Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable NSCLC
NCT ID: NCT02259621
Last Updated: 2025-12-03
Study Results
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View full resultsBasic Information
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Recruitment Status
ACTIVE_NOT_RECRUITING
Clinical Phase
PHASE2
Total Enrollment
39 participants
Study Classification
INTERVENTIONAL
Study Start Date
2014-09-30
Study Completion Date
2027-10-31
Brief Summary
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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.
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Detailed Description
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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.
The current amendment includes addition of a third arm (Arm C) combining nivolumab and platinum-doublet chemotherapy in the neoadjuvant setting.
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.
The current amendment includes addition of a third arm (Arm C) combining nivolumab and platinum-doublet chemotherapy in the neoadjuvant setting.
Conditions
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Non-Small Cell Lung Cancer
Study Design
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Allocation Method
NON_RANDOMIZED
Intervention Model
SEQUENTIAL
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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Arm B- Nivolumab
Nivolumab 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.
Group Type
EXPERIMENTAL
Nivolumab
Intervention Type
DRUG
Anti-PD-1 Therapy
Arm C- Nivolumab, Carboplatin, & Paclitaxel
Nivolumab 360 mg IV, Carboplatin AUC 5 or 6 IV, and Paclitaxel 175 or 200 mg/m2 IV every 21 days for 3 cycles prior to planned surgery on Day 0.
Group Type
EXPERIMENTAL
Nivolumab
Intervention Type
DRUG
Anti-PD-1 Therapy
Carboplatin
Intervention Type
DRUG
Anti-PD-1 Therapy
Paclitaxel
Intervention Type
DRUG
Anti-PD-1 Therapy
Arm A- Nivolumab and Ipilimumab
One dose of Nivolumab 3mg/kg IV \& Ipilimumab 1mg/kg will be administered to enrolled patients on Day-42, then 2 doses of Nivolumab 3mg/kg will be administered to enrolled patients on Day-28 and Day-14
Group Type
EXPERIMENTAL
Nivolumab
Intervention Type
DRUG
Anti-PD-1 Therapy
Ipilimumab
Intervention Type
DRUG
Anti-PD-1 Therapy
Interventions
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Nivolumab
Anti-PD-1 Therapy
Intervention Type
DRUG
Carboplatin
Anti-PD-1 Therapy
Intervention Type
DRUG
Paclitaxel
Anti-PD-1 Therapy
Intervention Type
DRUG
Ipilimumab
Anti-PD-1 Therapy
Intervention Type
DRUG
Other Intervention Names
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BMS-936558 or MDX1106
Paraplatin
Taxol
Onxal
Eligibility Criteria
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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.
* 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.
* 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.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Bristol-Myers Squibb
INDUSTRY
Sponsor Role
collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Patrick Forde, MD
Role: PRINCIPAL_INVESTIGATOR
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Locations
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Johns Hopkins at Bayview Medical Center
Baltimore, Maryland, United States
Site Status
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
Site Status
Memorial Sloan Kettering
New York, New York, United States
Site Status
Swedish Cancer Insitute
Edmonds, Washington, United States
Site Status
Johnathan Spicer
Montreal, Quebec, Canada
Site Status
Countries
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United States
Canada
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Zhang J, Ji Z, Caushi JX, El Asmar M, Anagnostou V, Cottrell TR, Chan HY, Suri P, Guo H, Merghoub T, Chaft JE, Reuss JE, Tam AJ, Blosser RL, Abu-Akeel M, Sidhom JW, Zhao N, Ha JS, Jones DR, Marrone KA, Naidoo J, Gabrielson E, Taube JM, Velculescu VE, Brahmer JR, Housseau F, Hellmann MD, Forde PM, Pardoll DM, Ji H, Smith KN. Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non-Small Cell Lung Cancer. Clin Cancer Res. 2020 Mar 15;26(6):1327-1337. doi: 10.1158/1078-0432.CCR-19-2931. Epub 2019 Nov 21.
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Jafarnejad M, Gong C, Gabrielson E, Bartelink IH, Vicini P, Wang B, Narwal R, Roskos L, Popel AS. A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer. AAPS J. 2019 Jun 24;21(5):79. doi: 10.1208/s12248-019-0350-x.
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Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, Rekhtman N, Anders RA, Cuda JD, Illei PB, Gabrielson E, Askin FB, Niknafs N, Smith KN, Velez MJ, Sauter JL, Isbell JM, Jones DR, Battafarano RJ, Yang SC, Danilova L, Wolchok JD, Topalian SL, Velculescu VE, Pardoll DM, Brahmer JR, Hellmann MD, Chaft JE, Cimino-Mathews A, Taube JM. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol. 2018 Aug 1;29(8):1853-1860. doi: 10.1093/annonc/mdy218.
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Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, Zahurak M, Yang SC, Jones DR, Broderick S, Battafarano RJ, Velez MJ, Rekhtman N, Olah Z, Naidoo J, Marrone KA, Verde F, Guo H, Zhang J, Caushi JX, Chan HY, Sidhom JW, Scharpf RB, White J, Gabrielson E, Wang H, Rosner GL, Rusch V, Wolchok JD, Merghoub T, Taube JM, Velculescu VE, Topalian SL, Brahmer JR, Pardoll DM. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018 May 24;378(21):1976-1986. doi: 10.1056/NEJMoa1716078. Epub 2018 Apr 16.
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Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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http://globocan.iarc.fr
Ferlay J, Shin HR, Bray F, Forman D, Mathers CD, Parkin D. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; Year 2010
http://www.seer.cancer.gov
Accessed 08/08/2012
http://www.clinicaltrials.gov/ct2/show/NCT01274338
Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery
Other Identifiers
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NA_00092076
Identifier Type: OTHER
Identifier Source: secondary_id
J1414
Identifier Type: -
Identifier Source: org_study_id
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