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

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ClinicalTrials.gov Identifier: NCT03158129
Recruitment Status : Recruiting
First Posted : May 17, 2017
Last Update Posted : April 28, 2021
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE May 16, 2017
First Posted Date  ICMJE May 17, 2017
Last Update Posted Date April 28, 2021
Actual Study Start Date  ICMJE June 9, 2017
Estimated Primary Completion Date July 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2019)
Major pathologic response (mPR) [ Time Frame: Up to 8 weeks ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 16, 2017)
Major pathologic response (mPR) [ Time Frame: 3 months ]
Major pathologic response defined as </= 10% viable tumor cells in the resected specimen using methods described by Pataer et al.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2019)
  • 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 ]
  • Peri-operative morbidity and mortality [ Time Frame: Up to 8 weeks ]
    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.
  • CD8 positive (+) tumor infiltrating lymphocytes (TILs) quantification [ Time Frame: During surgical procedure ]
    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.
  • Response rates as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 [ Time Frame: Up to 8 weeks ]
    Time-to-event endpoints will be computed using the Kaplan-Meier method.
  • Recurrence-free survival [ Time Frame: Up to 8 weeks ]
    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.
  • Overall survival [ Time Frame: Up to 8 weeks ]
    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.
  • Major pathologic response [ Time Frame: Up to 8 weeks ]
    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.
  • Evaluation of complete resection (R0) [ Time Frame: Up to 8 weeks ]
    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.
  • Pathological complete response [ Time Frame: Up to 8 weeks ]
  • Evaluate response assessed by imaging studies [ Time Frame: Up to 8 weeks ]
    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.
  • Evaluate blood, tissue, and stool-based biomarkers [ Time Frame: Up to 8 weeks ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2017)
  • Toxicity Assessed by the NCI CTCAE Version 4 [ Time Frame: 3 months ]
  • Quantification of CD8+ TILs [ Time Frame: At surgery ]
    Quantification of CD8+ TILs assessed by counting cells positive for staining with an anti-CD8 antibody by immunohistochemistry in five random square areas (1 mm2 each) in both intratumoral and peritumoral compartments using the automated Aperio system.
  • Response Rates to Induction Treatment by RECIST version 1.1 [ Time Frame: 3 months ]
Current Other Pre-specified Outcome Measures
 (submitted: May 22, 2019)
  • Identification of novel prognostic and predictive markers [ Time Frame: Up to 8 weeks ]
    Multivariate analysis will be used to explore the role of biomarkers in predicting pathologic response to treatment, in an exploratory way.
  • Modulation of markers by induction immunotherapy [ Time Frame: Up to 8 weeks ]
    Multivariate analysis will be used to explore the role of biomarkers in predicting pathologic response to treatment, in an exploratory way.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nivolumab With or Without Ipilimumab or Chemotherapy in Treating Patients With Previously Untreated Stage I-IIIA Non-small Cell Lung Cancer
Official Title  ICMJE Phase II Study of Induction Checkpoint Blockade for Untreated Stage I-IIIA Non-Small Cell Lung Cancers Amenable for Surgical Resection
Brief Summary 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. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin, 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 OBJECTIVE:

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. 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.

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

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

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

XII. 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: Patients are randomized to Arms A and B and enrolled in Arm C or D after completion of enrollment to Arms A and B.

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 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive ipilimumab IV over 90 minutes on day 1, nivolumab IV over 30 minutes on days 1, 22, and 43, and cisplatin (or carboplatin) IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Stage I Lung Non-Small Cell Cancer AJCC v7
  • Stage IA Lung Non-Small Cell Carcinoma AJCC v7
  • Stage IB Lung Non-Small Cell Carcinoma AJCC v7
  • Stage II Lung Non-Small Cell Cancer AJCC v7
  • Stage IIA Lung Non-Small Cell Carcinoma AJCC v7
  • Stage IIB Lung Non-Small Cell Carcinoma AJCC v7
  • Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Intervention  ICMJE
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Cisplatin
    Given IV
    Other Names:
    • Abiplatin
    • 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
    • Platosin
  • Drug: Docetaxel
    Given IV
    Other Names:
    • Docecad
    • RP56976
    • Taxotere
    • Taxotere Injection Concentrate
  • Biological: Ipilimumab
    Given IV
    Other Names:
    • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
    • BMS-734016
    • Ipilimumab Biosimilar CS1002
    • MDX-010
    • MDX-CTLA4
    • Yervoy
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Drug: Pemetrexed
    Given IV
    Other Names:
    • MTA
    • Multitargeted Antifolate
    • Pemfexy
Study Arms  ICMJE
  • Experimental: Arm A (nivolumab)
    Participants receive nivolumab IV over 60 minutes on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: Nivolumab
  • Experimental: Arm B (nivolumab, ipilimumab)
    Participants 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.
    Interventions:
    • Biological: Ipilimumab
    • Biological: Nivolumab
  • Experimental: Arm C (nivolumab, cisplatin, docetaxel, pemetrexed)
    Patients receive nivolumab IV over 30 minutes and cisplatin IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Drug: Docetaxel
    • Biological: Nivolumab
    • Drug: Pemetrexed
  • Experimental: Arm D (ipilimumab, nivolumab, chemotherapy)
    Patients receive ipilimumab IV over 90 minutes on day 1, nivolumab IV over 30 minutes on days 1, 22, and 43, and cisplatin (or carboplatin) IV over 2 hours on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity. Patients also receive docetaxel IV over 1 hour or pemetrexed IV over 10 minutes on days 1, 22, and 43 in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Carboplatin
    • Drug: Cisplatin
    • Drug: Docetaxel
    • Biological: Ipilimumab
    • Biological: Nivolumab
    • Drug: Pemetrexed
Publications * Cascone T, William WN Jr, Weissferdt A, Leung CH, Lin HY, Pataer A, Godoy MCB, Carter BW, Federico L, Reuben A, Khan MAW, Dejima H, Francisco-Cruz A, Parra ER, Solis LM, Fujimoto J, Tran HT, Kalhor N, Fossella FV, Mott FE, Tsao AS, Blumenschein G Jr, Le X, Zhang J, Skoulidis F, Kurie JM, Altan M, Lu C, Glisson BS, Byers LA, Elamin YY, Mehran RJ, Rice DC, Walsh GL, Hofstetter WL, Roth JA, Antonoff MB, Kadara H, Haymaker C, Bernatchez C, Ajami NJ, Jenq RR, Sharma P, Allison JP, Futreal A, Wargo JA, Wistuba II, Swisher SG, Lee JJ, Gibbons DL, Vaporciyan AA, Heymach JV, Sepesi B. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med. 2021 Mar;27(3):504-514. doi: 10.1038/s41591-020-01224-2. Epub 2021 Feb 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 17, 2020)
88
Original Estimated Enrollment  ICMJE
 (submitted: May 16, 2017)
66
Estimated Study Completion Date  ICMJE July 31, 2022
Estimated Primary Completion Date July 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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 American Joint Committee on Cancer [AJCC] 7th edition) are eligible for randomization into arms A and B only. Patients with stage IB >= 4 cm, 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
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Tina Cascone 713-792-6363 tcascone@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03158129
Other Study ID Numbers  ICMJE 2016-0982
NCI-2018-01210 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2016-0982 ( Other Identifier: M D Anderson Cancer Center )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Tina Cascone M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP