Clinical trial NCT05012254: Nivolumab and Ipilimumab Plus Chemotherapy for Patients With Stage IV Lung Cancer With Brain Metastases
Official title: Nivolumab Plus Ipilimumab Plus Two Cycles of Platinum-based Chemotherapy as First Line Treatment for Stage IV/Recurrent Non-small Cell Lung Cancer (NSCLC) Patients With Synchronous Brain Metastases
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Brain Metastases, Adult
Lung Cancer
Keywords: Lung Diseases
Chemotherapy
Immunotherapy
Induction chemotherapy
Maintenance treatment
Nivolumab
Ipilimumab
Lead sponsor: Fundación GECP
Sponsor class: OTHER
First posted: 2021-08-19
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open-label, non-randomised, phase II, multicenter clinical trial.

71 stage IV or recurrent, non-small cell lung cancer patients with synchronous brain metastases will be enrolled in this trial to evaluate the efficacy of Nivolumab plus Ipilimumab plus two cycles of platinum-based chemotherapy as first line treatment.

Detailed description: This is an open-label, non-randomised, phase II, multicenter clinical trial. The total sample size is 71 patients. The population to be included are stage IV or recurrent, non-small cell lung cancer patients with synchronous brain metastases.

Patients randomised will receive induction treatment with two cycles of platinum-based chemotherapy plus Nivolumab and Ipilimumab. At the end of induction treatment the patient with start maintenance with Nivolumab and Ipilimumab until disease progression, unacceptable toxicity, loss of clinical benefit as judged by the investigator or up to a maximum of 2 years of treatment

The primary objective of this trial is to determine the rate of intracranial clinical benefit, defined as the percentage of patients who had lack of radiological or clinical progression for at least 6 months according to RANO-BM assessment criteria.

Patient accrual is expected to be completed within 1.5 years, treatment is planned to extend for 1 year and the patients will be followed up for 2 years. The study will end once survival follow-up has concluded.

Eligibility 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 cytologically 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.3. 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. i. Neutrophils ≥ 1500×109/L ii. Platelets ≥ 100 ×109/L iii. Hemoglobin ≥ 9.0 g/dL iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 45 mL/min (if using the Cockcroft-Gault formula below): a. Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/dL b. Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL v. AST/ALT ≤ 3 x ULN. Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 x ULN) vii. PT/APTT ≤ 1.5 × upper limit of normal (ULN). This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
* 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 randomization.
* 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
  * nonmuscular propria 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 lymphoma kinase (ALK) and ROS Proto-Oncogene 1 (ROS1) rearrangements sensitive to available targeted inhibitor therapy
* 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 randomization
* Leptomeningeal carcinomatosis or metastases in the brain stem, mid-brain, pons, medulla or causing obstructive hydrocephalus
* Single exclusive 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 neoadjuvant, adjuvant chemotherapy, radiotherapy, or chemo-radiotherapy with curative intent for non-metastatic disease less than 6 months before 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 randomization 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 (unstable angina, congestive heart failure, myocardial infarction in the previous year or ventricular cardiac arrhythmias that require medication, history of atrioventricular conduction of second or third degree)
* 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 randomization. Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

Primary outcomes:
measure: Rate of intracranial clinical benefit
timeFrame: From the date of the end of treatment until the date of last follow up, assessed up to 24 months
Secondary outcomes:
measure: To assess the efficacy of the treatment in terms of the Progression Free Survival (PFS)
timeFrame: From the date of the end of treatment until the date of last follow up, assessed up to 24 months
measure: To evaluate the Overall Response Rate (ORR) of the treatment
timeFrame: From the date of the end of treatment until the date of last follow up, assessed up to 24 months
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
timeFrame: From the subject's written consent to participate in the study through 100 days after the final administration of the drug
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: ICO Badalona, Hospital Germans Trias i Pujol
state: Barcelona
city: Hospitalet de Llobregat
country: Spain
facility: ICO Hospitalet
state: Barcelona
city: Castelló de la Plana
country: Spain
facility: Hospital Provincial de Castellón
state: Castellon
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Universitario Insular de Gran canaria
state: Gran Canaria
city: A Coruña
country: Spain
facility: Hospitalario Universitario A Coruña
state: La Coruña
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d' Hebron
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Jaén
country: Spain
facility: Hospital Universitario de Jaén
city: León
country: Spain
facility: Hospital Universitario de León
city: Lugo
country: Spain
facility: Hospital Universitario Lucus Augusti
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital 12 De Octubre
city: Málaga
country: Spain
facility: Hospital Universitario Regional de Málaga
city: Palma De Mallorca
country: Spain
facility: Hospital Universitari Son Llatzer
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
Study officials:
affiliation: Fundación GECP Investigator
name: Ernest Nadal, MD
role: PRINCIPAL_INVESTIGATOR
References: