Breaking the big Five Barriers of Brain Metastasis: 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 brain CA209-7WF / Break B5-BM-NSCLC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Regensburg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Neoplasms [C04]

Trial duration

14 Apr 2021 → ongoing

Decision date (initial)

2024-08-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-512684-31-00

EudraCT number

2020-000693-18

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Primary Safety Objective
To assess safety of the new combined treatment regime. In the safety-lead-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.

Primary Efficacy Objective
To evaluate the central nervous system (CNS) clinical benefit rate (CBR defined as CR + PR
+ SD > 6 months per protocol-defined response criteria) of the new combined treatment
regime

Secondary objectives 9

1. To assess intracranial progression-free-survival (iPFS)
2. To assess extracranial progression-free-survival (ePFS)
3. To assess bi-compartimental progression-free survival (PFS)
4. To assess overall survival (OS)
5. To assess OS-rate at 12 and 24 months
6. To assess the duration of response (DOR) per RANO-BM and Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
7. 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.
8. 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)
9. To assess exploratory biomarkers

Conditions and MedDRA coding

non-squamous nonsmall-cell lung cancer (NSCLC) metastatic to the brain

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

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.
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)
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:  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
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 breast-feeding for at least six months following the last dose of bBevacizumab.
18. 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.
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.

Exclusion criteria 36

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
9. 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.
19. Active viral infection (e.g., COVID-19, influenza, SARS, MERS). (Two weeks after full recovery or a negative virus test patients are eligible.)
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
23. 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
24. History of allergy to study drug components
25. 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)
26. Prior history of hypertensive encephalopathy
27. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to start of study treatment
28. History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 1 month prior to start of study treatment
29. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
30. 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
31. 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.
32. 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
33. History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 6 months prior to start of study treatment
34. Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
35. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
36. Serious, non-healing wound, active ulcer, or untreated bone fracture

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. 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

Secondary endpoints 9

1. Intracranial progression free survival (iPFS)
2. Extracranial progression free survival (ePFS)
3. Bi-compartimental progression-free survival
4. Overall survival (OS)
5. OS rate at 12 and 24 months
6. Duration of response (DOR) per RANO BM and Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
7. CNS specific safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry.
8. 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)
9. Exploratory biomarkers

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Regensburg AöR

Sponsor organisation

Universitaetsklinikum Regensburg AöR

Address

Franz-Josef-Strauss-Allee 11, Grass-Oberisling Grass-Oberisling

City

Regensburg

Postcode

93053

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Regensburg AöR

Contact name

PD Dr. Daniel Heudobler

Public contact point

Organisation

Universitaetsklinikum Regensburg AöR

Contact name

PD Dr. Daniel Heudobler

Third parties 2

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications