| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-squamous non-small-cell lung cancer (NSCLC) metastatic to the brain |
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| E.1.1.1 | Medical condition in easily understood language |
| non-squamous non-small-cell lung cancer (NSCLC) metastatic to the brain |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
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| E.2.2 | Secondary objectives of the trial |
• 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
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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) 1
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:
f. ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks of test)
g. WBC counts > 2000/μL
h. Lymphocyte count ≥ 500/μL
i. Platelet count ≥ 100,000/μL (transfusion within 2 weeks of test)
j. 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:
d. Subjects with Gilbert Syndrome who must have a total bilirubin level < 3.0 mg/dL
e. Subjects with documented liver metastases: AST and/or ALT ≤ 5 × ULN
f. 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
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. 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.
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| E.4 | Principal exclusion criteria |
1. History of known leptomeningeal involvement (lumbar puncture not required).
2. History of whole brain irradiation
3. History of intracranial hemorrhage
4. Spinal cord compression not definitively treated with surgery and/or radiation, or previously treated spinal cord compression that has been clinically stable for less than 2 weeks prior to first dose of study drug
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). Subjects with unknown or indeterminate EGFR or ALK
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
9. Autoimmune disease
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.
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.
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 the study
14. Prior allogeneic bone marrow transplantation or solid organ transplant
15. Active or latent tuberculosis
16. Symptomatic interstitial lung disease
17. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
18. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
19. Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study Treatment
20. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to start of study treatment
21. Simultaneous treatment with another investigational agent or simultaneous anticancer treatment outside this trial
22. Administration of a live, attenuated vaccine within 4 weeks before randomization
23. History of allergy to study drug components
24. Inadequately controlled hypertension
25. Prior history of hypertensive encephalopathy
26. Significant vascular disease within 6 months prior to start of study treatment
27. History of hemoptysis within 1 month prior to start of study treatment
28. Evidence of bleeding diathesis or coagulopathy
29. 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
30. Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable for > 2 weeks prior to study start
31. 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
32. History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 6 months prior to start of study treatment
33. Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
34. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
35. Serious, non-healing wound, active ulcer, or untreated bone fracture
36. Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine Collection
37. Active viral infection (e.g., COVID-19, influenza, SARS, MERS). (Two weeks after full recovery or a negative virus test patients are eligible.)
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| E.5 End points |
| E.5.1 | 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), defined as either
• complete response [CR],
• partial response [PR] or
stable disease [SD] ≥ 6 months
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|
| E.5.1.1 | 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. For CNS-clinical benefit rate (CNS-CBR) is defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) 6 months after study inclusion (pCBR). |
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| E.5.2 | 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
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|
| E.5.2.1 | 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. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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FPFV: Jan-2021
LPFV: Jul-2023
LPLV: Jul-2026
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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