Patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) and patients with Small cell lung cancer (SCLC) after failure of platinum-based first-line therapy. MedDRA version: 21.1 Level: PT Classification code 10029522 Term: Non-small cell lung cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10041068 Term: Small cell lung cancer extensive stage
Conditions
Interventions
Trade Name: OPDIVO
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Nivolumab
CAS Number: 946414-94-4
Other descriptive name: NIVOLUMAB
Concentration unit: mg milligram(
Sponsors
University of Cologne
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Note: Cohort 1 is closed for enrollment. Subjects who started screening for cohort 1 prior to stop of recruitment initiated by Coordinating PI on April 25 2019 will continue to receive treatment. • Cohort 1: Subjects with histologically or cytologically confirmed advanced non-squamous non-small cell lung cancer who present with stage IIIB/IV disease after failure of platinum-based first-line therapy (second line). Subjects who received adjuvant/neoadjuvant therapy or definitive chemoradiation and develop recurrence or progression, with evidence of stage IIIB-IV disease within 6 months after completion of therapy, are eligible. • Cohort 2a: Subjects with histologically or cytologically confirmed limited-stage or extensive-stage small cell lung cancer after failure of platinum-based first-line therapy with or without anti-PD-1/PD-L1 treatment.(TMB non-discrimated SCLC patients). Note: Cohort 2a is closed for enrollment. • Cohort 2b: Subjects with histologically or cytologically confirmed limited-stage or extensive-stage TMB high small cell lung cancer after failure of platinum-based first-line therapy with or without anti-PD-1/PD-L1 treatment.Inclusion after 2nd line Topotecan-Therapy is allowed. Only TMB high SCLC patients are included, as tested on tumor material during routine biopsies for first diagnosis (whole exome sequencing on FFPE tissue). For definition of TMB high, please refer to chapter 5.5.1.2 The following inclusion criteria apply for Cohort 1, 2a and 2b: • Signed and dated IRB/IEC-approved written informed consent form must be obtained before the performance of any study-specific procedure • Male or female patients over 18 years of age • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 • Subjects must be willing to undergo at baseline screening biopsy. • Subjects must be considered as suitable for conduction of 2 biopsies (baseline and in case of progression) by the responsible local investigator. • Measurable disease by CT or MRI per RECIST 1.1 criteria. Target lesions may be located in a previously irradiated field if there is documented disease progression in that site after completion of radiation therapy • Subjects with CNS metastases are eligible if CNS metastases are treated and subjects have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 28 days prior to first dose of study drug administration. In addition, subjects must either be off corticosteroids or on a stable dose or decreasing dose of = 10 mg daily prednisone (or equivalent). • Cohort 2b: Subjects with CNS metastases are eligible. Radiation of CNS metastases at initiation of study drug treatment is allowed if the trial subject has target lesions outside of the brain. • Note for Cohort 2b: higher doses of corticosteroids for patients receiving radiation therapy of brain metastases are allowed Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 45 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 45
Exclusion criteria
Exclusion criteria: • Subjects with squamous cell NSCLC • For Cohort 1 only: EGFR activating mutation or ALK translocation • More than one prior line of chemotherapy for treatment of advanced disease • Medical conditions associated with significantly increased risk for bleeding complications caused by biopsy procedures (e.g. known coagulopathies, therapeutic anticoagulation) • Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 4 weeks after treatment has been completed and within 28 days prior to the first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. • Presence or history of any other primary malignancy other than non-squamous NSCLC for Cohort 1 and SCLC for Cohort 2a/2b within 5 years prior to enrolment into the trial, except for adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma. • Subjects with active, known or suspected autoimmune disease. Subjects are permitted to enrol 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 • Positive test for hepatitis B virus surface antigen (HBV sAg or HBV-DNA) or hepatitis C virus ribonucleic acid (HCV-RNA) indicating acute or chronic infection • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) • Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease • Note for Cohort 2b: higher doses of corticosteroids for patients receiving radiation therapy of brain metastases are allowed • Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity • Prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways Note for Cohort 2b: inclusion of patients who received 2nd line treatment is allowed if 2nd line did not include an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA-4 antibody as monotherapy or in combination with other than platinum-based chemotherapy. • Any other serious or uncontrolled medical disorder, active infections, physical exam findings, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject’s ability to comply with the study requirements, substantially increase risk to the subject, or negatively impact the interpretation of study results. • History of allergies or severe hypersensitivity reaction to study drug components or to any monoclonal antibody
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Cohort 1: To assess ORR when ipilimumab is added to nivolumab after progression on nivolumab monotherapy in patients relapsed with non-squamous NSCLC (second line). Note: Cohort 1 is closed for enrollment. Subjects who started screening for cohort 1 prior to stop of recruitment initiated by Coordinating PI on April 25 2019 will continue to receive treatment. SCLC subjects eligible for BIOLUMA will be enrolled in cohort 2b after TMB-Prescreening from October 29 2018 on. Cohort 2a: To assess ORR of the combination therapy of ipilimumab and nivolumab in patients with relapsed SCLC and non-discriminated TMB (second line). Note: Cohort 2a is closed for enrollment. SCLC Subjects eligible for BIOLUMA will be enrolled in Cohort 2b after TMB-Prescreening from October 29 2018on. Cohort 2b: To assess ORR of the combination therapy of ipilimumab and nivolumab in patients with relapsed SCLC and high TMB (second line). ;Secondary Objective: •To assess efficacy of nivolumab monotherapy/ nivolumab + ipilimumab combination therapy •To characterize safety and tolerability of nivolumab monotherapy/ nivolumab + ipilimumab combination therapy •To assess the predictive value of PD-L1- and PD-L2 positivity of tumor cells for response to nivolumab monotherapy/ nivolumab + ipilimumab combination therapy •To correlate overall TMB and neoepitope signatures with clinical outcome in the NSCLC cohort and in the SCLC cohort recruited before restriction to TMB high patients •To correlate neoepitope signatures with clinical outcome in the SCLC TMB high cohort ;Primary end point(s): Cohort 1 (NSCLC): ORR according to investigator-assessed RECIST 1.1 criteria of the combination of nivolumab and ipilimumab after progression on nivolumab monotherapy in patients relapsed with non-squamous NSCLC. Cohort 2a and 2b (SCLC): ORR according to investigator-assessed RECIST 1.1 criteria of the combination of nivolumab and ipilimumab in patients with relapsed SCLC and TMB. ;Timepoint(s) of eva | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •OS, PFS, DCR and DOR of nivolumab monotherapy/ nivolumab + ipilimumab combination therapy •Incidence, severity and grading of AEs and SAEs during nivolumab monotherapy/ nivolumab + ipilimumab combination therapy All biomarker related secondary endpoints will be assessed for nivolumab monotherapy as well as for the nivolumab + ipilimumab combination therapy •Predictive value of the pretreatment =1%, =5%, =10%, =25% and =50% PD-L1/ PD-L2 positive tumor cell cut-offs for ORR, DCR, PFS, OS, TTR and DOR •Correlation of pretreatment tumor-associated immune cells PD-L1/ PD-L2/ PD-1 positivity with ORR, DCR, PFS, OS, TTR and DOR •Predictive value of the composite of the pretreatment immune cell infiltrate for ORR, DCR, PFS, OS, TTR and DOR •Predictive value of additional co-inhibitory molecules for ORR, DCR, PFS, OS, TTR and DOR •Predictive value of PD-L1 and PD-L2 RNA expression for ORR, DCR, PFS, OS, TTR and DOR •Predictive value of TMB and predicted neoepitopes for ORR, PFS and OS in the NSCLC cohort and in the SCLC cohort before recruitment of TMB high patients only for SCLC patients •Predicitve value of predicted neoepitopes for ORR, PFS and OS in the TMB high SCLC cohort ;Timepoint(s) of evaluation of this end point: Cohorte 1 (NSCLC); Part A: every 8 weeks (+/- 1 week). Part B: every 8 weeks until Week 48 (C24D1), then every 12 weeks (+/- 1 week). Cohorte 2 (SCLC); Part A: tumor assessment is performed at Week 5 (C3D1) and Week 11 (C6D1). Part B: first tumor assessment is performed at C4D1 (+/- 1 week) and then every 8 weeks until Week 48 (C24D1), then every 12 weeks (+/- 1 week). | — |
Countries
Germany
Contacts
Public ContactInken Terjung
University of Cologne
Outcome results
None listed