A prospective phase II, open-label, multi-center trial of combined nivolumab, ipilimumab and bevacizumab together with 2 cycles of induction chemotherapy in patients with non-squamous non-small-cell lung cancer (NSCLC) metastatic to the brai
- Conditions
- non-squamous non-small-cell lung cancer (NSCLC) metastatic to the brainMedDRA version: 21.1Level: PTClassification code 10029522Term: Non-small cell lung cancer stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-000693-18-DE
- Lead Sponsor
- niversity Hospital Regensburg
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 39
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
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method