non-squamous non-small-cell lung cancer (NSCLC) metastatic to the brain 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)
Conditions
Interventions
Trade Name: Yervoy (TM)
Product Code: BMS-734016
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: Ipilimumab
CAS Number: 477202-00-9
Current Sponsor code: BMS-7340
Sponsors
University Hospital Regensburg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Signed Written Informed Consent 1. Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care 2. Subjects must be willing and able to comply with protocol. Target Population 3. Males and Females, ages = 18 years of age 4. ECOG performance status of 0, 1 and 2 (patients with a decline in performance status due to neurologic symptoms of brain metastasis are eligible for the study up to ECOG 3) 5. Life expectancy = 12 weeks 6. Histologically or cytologically documented metastatic non-squamous NSCLC stage IVB (IASLC) 90 7. Measurable disease, as defined by RANO-BM (intracranial) and RECIST v1.1 (extracranial) 8. at least one measurable brain metastasis (tumor diameter: 0.5 to 3 cm) which has not been previously irradiated and is not judged to require immediate local intervention (radiation/surgery) 9. Known PD-L1 tumor status 10. no prior cytotoxic/systemic (chemo)therapy regimens for metastatic disease (in this context neo-/adjuvant therapy including immunotherapy is not counted as line of therapy) 11. The last dose of prior (neo-/adjuvant) systemic anti-cancer therapy or immunotherapy must have been administered = 21 days prior to first dose of study treatment. 12. The last dose of treatment with any investigational agent or participation in a clinical trial with therapeutic intent must have ended = 28 days prior to first dose of study treatment. 13. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first study treatment: a. ANC = 1500 cells/µL (without granulocyte colony-stimulating factor support within 2 weeks of test) b. WBC counts > 2000/µL c. Lymphocyte count = 500/µL d. Platelet count = 100.000/µL e. Hemoglobin = 9.0 g/dL. Patients may be transfused or receive erythropoietic treatment to meet this criterion. 14. Serum creatinine = 1.5 x ULN or calculated creatinine clearance = 50 mL/min (using the Cockcroft Gault formula) 15. Adequate liver function: AST or ALT = 3 × ULN; Serum bilirubin = 1.5 × ULN. With the following exceptions: a. Subjects with Gilbert Syndrome who must have a total bilirubin level < 3.0 mg/dL b. Subjects with documented liver metastases: AST and/or ALT = 5 × ULN c. Subjects with documented liver or bone metastases: alkaline phosphatase = 5 × ULN. Reproductive Status 16. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test [minimum sensitivity 25 units per litre (IU/L) or equivalent units of human chorionic gonadotropin (HCG)] within 3 days prior to the start of study drug. 17. Women must not be breastfeeding and not start breastfeeding for at least six months following the last dose of bevacizumab. 18. WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment plus 5 half-lives of nivolumab (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment completion. 19. Male patients should seek advice on conservation of sperm prior to treatment. Carboplatin and nab-Paclitaxel could cause irreversible infertility. 20.Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of n
Exclusion criteria
Exclusion criteria: 1. History of known leptomeningeal involvement (lumbar puncture not required). 2. History of whole brain irradiation 3. History of previous intracranial hemorrhage (patients brain metastasis showing signs of bleeding without mass effect/signs of increased intracranial pressure may be eligible upon investigator’s decision) 4. 'Untreated (surgery and/or radiation) and/or clinically unstable spinal cord compression' 5. Subjects with oligometastatic disease according to IASLC eligible for a definitive local therapy in curative intent 6. Subjects with oncogenic driver mutations which are sensitive to available targeted inhibitor therapy (i.e. EGFR mutation, ALK or ROS1 translocation, BRAF V600 mutation, NTRK fusion). In subjects with high therapeutic pressure and low pretest probability for the presence of druggable oncogenic driver mutations (i.e. smoking status) study treatment may be initiated at investigators’s discretion while molecular pathology results are pending. Patients with druggable alterations are excluded. 7. Uncontrolled pleural effusion, pericardial effusion, or ascites (patients with pleural drainage system like PleurX catheter and controlled situation are eligible) 8. Uncontrolled tumor-related pain: Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) may be treated by radiotherapy Autoimmune disease: subjects with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease are excluded from study treatment as are subjects with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [eg, Granulomatosis with polyangiitis, (Wegener's)], and sarcoidosis including interferon-induced sarcoidosis. Subjects with motor neuropathy considered of autoimmune origin (eg, Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from study treatment. a. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. b. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are eligible for this study. 10. Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled. 11. Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. For any prior invasive malignancy, at least 3 years must have elapsed since curative therapy and patients must have no residual sequelae of prior therapy. 12. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to start of study treatment, unstable arrhythmias, or unstable angina. a. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate. 13. Major surgical procedure other than for diagnosis or treatment of symptomatic brain metastasis within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess safety of the new combined treatment regime. In the safety run in phase, the occurrence and frequency of dosis limiting toxicities (DLTs) is of primary interest. Further throughout the whole study, an evaluation of incidence and intensity of adverse events (AEs) and serious adverse events (SAE) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0 of the combination is a primary objective. - To evaluate the central nervous system (CNS) clinical benefit rate (CBR) of the new combined treatment regime.;Secondary Objective: •To assess intracranial progression-free-survival (iPFS) •To assess extracranial progression-free-survival (ePFS) •To assess overall survival (OS) •To assess OS-rate at 12 and 24 months •To assess the duration of response (DOR) per RANO-BM and Response Evaluation Criteria in Solid Tumors (RECIST v1.1) •To evaluate the CNS-specific safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry. •To assess patient reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL), using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30), Quality-of-Life Questionnaire brain module (EORTC QLQ-BN20) and Lung Cancer Module (LC29) •To assess exploratory biomarkers ;Primary end point(s): Safety Safety will be monitored throughout the whole study, with a specific focus on the safety-lead-in phase. •Predefined dose limiting toxicities (DLTs) will be counted and dosing will be adjusted according to the recommendations of the DSMB. •Incidence and intensity of adverse events (AEs) and serious adverse events (SAEs) according to Common Terminology Criteria for Adverse Events (CTCAE) version v5.0 Primary Efficacy Endpoint Central nervous system (CNS) clinical benefit rate (CBR) 6 months after patient inclusion (pCBR), defin | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Intracranial progression free survival (iPFS) • Extracranial progression free survival (ePFS) • Overall survival (OS) • OS rate at 12 and 24 months • Duration of response (DOR) per RANO BM and Response Evaluation Criteria in Solid Tumors (RECIST v1.1) • CNS specific safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry. • Patient reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health related quality of life (HRQoL), using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30), Quality-of-Life Questionnaire brain module (EORTC QLQ-BN20) and Lung Cancer Module (LC29) • Exploratory biomarkers ;Timepoint(s) of evaluation of this end point: Safety will be monitored throughout the whole study, with a specific focus on the safety-lead-in phase. Subjects will be followed for drug-related toxicities until these toxicities resolve, return to baseline or are deemed irreversible. All adverse events will be documented for a minimum of 100 days after the last dose of study medication. After completion of the safety follow-up visit, subjects will be followed every 3 months for survival. Survival Follow-up visits may be performed by phone contact or office visit. All AEs (including SAEs) that occur during the time period beginning with the subject’s written informed consent and ending 100 days after the last dose of IMP must be reported, whether related or unrelated to the study treatments. | — |
Countries
Germany
Contacts
Public ContactDr. Daniel Heudobler
University Hospital Regensburg
Outcome results
None listed