose of study drug.

          -  History of psychiatric illness or social situations that would limit compliance with
             study requirements.

          -  Clinically active infection as judged by the site investigator (≥ Grade 2 by CTCAE
             v4).

          -  History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the site investigator.

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  Hypersensitivity to nivolumab, ipilimumab, or any of their excipients.

          -  Has received a live vaccine within 30 days prior to planned start of study therapy.
             Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
             and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:18 months
Safety Issue:
Description:PFS is defined as the time from randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death as a result of any cause.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:4 years
Safety Issue:
Description:The time from randomization until death from any cause. Will be assessed with RECIST 1.1
Measure:Time to Metastatic Disease
Time Frame:4 years
Safety Issue:
Description:the time from randomization until evidence of disease outside of the radiated field. Will be assessed with RECIST 1.1
Measure:Assess Adverse Events
Time Frame:4 years
Safety Issue:
Description:By the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Greg Durm, MD

Trial Keywords

  • Nivolumab
  • Ipilimumab
  • immunotherapy

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