Evaluation of Nivolumab, Ipilimumab, and Platinum-Based Chemotherapy in Stage IV Non-Small Cell Lung Cancer with Brain Metastases
- Trial ID
- 2024-513866-20-00
- Protocol
- GECP 21/02
- Sponsor
- Fundacion GECP
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to determine the rate of intracranial clinical benefit in patients with **non-small cell lung cancer** (NSCLC) with synchronous brain metastases. This is defined as the percentage of patients who exhibit no radiological or clinical progression for at least six months, as assessed by the RANO-BM criteria. This objective is clinically relevant as it addresses the effectiveness of the treatment regimen in controlling disease progression within the central nervous system, a critical concern for patients with brain metastases.
Secondary objectives include:
- Evaluating the efficacy of Nivolumab, Ipilimumab, and two cycles of chemotherapy in terms of objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
- Assessing the bicompartimental PFS, which includes systemic PFS (excluding CNS) as per RECIST version 1.1 and PFS in the CNS as per RANO-BM criteria.
- Evaluating the safety profile of the treatment regimen.
- Measuring overall survival at 12, 18, and 24 months from enrollment.
- Determining the quality of life (QoL) of patients undergoing this treatment.
Participants
The clinical trial involves participants diagnosed with **non-small cell lung cancer** with brain metastasis. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a good performance status, specifically an ECOG performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have systemic measurable disease by computed tomography and brain measurable disease by magnetic resonance imaging. The trial population was selected based on specific inclusion criteria, such as having histologically or cytologically confirmed stage IV non-small cell lung cancer, with either untreated brain metastases or brain metastases controlled with medium-low doses of corticosteroids. Participants must also have correct hematological, hepatic, and renal function. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **nivolumab** and **ipilimumab**, along with two cycles of platinum-based chemotherapy, as a first-line treatment for patients with stage IV non-small cell lung cancer (NSCLC) with synchronous brain metastases. This trial is structured as a randomized, double-blind, controlled study, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to span a duration of approximately five years, with an estimated end date in December 2029.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histologically or cytologically confirmed stage IV NSCLC and the presence of brain metastases. Following the screening, participants will be enrolled and randomized to receive the investigational treatment. Regular follow-up visits will be scheduled to monitor the participants' response to the treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination, where final assessments will be conducted to evaluate the primary and secondary endpoints.
The expected length of participant involvement in the study is up to 24 months, depending on individual response and tolerability to the treatment. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, withdrawal of consent, or any other medical condition that, in the opinion of the investigator, warrants discontinuation of the study treatment. The primary endpoint of the trial is to determine the rate of intracranial clinical benefit, defined as the percentage of patients who exhibit no radiological or clinical progression for at least six months according to RANO-BM assessment criteria. Secondary endpoints include evaluating the objective response rate, duration of response, progression-free survival, overall survival, and quality of life.
Treatment
The clinical trial involves the administration of **YERVOY** (ipilimumab) as an experimental medication. YERVOY is provided as a 5 mg/mL concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The dosage is calculated based on body weight, with a maximum daily dose of 1 mg/kg. The treatment period is set for a maximum of 24 months. The active substance, ipilimumab, is a protein of non-human origin, and it is produced by Bristol-Myers Squibb Pharma EEIG. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the protocol.
Another experimental medication used in the trial is **OPDIVO** (nivolumab). OPDIVO is available as a 10 mg/mL concentrate for solution for infusion, also administered intravenously. The maximum daily dose is 360 mg, with a treatment period extending up to 24 months. Nivolumab, like ipilimumab, is a protein of non-human origin and is manufactured by Bristol-Myers Squibb Pharma EEIG. The administration of OPDIVO is carefully monitored to maintain compliance with the dosing schedule outlined in the study protocol.
In addition to the experimental medications, the trial includes two cycles of platinum-based chemotherapy as part of the treatment regimen for patients with stage IV or recurrent non-small cell lung cancer (NSCLC) with synchronous brain metastases. The chemotherapy serves as a standard-of-care therapy and is administered according to established clinical guidelines. The combination of nivolumab, ipilimumab, and chemotherapy aims to evaluate the intracranial clinical benefit in the patient population, with compliance and response to treatment being closely monitored throughout the study duration.
Efficacy
Efficacy in this clinical trial will be assessed primarily by determining the rate of intracranial clinical benefit in patients with stage IV/recurrent non-small cell lung cancer (NSCLC) with synchronous brain metastases. This is defined as the percentage of patients who exhibit a lack of radiological or clinical progression for at least 6 months, evaluated according to the RANO-BM assessment criteria. Secondary endpoints include evaluating the efficacy of the combination treatment of Nivolumab, Ipilimumab, and two cycles of chemotherapy in terms of objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Additionally, the trial will assess the investigator-assessed bicompartmental PFS, which includes systemic PFS (excluding CNS) as per RECIST version 1.1 and PFS in the CNS as per RANO-BM criteria. Safety, overall survival at 12, 18, and 24 months, and quality of life (QoL) will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- COHORT A - Patients with histologically or cytologically confirmed stage IV NSCLC who did not receive any prior systemic therapy for advanced disease and have synchronous untreated brain metastases which does not cause neurologic symptoms and does not require systemic corticosteroid treatment within 10 days before initiating study treatment (controlled seizures with antiepileptic drugs should be allowed).
- COHORT B: -Patients with histologically or cytolotically confirmed stage IV NSCLC who did not receive any prior systemic therapy for advanced disease and have synchronous brain metastasis causing neurologic signs and symptoms controlled with medium-low doses of corticosteroids (≤ 25mg/d of prednisone or ≤ 4mg/d of dexamethasone) but have good performance status (ECOG PS0-1). -At least one untreated brain lesion in patients who already received focal radiotherapy (stereotactic focal radiotherapy) of prior brain lesions are eligible if novel brain lesions appear which are measurable and not suitable for focal radiotherapy
- Patients with early or locally advanced NSCLC who have recurred after 6 months of completing adjuvant or neoadjuvant chemotherapy and have brain metastases are also eligible
- ECOG performance status 0-1
- Patients aged ≥ 18 years
- Systemic measurable disease by computed tomography (CT) per response evaluation criteria in solid tumors version (RECIST) 1.1 criteria and brain measurable disease by magnetic resonance imaging (MRI) per RANO-BM criteria
- Availability of a formalin-fixed paraffin-embedded block containing tumor tissue or 10 unstained slides. Archival tumor tissue can be sent if it was obtained less than 12 months ago.
- Correct hematological, hepatic and renal function
- Patient consent must be obtained in the appropriate manner as established in the applicable local and regulatory requirements
- Patients must be accessible for treatment and follow-up
- Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 3 days before enrollment.
- All sexually active men and women of childbearing potential must use a highly effective contraceptive method (<1% failure rate) during the study treatment and for a period of at least 5 months for females and 7 months for males following the last administration of trial drugs
Exclusion Criteria
- Patients with a history of other malignant diseases within the past 3 years, with the exception of the following: properly treated non-melanotic skin cancer; cancer in situ treated with curative intent; nonmuscularis propia invasive carcinoma of the bladder; or other malignancies treated with curative intent and without signs of disease for a period of > 3 years after the end of the treatment and which, in the opinion of the physician in charge of their treatment, do not present a substantial risk of relapse of the previous malignant disease.
- Patients harboring epidermal growth factor receptor (EGFR) mutations or anaplastic lym-phoma kinase (ALK) and ROS Proto-Oncogene 1 (ROS1) rearrangements
- Patients with a combination of small cell lung cancer and non-small cell lung cancer, a carcinoid lung tumor or large cell neuroendocrine carcinoma
- Patients that received live attenuated vaccines within 30 days prior to enrollment
- Leptomeningeal carcinomatosis or metastases in the brain stem, mid-brain, pons, medulla or causing obstructive hydrocephalus
- Brain metastasis amenable to surgical treatment or radiosurgery
- Prior surgical resection of brain or spinal lesions in the prior 28 days
- Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemo-radiotherapy with curative intent for non-metastatic disease less than 6 months be-fore enrollment since the last chemotherapy, radiotherapy, or chemo-radiotherapy
- History of a primary immunodeficiency, history of organ allogeneic transplantation, use of immunosuppressive drugs within 28 days before enrollment or previous history of toxicity of severe immune mechanism (grade 3 or 4) with other immunological treatments
- Patients with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to be enrolled
- Patients with active or uncontrolled infections or with serious medical conditions or disorders that may not allow patient management as established in the protocol
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of radiation pneumonitis put of the radiation field on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Significant comorbidities that preclude the administration of chemotherapy according to the investigator’s criteria
- Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative)
- Previous treatment with immune checkpoint inhibitors
- Patients who have suffered untreated and / or uncontrolled cardiovascular disorders and / or who have symptomatic cardiac dysfunction
- Pregnant or breastfeeding women
- History of allergy or hypersensitivity to any of the study drug components
- Patients with a condition other than brain metastases requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 30 May 2024 | 71 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
YERVOY 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1 | 24 | PRD2341715 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 360 | 24 | PRD9754364 |