Evaluation of Intracranial Efficacy of Sacituzumab Govitecan and Bevacizumab in Asymptomatic Brain Metastases from Non-Small Cell Lung Cancer
- Trial ID
- 2024-514066-40-00
- Protocol
- CO-NL-979-6888
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **brain metastases overall response rate (BM ORR)** of Sacituzumab govitecan (SG) combined with bevacizumab, as measured by the Response Assessment in Neuro-Oncology (RANO)-BM criteria. This is clinically relevant as it aims to assess the efficacy of this combination therapy in treating asymptomatic brain metastases in patients with non-small cell lung cancer (NSCLC), potentially offering a new therapeutic option for this challenging condition.
Secondary objectives include:
- Evaluating the BM disease control rate (DCR) and median central nervous system progression-free survival (CNS PFS) of SG plus bevacizumab according to RANO-BM criteria.
- Assessing the extracranial overall response rate (ORR) and DCR of SG plus bevacizumab using RECIST 1.1 criteria.
- Evaluating the extracranial progression-free survival (PFS) of SG plus bevacizumab according to RECIST 1.1.
- Assessing the overall PFS of SG plus bevacizumab, using RANO-BM for brain metastases and RECIST 1.1 for extracranial lesions.
- Evaluating the median overall survival (OS) of SG plus bevacizumab.
- Assessing the safety of SG plus bevacizumab according to CTCAE v5.0 criteria.
- Exploring the correlation of UGT1A1 genotype with the tolerability and efficacy of SG plus bevacizumab.
Participants
The clinical trial involves participants diagnosed with **metastatic non-squamous non-small cell lung cancer (NSCLC)** who have been pre-treated with platinum-doublet chemotherapy and immune checkpoint inhibitors (ICI). For those with targetable oncogenic drivers, prior treatment with at least one tyrosine kinase inhibitor and platinum-doublet chemotherapy is required. The study population includes both male and female adults aged 18 years and older. Participants are required to have active brain metastases, defined as asymptomatic untreated or unequivocally progressive after local treatment. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the need for participants to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, an estimated life expectancy of 12 weeks or more, and adequate organ function. Lifestyle considerations such as diet and physical activity are not specified. The trial population was selected based on specific medical and treatment history criteria, ensuring that participants have recovered from prior treatment toxicities to a manageable level and are capable of complying with study procedures.
Plans and Procedures
The clinical trial is designed as a **single-arm phase II study** to evaluate the intracranial efficacy of **sacituzumab govitecan** combined with **bevacizumab** in patients with asymptomatic brain metastases from non-small cell lung cancer (NSCLC). The trial aims to assess the brain metastases objective response rate (BM ORR) using the Response Assessment in Neuro-Oncology (RANO)-BM criteria. The study is expected to commence recruitment on September 2, 2024, and conclude by April 29, 2027. Participants will be involved in the study for a maximum treatment period of 90 days for sacituzumab govitecan and 36 days for bevacizumab, with the treatment administered via **intravenous infusion**.
The trial will include a sequence of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as having at least one untreated brain metastasis of ≥5 mm and adequate organ function. Participants must be adults aged 18 years or older, with a life expectancy of at least 12 weeks, and must have recovered from prior treatment-related toxicities to grade ≤1, except for alopecia and neuropathy. The primary endpoint will be evaluated with MRI brain scans after six weeks of treatment and every six weeks thereafter, with confirmed BM ORR measured at 12 weeks. Secondary endpoints include imaging-related outcomes for both brain and extracranial metastases, assessed using MRI and CT scans, respectively.
Follow-up visits will occur every six weeks to monitor safety and efficacy, with assessments based on CTCAE v5.0 criteria. The end-of-study visit will involve a comprehensive evaluation of the participant's response to treatment and any adverse events experienced. Participants may be terminated early from the study if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial is not categorized as low intervention, given its phase II status and the investigational nature of the treatment combination for this specific patient population.
Treatment
The clinical trial involves the administration of **Trodelvy**, a 200 mg powder for concentrate for solution for infusion, containing the active substance **sacituzumab govitecan**. This investigational medication is provided in a pharmaceutical form suitable for intravenous use. The maximum daily dose is 10 mg/kg, with a total treatment period not exceeding 90 days. The administration route is strictly intravenous, ensuring precise delivery of the medication. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.
Additionally, the trial includes the use of **VEGZELMA**, a 25 mg/mL concentrate for solution for infusion, containing the active substance **bevacizumab**. This medication is also administered as a solution for infusion. The maximum daily dose is set at 1500 mg/kg, with a treatment period limited to 36 days. The administration is conducted via infusion, and participant compliance is closely monitored to maintain the integrity of the study.
Both medications are classified under the category of proteins, specifically "Protein - Other," and are not formulated for pediatric use. The trial does not involve any orphan drug designations. The study aims to evaluate the intracranial efficacy of sacituzumab govitecan in combination with bevacizumab in patients with asymptomatic brain metastases from non-small cell lung cancer, using the Response Assessment in Neuro-Oncology (RANO)-BM criteria.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **intracranial efficacy** of Sacituzumab govitecan (SG) combined with bevacizumab in patients with asymptomatic brain metastases from non-small cell lung cancer (NSCLC). The primary endpoint for efficacy evaluation is the Brain Metastases Objective Response Rate (BM ORR), which will be measured using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. This assessment will be conducted through MRI brain scans after six weeks of treatment and subsequently every six weeks, with a confirmed BM ORR measurement at 12 weeks.
Secondary endpoints include various imaging-related outcomes, which will be measured using MRI for brain metastases and CT scans for extracranial outcomes. These assessments will also occur every six weeks. Additional secondary endpoints include BM Disease Control Rate (DCR), median Central Nervous System Progression-Free Survival (CNS PFS), extracranial ORR and DCR based on RECIST 1.1 criteria, median extracranial PFS, median overall PFS, and median Overall Survival (OS). Safety will be evaluated using the CTCAE v5.0 criteria during every visit. The trial aims to provide comprehensive data on the efficacy and safety of the treatment regimen in the specified patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent must be obtained prior to participation in the study.
- Participant is an adult ≥ 18 years of age at the time of informed consent.
- ECOG performance status ≤1.
- Estimated life expectancy of 12 weeks or more.
- Pathology proven metastatic non-squamous NSCLC
- For those without an actionable oncogenic driver: progression on immunotherapy and/or platinum-doublet chemotherapy (concurrent or sequential, in any order). If contra-indication for immunotherapy: progression on platinum-doublet chemotherapy.
- For those with an actionable oncogenic driver: progression on targeted therapy and platinum-doublet chemotherapy. For the latter group, previous ICI is allowed but not mandatory.
- BM not in eloquent area (all patients have at least to be discussed with a neurologist, and preferably they are discussed in the local neuro-oncology MDT).
- Maximum BM size 2 cm in longest diameter (for each BM).
- At least one untreated brain metastasis ≥ 5mm: a. Patients with largest measurable intracranial lesion ≥5 mm but <10 mm may be allowed to enroll upon agreement with the principal investigator (for patients with target lesions of ≥ 5mm but <10 mm, 1.5 mm slice thickness brain MRI is required). b. Prior local treatment is permissible provided unequivocal progression in the lesion has since occurred (discussed in neuro-oncology MDT) or if new lesions have occurred. c. For at least 7 days prior to first dose of SG and bevacizumab in this study: Patient must be asymptomatic from CNS metastases and on a stable dose of corticosteroids, with a maximum of 4 mg dexamethasone/day. Anti-epileptic dose should also be stable for 7 days.
- Participant must have recovered from all toxicities related to prior treatments to grade ≤ 1 (CTCAE v 5.0). Exception to this criterion are alopecia and neuropathy of any grades.
- Adequate organ function including the following laboratory values at the screening visit: · Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (without growth factor support), · Platelets ≥ 100 x 109/L (without growth factor support), · Hemoglobin (Hb) ≥ 6 mmol/l (= 9 g/dl) (7 days without transfusions or growth factor support), · Aspartate transaminase (AST) ≤ 2.5 x ULN, or ≤ 5 × ULN if known liver metastases · Alanine transaminase (ALT) ≤ 2.5 x ULN, or ≤ 5 × ULN if known liver metastases · Serum albumin > 3 g/dL · Total bilirubin ≤ 1.5 ULN, · Creatinine clearance ≥ 30 mL/min by calculation using Cockcroft-Gault formula or based on 24-hour urine sample assessment.
- Participant is capable of following instructions regarding study treatment administration, and must be able to communicate with the Investigator and comply with the requirements of the study procedures.
- Negative serum or urine pregnancy test within 7 days prior to study treatment in women with childbearing potential. Patient must be willing to use effective methods of contraception. Female patients must be postmenopausal, surgically sterile, or they must agree to use a physical barrier method of contraception in addition to either an intrauterine device or hormonal contraception until at least 4 months after termination of study drug.
Exclusion Criteria
- Leptomeningeal metastasis (based on MRI or CSF cytology, if strong suspicion despite negative MRI, CSF analysis should be done).
- Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or GI perforation within 6 months of enrolment.
- Have active serious infection requiring antibiotics.
- Have known history of HIV-1 or 2 (or positive HIV-1/2 antibody, if done at screening) with detectable viral load OR taking medications that may interfere with SN-38 metabolism.
- Have known active hepatitis B virus (HBV) or hepatitis C virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded.
- Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
- Any medical condition that, in the investigator’s or sponsor’s opinion, poses an undue risk to the patient’s participation in the study
- Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of first dose of study drug.
- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary embolism within 1 months of enrolment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, uncontrolled pleural effusion, etc.); any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjogren syndrome, sarcoidosis, etc.); or prior pneumonectomy.
- Contra-indications specific to bevacizumab a. 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. b. Prior history of hypertensive crisis or hypertensive encephalopathy. c. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to start of treatment. d. History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 1 month prior to start of treatment. e. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation). f. Current or recent (within 10 days of start of treatment) use of aspirin (> 325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, and cilostazol. g. 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 start of treatment. 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 for at least 2 weeks prior to start of treatment. h. 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 within 14 days prior to start of treatment. i. Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is permitted. j. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to the first dose of bevacizumab. k. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to start of treatment. l. Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding. m. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure. n. Serious, non-healing wound, active ulcer, or untreated bone fracture. o. Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine collection. All patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours. p. Clear tumour infiltration into the thoracic great vessels is seen on imaging. q. Clear cavitation of pulmonary lesions is seen on imaging.
- Previous treatment with TROP2 inhibitor or angiogenesis inhibitor.
- Known hypersensitivity to the study drugs, its metabolites, or formulation excipient.
- Positive serum pregnancy test or women who are breastfeeding.
- Contra-indication for MRI.
- History of allogeneic bone marrow or solid organ transplant.
- Have had a prior anticancer biologic agent (ADC, ICI) within 4 weeks prior to enrolment or have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to enrolment and have not recovered (ie, ≥ Grade 2 is considered not recovered) from AEs at the time of study entry. a. Note: Patients participating in observational studies are eligible.
- Have an active second malignancy. Note: patients with a history of malignancy that has been treated completely, with no evidence of active cancer for 3 years prior to enrollment, or patients with surgically cured tumours with low risk of recurrence (eg, nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.
- Met any of the following criteria for cardiac disease: a. Myocardial infarction or unstable angina pectoris within 6 months of enrollment. b. History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation. c. New York Heart Association (NYHA) class III or greater congestive heart failure or left ventricular ejection fraction of < 40%.
- Known hypersensitivity to iodinated contrast agents.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Recruiting | 02 Sept 2024 | — |
| Netherlands | — | — | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Trodelvy 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 10 | 90 | PRD9406692 |
VEGZELMA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 1500 | 36 | PRD9890805 |
VEGZELMA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 1500 | 36 | PRD9890813 |