IPILIMUMAB for Non-small cell lung cancer (non-squamous) with brain metastases

Inclusion criteria

• {"criterion_text":"- 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\n- 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)\n- 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.\n- 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.\n- 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\n- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 mL/min (using the Cockcroft Gault formula)\n- Adequate liver function: AST or ALT ≤ 3 × ULN; Serum bilirubin ≤ 1.5 × ULN. With the following exceptions:  Subjects with Gilbert Syndrome who must have a total bilirubin level < 3.0 mg/dL  Subjects with documented liver metastases: AST and/or ALT ≤ 5 × ULN  Subjects with documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN\n- 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.\n- Women must not be breastfeeding and not start breast-feeding for at least six months following the last dose of bBevacizumab.\n- Women 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.\n- Male patients should seek advice on conservation of sperm prior to treatment. Carboplatin and nab-Paclitaxel could cause irreversible infertility.\n- Subjects must be willing and able to comply with protocol.\n- 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 nivolumab plus 90 days (duration of sperm turnover) for a total of 31 weeks post treatment completion.\n- Males and Females, ages ≥ 18 years of age\n- 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)\n- Life expectancy ≥ 12 weeks\n- Histologically or cytologically documented metastatic non-squamous NSCLC stage IVB (IASLC)\n- Measurable disease, as defined by RANO-BM (intracranial) and RECIST v1.1 (extracranial)\n- 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)\n- Known PD-L1 tumor status"}

Exclusion criteria

• {"criterion_text":"- History of known leptomeningeal involvement (lumbar puncture not required).\n- 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.\n- 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.\n- 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.\n- 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 the study\n- Prior allogeneic bone marrow transplantation or solid organ transplant\n- Active or latent tuberculosis\n- Symptomatic interstitial lung disease\n- Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.\n- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART—due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV.\n- Active viral infection (e.g., COVID-19, influenza, SARS, MERS). (Two weeks after full recovery or a negative virus test patients are eligible.)\n- History of whole brain irradiation\n- Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed: Hormone-replacement therapy or oral contraceptives\n- Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to start of study treatment\n- Simultaneous treatment with another investigational agent or simultaneous anticancer treatment outside this trial\n- Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study\n- History of allergy to study drug components\n- Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) (anti-hypertensive therapy to achieve these parameters is allowable)\n- Prior history of hypertensive encephalopathy\n- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to start of study treatment\n- History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 1 month prior to start of study treatment\n- Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)\n- 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)\n- Current or recent (within 10 days of start of study treatment) use of aspirin (> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol\n- Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable prior to study start - The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants prior to start of study treatment - Prophylactic anticoagulation for the patency of venous access devices is allowed, provided the activity of the agent results in an INR < 1.5 × ULN and aPTT is within normal limits prior to start of study treatment. - Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is permitted.\n- Core biopsy or other minor surgical procedure, excluding placement of a vascular/pleural access device, within 7 days prior to the first dose of bevacizumab\n- History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 6 months prior to start of study treatment\n- Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding\n- Evidence of abdominal free air not explained by paracentesis or recent surgical procedure\n- Serious, non-healing wound, active ulcer, or untreated bone fracture\n- Untreated (surgery and/or radiation) and/or clinically unstable spinal cord compression'\n- Subjects with oligometastatic disease according to IASLC eligible for a definitive local therapy in curative intent\n- 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.\n- Uncontrolled pleural effusion, pericardial effusion, or ascites (patients with pleural drainage system like PleurX catheter and controlled situation are eligible)\n- 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\n- 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."}

Primary endpoints

• {"endpoint_text":"- Primary Safety Endpoint Safety will be monitored throughout the whole study, with a specific focus on the safety-lead-in phase.  Predefined dosis limiting toxicities (DLTs) will be counted and dosing will 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.","definition_or_measurement_approach":"Safety-lead-in DLTs counted; dosing adjusted per DSMB recommendations. Incidence and intensity of AEs and SAEs graded by CTCAE v5.0."}
• {"endpoint_text":"- Primary efficacy Endpoint Central nervous system (CNS) clinical benefit rate (CBR) defined as the proportion (pCBR) of all treated patients whose best CNS response is either  Intracranial complete response [CR], OR  Intracranial partial response [PR] OR  Intracranial stable disease [SD] ≥ 6 months","definition_or_measurement_approach":"CBR (pCBR) = proportion of treated patients with best CNS response CR, PR, or SD ≥ 6 months assessed by protocol-defined response criteria (RANO-BM for intracranial)."}

Secondary endpoints

• {"endpoint_text":"- Intracranial progression free survival (iPFS)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Extracranial progression free survival (ePFS)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Bi-compartimental progression-free survival","definition_or_measurement_approach":""}
• {"endpoint_text":"- Overall survival (OS)","definition_or_measurement_approach":""}
• {"endpoint_text":"- OS rate at 12 and 24 months","definition_or_measurement_approach":""}
• {"endpoint_text":"- Duration of response (DOR) per RANO BM and Response Evaluation Criteria in Solid Tumors (RECIST v1.1)","definition_or_measurement_approach":""}
• {"endpoint_text":"- CNS specific safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry.","definition_or_measurement_approach":""}
• {"endpoint_text":"- 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)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Exploratory biomarkers","definition_or_measurement_approach":""}

Germany

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

26-08-2024

Processing Time Days

27

Number Of Sites

1

Number Of Participants

39

Primary sponsor

Full Name

Universitaetsklinikum Regensburg AöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Universitaetsklinikum Regensburg AöR","duties_or_roles":"1,8","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Regensburg AöR","duties_or_roles":"10,6","organisation_type":"Hospital/Clinic/Other health care facility"}