| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| non-squamous non-small-cell lung cancer (NSCLC) metastatic to the brain |
|
| 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) |
|
| 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. |
|
| 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
|
|
| 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) 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 nivolumab plus 90 days (duration of sperm turnover) for a total of 31 weeks post treatment completion.
|
|
| E.4 | Principal 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 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) 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.
Active viral infection (e.g., COVID-19, influenza, SARS, MERS). (Two weeks after full
recovery or a negative virus test patients are eligible.)
Exclusion Criteria related to Medications
20. 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
21. Treatment with any other investigational agent or participation in another clinical trial
with therapeutic intent within 28 days prior to start of study treatment
22. Simultaneous treatment with another investigational agent or simultaneous
anticancer treatment outside this trial
|
|
| 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
|
|
| 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). |
|
| 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
|
|
| 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. |
|
| 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
|
FPFV: Jan-2021
LPFV: Jul-2023
LPLV: Jul-2026
|
|
| 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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