Clinical Trials /

Nivolumab With or Without Ipilimumab or Chemotherapy in Treating Patients With Previously Untreated Stage I-IIIA Non-small Cell Lung Cancer

NCT03158129

Description:

This phase II trial studies how well nivolumab works when given alone and in combination with ipilimumab or chemotherapy in treating patients with previously untreated stage I-IIIA non-small cell lung cancer. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin,(or Carboplatin) docetaxel, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab with ipilimumab or chemotherapy may work better in treating patients with non-small cell lung cancer compared to chemotherapy alone.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab With or Without Ipilimumab or Chemotherapy in Treating Patients With Previously Untreated Stage I-IIIA Non-small Cell Lung Cancer
  • Official Title: Phase II Study Of Induction Checkpoint Blockade for Untreated Stage I-IIIA Non-Small Cell Lung Cancers Amenable for Surgical Resection, NEOSTAR/INDUCTION - Strategic Alliance: BMS

Clinical Trial IDs

  • ORG STUDY ID: 2016-0982
  • SECONDARY ID: NCI-2018-01210
  • SECONDARY ID: 2016-0982
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03158129

Conditions

  • Stage I Non-Small Cell Lung Cancer AJCC v7
  • Stage IA Non-Small Cell Lung Carcinoma AJCC v7
  • Stage IB Non-Small Cell Lung Carcinoma AJCC v7
  • Stage II Non-Small Cell Lung Cancer AJCC v7
  • Stage IIA Non-Small Cell Lung Carcinoma AJCC v7
  • Stage IIB Non-Small Cell Lung Carcinoma AJCC v7
  • Stage IIIA Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm C (nivolumab, cisplatin, docetaxel, pemetrexed)
DocetaxelDocecad, RP56976, Taxotere, Taxotere Injection ConcentrateArm C (nivolumab, cisplatin, docetaxel, pemetrexed)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm B (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (nivolumab)
PemetrexedMTA, Multitargeted AntifolateArm C (nivolumab, cisplatin, docetaxel, pemetrexed)

Purpose

This phase II trial studies how well nivolumab works when given alone and in combination with ipilimumab or chemotherapy in treating patients with previously untreated stage I-IIIA non-small cell lung cancer. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin,(or Carboplatin) docetaxel, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab with ipilimumab or chemotherapy may work better in treating patients with non-small cell lung cancer compared to chemotherapy alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the major pathologic response rate (MPRR) in patients treated with induction
      nivolumab, nivolumab plus ipilimumab, and nivolumab plus platinum-based chemotherapy.

      SECONDARY OBJECTIVES:

      I. Toxicity (assessed by the National Cancer Institute [NCI] Common Terminology Criteria for
      Adverse Events [CTCAE] version 4).

      II. Peri-operative morbidity and mortality. III. CD8 positive (+) tumor infiltrating
      lymphocytes (TILs) in resected tumor tissues of patients treated with nivolumab alone and
      nivolumab plus ipilimumab and nivolumab plus platinum-based chemotherapy.

      IV. Response rates to induction treatment (by Response Evaluation Criteria in Solid Tumors
      [RECIST] version 1.1).

      V. Recurrence-free survival. VI. Overall survival. VII. To correlate major pathologic
      response with recurrence-free and overall survival.

      VIII. Complete resection (R0) rate. IX. Pathologic complete response (pCR) in resected tumor
      specimens. IX. To correlate response assessed by imaging studies with outcomes (both major
      pathologic response to treatment and long-term recurrence-free survival).

      X. To correlate blood, tissue, and stool-based biomarkers with efficacy and toxicity.

      EXPLORATORY OBJECTIVES:

      I. To identify novel prognostic and predictive markers present at diagnosis. II. To determine
      modulation of markers by induction immunotherapy and/or immunotherapy plus platinum-based
      chemotherapy in order to inform future translational studies.

      OUTLINE: Upon confirmation of eligibility, patients will be stratified by stage (I vs. II vs.
      III) and randomized to Arm A or Arm B using a minimization technique. Upon completion of
      enrollment in these two arms, eligible patients will be enrolled to Arm C or D.

      ARM A: Patients receive nivolumab intravenously (IV) over 60 minutes on days 1, 15, and 29 in
      the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive nivolumab as in Arm A and receive ipilimumab IV over 90 minutes on
      day 1 in the absence of disease progression or unacceptable toxicity.

      ARM C: Patients receive nivolumab IV over 30 minutes and cisplatin IV over 2 hours on days 1,
      22, and 43. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes
      on days 1, 22, and 43. Treatment repeats every 3 weeks for up to 3 cycles in the absence of
      disease progression or unacceptable toxicity.

      ARM D: Patients receive Ipilimumab 1 mg/kg intravenously on day 1 only plus Nivolumab 360 mg
      IV every 3 weeks (D1, D22, D43) plus Cisplatin (or Carboplatin) and Docetaxel IV administered
      every 3 weeks (D1, D22, D43), up to a maximum of 3 cycles for squamous histology NSCLCs, or
      Ipilimumab 1 mg/kg intravenously on day 1 only plus Nivolumab 360 mg IV every 3 weeks (D1,
      D22, D43) plus Cisplatin (or Carboplatin) and Pemetrexed IV administered every 3 weeks (D1,
      D22, D43), up to a maximum of 3 cycles for non-squamous histology NSCLCs. For carcinomas with
      neuroendocrine features and/or differentiation Cisplatin (or Carboplatin) and Docetaxel or
      Cisplatin (or Carboplatin) and Pemetrexed regimens plus Ipilimumab and Nivolumab may be used
      based on the treating physician's preference.

      After completion of study treatment and surgery, patients are followed up at 8 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (nivolumab)ExperimentalParticipants receive nivolumab IV over 60 minutes on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
Arm B (nivolumab, ipilimumab)ExperimentalParticipants receive nivolumab as in Arm A and receive ipilimumab IV over 90 minutes on day 1 in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab
Arm C (nivolumab, cisplatin, docetaxel, pemetrexed)ExperimentalPatients receive nivolumab IV over 30 minutes and cisplatin IV over 2 hours on days 1, 22, and 43. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43. Treatment repeats every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
  • Cisplatin
  • Docetaxel
  • Nivolumab
  • Pemetrexed
Arm D ipilimumab, nivolumab, cisplatin, docetaxel, pemetrexedExperimentalPatients receive Ipilimumab 1 mg/kg intravenously on day 1 only plus Nivolumab 360 mg IV every 3 weeks (D1, D22, D43) plus Cisplatin (or Carboplatin) and Docetaxel IV administered every 3 weeks (D1, D22, D43), up to a maximum of 3 cycles for squamous histology NSCLCs, or Ipilimumab 1 mg/kg intravenously on day 1 only plus Nivolumab 360 mg IV every 3 weeks (D1, D22, D43) plus Cisplatin (or Carboplatin) and Pemetrexed IV administered every 3 weeks (D1, D22, D43), up to a maximum of 3 cycles for non-squamous histology NSCLCs.
  • Cisplatin
  • Docetaxel
  • Ipilimumab
  • Nivolumab
  • Pemetrexed

Eligibility Criteria

        Inclusion Criteria:

          -  Age >/= 18 years

          -  Histologically or cytologically confirmed previously untreated non-small cell lung
             cancer. If a diagnostic biopsy is available, a pre-treatment biopsy is not required.
             Patients with a suspected lung cancer are eligible, but pathology must be confirmed
             prior to initiating treatment on study. Neuroendocrine carcinomas are not eligible.
             Carcinomas with neuroendocrine differentiation are eligible

          -  Patients with stage IA or stage IB < 4 cm (according to AJCC 7th edition) are eligible
             for randomization into arms A and B only. Patients with stage IB >/= 4cm, IIA, IIB, or
             IIIA disease (according to AJCC 7th edition) are eligible for randomization into arms
             A and, B, and for enrollment into arms C and D.

          -  Patients with stage IIIA must not have more than one mediastinal lymph node station
             involved by tumor

          -  All patients must have lymph node evaluation of contralateral stations 2 and/or 4 to
             exclude N3 disease

          -  The patient must be a suitable candidate for surgery, in the opinion of the treating
             physician

          -  Signed and dated written informed consent must be provided by the patient prior to
             admission to the study in accordance with International Conference on
             Harmonization-Good Clinical Practice (ICH-GCP) guidelines and to the local legislation

          -  Eastern Cooperative Oncology Group (ECOG) performance status score 0-1

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  Hemoglobin >= 8.0 g/dL

          -  Platelets >= 100 x 10^9/L

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert
             syndrome who can have total bilirubin < 3.0 mg/dL)

          -  Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 50 mL/min using
             Cockcroft-Gault formula for creatinine clearance calculation OR 24-hour urine
             creatinine clearance >= 50 mL/min

        Exclusion Criteria:

          -  Prior systemic therapy or radiation therapy for treatment of the current lung cancer

          -  Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or
             biologic therapy) or investigational anti-cancer drug

          -  Pregnant or lactating female: Women of childbearing potential (WOCB) 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
             nivolumab; Women of childbearing potential is defined as any female who has
             experienced menarche and who has not undergone surgical sterilization (hysterectomy or
             bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically
             as 12 months of amenorrhea in a woman over 45 in the absence of other biological or
             physiological causes

          -  Unwillingness or inability to follow the procedures required in the protocol

          -  Patients with pre-existing sensorineural hearing impairment/loss or newly diagnosed as
             documented by an audiology assessment performed prior to study enrollment may not be
             eligible for cisplatin and may be dispositioned to carboplatin, as determined by the
             treating physician.

          -  Patients with a history of severe hypersensitivity reaction to taxotere and or
             polysorbate 80 must be excluded

          -  Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the subject to receive protocol therapy, or
             interfere with the interpretation of study results

          -  Prior malignancy active within the previous 2 years. Patients with locally curable
             cancers that have been apparently cured, such as basal or squamous cell skin cancer,
             superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
             with local control measures (surgery, radiation) are eligible

          -  Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted
             to enroll

          -  Subjects with 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. 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

          -  Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody

          -  Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
             virus ribonucleic acid indicating acute or chronic infection

          -  Known history of testing positive for human immunodeficiency virus or known acquired
             immunodeficiency syndrome

          -  History of severe hypersensitivity reaction to any monoclonal antibody and/or to study
             drug components

          -  Serious illness or concomitant non-oncological disease such as neurologic,
             psychiatric, infectious disease or laboratory abnormality that may increase the risk
             associated with study participation or study drug administration and in the judgment
             of the investigator would make the patient inappropriate for entry into the study

          -  Patients who are sexually active, with preserved reproductive capacity, and unwilling
             to use a medically acceptable method of contraception (e.g. such as implants,
             injectables, combined oral contraceptives, some intrauterine devices or vasectomized
             partner for participating females, condoms for participating males) during and after
             the trial

          -  Women of child bearing potential (WOCBP) should use an adequate method to avoid
             pregnancy for 23 weeks after the last dose of investigational drug(s); Men who are
             sexually active with WOCBP must use any contraceptive method with a failure rate of
             less than 1% per year; Men receiving nivolumab 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; Women who are not of childbearing potential as well
             as azoospermic men do not require contraception

          -  Psychological, familial, sociological or geographical factors potentially hampering
             compliance with the study protocol and follow-up schedule
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Major pathologic response (mPR)
Time Frame:Up to 8 weeks
Safety Issue:
Description:Will be compared to historical controls. Simon's minimax two-stage design will be applied to test the major pathologic response rate for each one of the three treatment arms. The study will also apply the Bayesian framework to calculate the posterior probability of mPR rate. The 95% credible interval of the mPR rate will be constructed. In addition, we will calculate the probability that the mPR rate is at least 15% (i.e., defining that drug is efficacious) under the beta-binomial model.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:Up to 8 weeks
Safety Issue:
Description:
Measure:Peri-operative morbidity and mortality
Time Frame:Up to 8 weeks
Safety Issue:
Description:Descriptive statistics will be provided to summarize the data distribution. Association analysis by Pearson or Spearman correlation coefficient will be calculated for continuous data and chi-square or Fisher's exact test for categorical data. The goals for these analyses are for hypothesis generating. The results will need to be confirmed by future studies.
Measure:CD8 positive (+) tumor infiltrating lymphocytes (TILs) quantification
Time Frame:During surgical procedure
Safety Issue:
Description:Quantification of CD8+ TILs will be assessed by counting the cells positive for staining with an anti-CD8 antibody by immunohistochemistry in five random square areas (1 mm^2 each) in both intratumoral and peritumoral compartments using the automated Aperio system.
Measure:Response rates as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1
Time Frame:Up to 8 weeks
Safety Issue:
Description:Time-to-event endpoints will be computed using the Kaplan-Meier method.
Measure:Recurrence-free survival
Time Frame:Up to 8 weeks
Safety Issue:
Description:Descriptive statistics will be provided to summarize the data distribution. Association analysis by Pearson or Spearman correlation coefficient will be calculated for continuous data and chi-square or Fisher's exact test for categorical data. The goals for these analyses are for hypothesis generating. The results will need to be confirmed by future studies.
Measure:Overall survival
Time Frame:Up to 8 weeks
Safety Issue:
Description:Descriptive statistics will be provided to summarize the data distribution. Association analysis by Pearson or Spearman correlation coefficient will be calculated for continuous data and chi-square or Fisher's exact test for categorical data. The goals for these analyses are for hypothesis generating. The results will need to be confirmed by future studies.
Measure:Major pathologic response
Time Frame:Up to 8 weeks
Safety Issue:
Description:Will be correlated with recurrence-free and overall survival. Descriptive statistics will be provided to summarize the data distribution. Association analysis by Pearson or Spearman correlation coefficient will be calculated for continuous data and chi-square or Fisher's exact test for categorical data. The goals for these analyses are for hypothesis generating. The results will need to be confirmed by future studies.
Measure:Evaluation of complete resection (R0)
Time Frame:Up to 8 weeks
Safety Issue:
Description:Descriptive statistics will be provided to summarize the data distribution. Association analysis by Pearson or Spearman correlation coefficient will be calculated for continuous data and chi-square or Fisher's exact test for categorical data. The goals for these analyses are for hypothesis generating. The results will need to be confirmed by future studies.
Measure:Pathological complete response
Time Frame:Up to 8 weeks
Safety Issue:
Description:
Measure:Evaluate response assessed by imaging studies
Time Frame:Up to 8 weeks
Safety Issue:
Description:Will be correlated with outcomes (both major pathologic response to treatment and long-term recurrence-free survival). Descriptive statistics will be provided to summarize the data distribution. Association analysis by Pearson or Spearman correlation coefficient will be calculated for continuous data and chi-square or Fisher's exact test for categorical data. The goals for these analyses are for hypothesis generating. The results will need to be confirmed by future studies.
Measure:Evaluate blood, tissue, and stool-based biomarkers
Time Frame:Up to 8 weeks
Safety Issue:
Description:Will be correlated with efficacy and toxicity. Descriptive statistics will be provided to summarize the data distribution. Association analysis by Pearson or Spearman correlation coefficient will be calculated for continuous data and chi-square or Fisher's exact test for categorical data. The goals for these analyses are for hypothesis generating. The results will need to be confirmed by future studies.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

February 14, 2020