BIOLUMA: Biomarkers for Nivolumab and Ipilimumab and Evaluation of the Combination in Lung Cancer

NCT03083691 | Completed Phase 2 DMC

• 2 other identifiers: Uni-Koeln-27852016-003334-25
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 16

Brief Summary

BIOLUMA is a multicentric non-randomised phase II trial in patients with non-squamous non-small cell lung cancer (NSCLC) (Cohort 1) and patients with small-cell lung cancer (SCLC) (Cohort 2) after failure of platinum-based first-line therapy. NSCLC patients are treated with nivolumab until disease progression and subsequently receive a combination therapy of nivolumab and ipilimumab. SCLC patients receive four cycles of nivolumab in combination with ipilimumab and subsequent nivolumab monotherapy. Primary endpoint for both cohorts is overall response rate of combination therapy. Within the diagnostic part tumor biopsies will be analysed. Tumor tissue will be obtained before initiation of therapy and after progression on nivolumab monotherapy before addition of ipilimumab in Cohort 1 and after completion of the four nivolumab/ipilimumab combination cycles before continuation of nivolumab monotherapy in Cohort 2, respectively. Flow cytometry of blood samples and microbiome analysis of deep rectal swaps are performed prior to therapy as well as during course of treatment. Cohort 1 (NSCLC) is closed for enrollment due to Sponsor decision. In Cohort 2 (SCLC) a prescreening for high Tumor Mutation Burden is necessary before enrollment.

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell Lung

Keywords

Nivolumab; Ipilimumab

Outcome Measures

Primary Outcomes (2)

• Cohort 1: ORR after addition of ipilimumab to nivolumab treatment.

  ORR is defined as proportion of patients with reduction in tumor burden as assessed by RECIST 1.1 criteria (investigator-assessed).

  From beginning of combination therapy until the date of first documented progression, or date of death of any cause, whichever occurs first, assessed up to 120 months.

• Cohort 2: ORR of the combination therapy nivolumab and ipilimumab.

  ORR is defined as proportion of patients with reduction in tumor burden as assessed by RECIST 1.1 criteria (investigator-assessed).

  From beginning of combination therapy until the date of first documented progression, or date of death of any cause, whichever occurs first, assessed up to 120 months.

Secondary Outcomes (5)

• Overall survival of nivolumab monotherapy/nivolumab + ipilimumab combination therapy

  From date of first dose until death, withdrawal of informed consent or lost to follow-up, through study completion, an average of 1 year, up to 120 months.

• Progression-free survival of nivolumab monotherapy/nivolumab + ipilimumab combination therapy

  From date of first dose to first documentation of objective disease progression or to death on study due to any cause, an average of 6 months, up to 120 months.

• Duration of response of nivolumab monotherapy/nivolumab + ipilimumab combination therapy

  First on-study tumor assessment is performed at Week 9 in Cohort 1 and at Week 5 in Cohort 2 and subsequently every 8 weeks through study completion, an average of 1 year.

• Incidence, severity and grading of adverse events (AEs) during nivolumab monotherapy/ nivolumab + ipilimumab combination therapy

  From initiation of study drug, continuously during the treatment period and for a minimum of 100 days following the last dose of study treatment.

• Incidence, severity and grading of serious adverse events (SAEs) during nivolumab monotherapy/ nivolumab + ipilimumab combination therapy

  Following the subject's written consent, SAEs are collected that occur within survival follow-up through study completion, an average of 6 months. For subjects who did not receive study medication, SAEs are collected until resolved.

Study Arms (2)

Cohort 1, NSCLC

OTHER

During Treatment Part A nivolumab 240 mg IV q2w as monotherapy is administered. At the time of disease progression a re-biopsy is performed before initiation of combination therapy (Treatment Part B). Within Treatment Part B, nivolumab is given in a dose of 3 mg/kg q2w together with ipilimumab 1 mg/kg IV q6w.

Drug: Nivolumab, Ipilimumab

Cohort 2, SCLC

OTHER

Within Treatment Part A, nivolumab 1 mg/kg q3w together with ipilimumab 3 mg/kg q3w for a total of four doses is administered. After the four combined doses have been administered, a re-biopsy is performed before initiation of Treatment Part B. In Treatment Part B, nivolumab 240 mg q2w monotherapy is administered until disease progression or unacceptable toxicity

Drug: Nivolumab, Ipilimumab

Interventions

Nivolumab, Ipilimumab DRUG

Cohort 1: addition of ipilimumab in case of progression on nivolumab monotherapy.

Cohort 1, NSCLC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cohort 1: Subjects with histologically or cytologically confirmed advanced non-squamous non-small cell lung cancer who present with stage IIIB or stage IV disease after failure of platinum-based first-line therapy. 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 2: Subjects in Cohort 2 have to undergo Prescreening to determine Tumor Mutation Burden. Only patients with high Tumor Mutation Burden are eligible.
• Subjects with histologically or cytologically confirmed limited-stage or extensive-stage small cell lung cancer after failure of platinum-based first-line therapy.
• Cohort 1 and Cohort 2:
• Signed and dated written informed consent form must be obtained before the performance of any study-specific procedure
• Male or female patients ≥ 18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
• Subjects must be willing to undergo the baseline biopsie during screening, if medically feasible
• Measurable disease by CT or MRI per RECIST 1.1 criteria.
• Screening laboratory values must meet the following criteria and should be obtained within 28 days prior to registration: white blood cell count ≥ 2000/μL, Neutrophils ≥ 1500/μL, Platelets ≥ 100 x103/μL, Hemoglobin \> 9.0 g/dL, Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 40 mL/min, AST/ALT ≤ 3 x ULN for patients without liver metastasis, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 x ULN for patients with liver metastasis, Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
• Prior chemotherapy must have been completed at least 4 weeks before study drug administration, and all AEs have either returned to baseline or stabilized.
• Prior palliative radiotherapy must have been completed at least 14 days prior to study drug administration
• Prior targeted therapy must have been completed at least 4 weeks prior to study drug administration
• Cohort 1 and 2a: Subjects with central nervous system (CNS) metastasis 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.

You may not qualify if:

• Subjects with squamous cell NSCLC
• Cohort 1: activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation
• Medical conditions associated with significantly increased risk for bleeding complications caused by biopsy procedures (e.g. known coagulopathies, therapeutic anticoagulation)
• Cohort 1 and 2a only: Patients are excluded if they have 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 is complete 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 NSCLC for Cohort 1 and SCLC for Cohort 2 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.
• 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 or hepatitis C indicating acute or chronic infection
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Subjects with a 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.
• 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: SCLC-Patients who where treated with a combination therapy of platinum-based chemotherapy together with anti-PD-1/PD-L1 treatment are eligible.
• Prisoners or subjects who are involuntarily incarcerated.
• 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 impact the interpretability or study results.

Sponsors & Collaborators

• Lung Cancer Group Cologne: lead
• Bristol-Myers Squibb: collaborator

Study Sites (16)

SLK-Fachklinik Löwenstein

Löwenstein, Baden-Wurttemberg, 74245, Germany

Location

Universitätsklinikum Tübingen, Innere Medizin VIII - Medizinische Onkologie und Pneumologie

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

Universitätsklinikum Würzburg - Comprehensive Cancer Center Mainfranken

Würzburg, Bavaria, 97080, Germany

Location

Universitätsklinikum Frankfurt - Medizinische Klinik II

Frankfurt am Main, Hesse, 60590, Germany

Location

Klinikum Kassel - Klinik für Hämatologie und Onkologie

Kassel, Hesse, 34125, Germany

Location

Pius Hospital Oldenburg

Oldenburg, Lower Saxony, 26121, Germany

Location

Uniklinik RWTH - Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzellentransplantation

Aachen, North Rhine-Westphalia, 52074, Germany

Location

Universitätsklinikum Bonn - Medizinische Klinik und Poliklinik III

Bonn, North Rhine-Westphalia, 53127, Germany

Location

University Hospital Cologne

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Kliniken der Stadt Köln - Lungenkrebszentrum Köln-Merheim

Cologne, North Rhine-Westphalia, 51109, Germany

Location

St.-Johannes-Hospital Dortmund

Dortmund, North Rhine-Westphalia, 44137, Germany

Location

Uniklinik Düsseldorf - Klinik für Hämatologie und Onkologie

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Lungenklinik Hemer

Hemer, North Rhine-Westphalia, 58675, Germany

Location

Universitätsklinikum Münster - Medizinische Klinik A, Pneumologie

Münster, North Rhine-Westphalia, 48149, Germany

Location

Malteser Krankenhaus St. Franziskus-Hospital

Flensburg, Schleswig-Holstein, 24939, Germany

Location

Evangelische Lungenklinik Berlin

Berlin, 13125, Germany

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Jürgen Wolf, MD

  University ClinicCologne

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The treatment period is subdivided in Treatment Part A and B which differ between the two cohorts: Cohort 1 (non-squamous NSCLC): During Treatment Part A nivolumab 240 mg IV q2w as monotherapy is administered. At time of disease progression another re-biopsy is mandatory before initiation of combination therapy (Treatment Part B). Within Treatment Part B, nivolumab is given in a dose of 3 mg/kg q2w together with ipilimumab 1 mg/kg IV q6w. Cohort 2 (SCLC): Patients have to undergo a prescreening for high Tumor Mutation Burden. Within Treatment Part A, nivolumab 1 mg/kg q3w together with ipilimumab 3 mg/kg q3w for a total of four doses is administered. After the four combined doses have been administered, another re-biopsy is mandatory before initiation of Treatment Part B. In Treatment Part B, nivolumab 240 mg q2w monotherapy is administered until disease progression or unacceptable toxicity.

Study Record Dates

• First Submitted: March 2, 2017
• First Posted: March 20, 2017
• Study Start: April 13, 2017
• Primary Completion: August 31, 2022
• Study Completion: November 20, 2023
• Last Updated: January 17, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (16)