Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable NSCLC (NA_00092076)

February 22, 2024 updated by: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable Non-Small-Cell Lung Cancer.

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

The current amendment includes addition of a third arm (Arm C) combining nivolumab and platinum-doublet chemotherapy in the neoadjuvant setting.

Study Type

Interventional

Enrollment (Actual)

39

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Quebec
      • Montréal, Quebec, Canada, H4 3J1
        • Johnathan Spicer
  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
      • Baltimore, Maryland, United States, 21224
        • Johns Hopkins at Bayview Medical Center
    • New York
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering
    • Washington
      • Edmonds, Washington, United States, 98026
        • Swedish Cancer Insitute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: Nivolumab
Anti-PD-1 Therapy
Other Names:
  • BMS-936558 or MDX1106
Experimental: 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.
Drug: Nivolumab
Anti-PD-1 Therapy
Other Names:
  • BMS-936558 or MDX1106
Drug: Carboplatin
Anti-PD-1 Therapy
Other Names:
  • Paraplatin
Drug: Paclitaxel
Anti-PD-1 Therapy
Other Names:
  • Taxol
  • Onxal
Experimental: 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
Drug: Nivolumab
Anti-PD-1 Therapy
Other Names:
  • BMS-936558 or MDX1106
Drug: Ipilimumab
Anti-PD-1 Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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 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.
8 weeks
Safety as Assessed by Number of Grade 3 and 4 Adverse Events
Time Frame: 8 weeks
Number of Grade 3 and 4 adverse events as defined by CTCAE v4.03 that occur while a subject is participating in the study.
8 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathologic Response
Time Frame: 6 weeks
Pathologic response to neoadjuvant nivolumab, nivolumab plus ipilimumab, and nicvolumab, carboplatin, and paclitaxel 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.
6 weeks
Radiographic Response
Time Frame: 5 weeks
Radiographic response to neoadjuvant nivolumab, nivolumab plus ipilimumab, and carboplatin and paclitaxel as defined by RECIST 1.1.
5 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

Bristol-Myers Squibb

Investigators

  • Principal Investigator: Patrick Forde, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2014

Primary Completion (Actual)

October 14, 2022

Study Completion (Estimated)

October 1, 2027

Study Registration Dates

First Submitted

September 18, 2014

First Submitted That Met QC Criteria

October 3, 2014

First Posted (Estimated)

October 8, 2014

Study Record Updates

Last Update Posted (Actual)

March 20, 2024

Last Update Submitted That Met QC Criteria

February 22, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • J1414
  • NA_00092076 (Other Identifier: JHMIRB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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