Inclusion Criteria:
- - In order to be eligible to participate in this study, a subject must meet all of the
following criteria:
1.
Signed informed consent must be obtained prior to participation in the study.
2. Participant is an adult ≥ 18 years of age at the time of informed consent.
3. ECOG performance status ≤1.
4. Estimated life expectancy of 12 weeks or more.
5. Pathology proven metastatic non-squamous NSCLC. 6. 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.
7. 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.
8. 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).
9. Maximum BM size 2 cm in longest diameter (for each BM).
10. At least one untreated brain metastasis ≥ 5mm:
1. 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).
2. 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.
3. 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.
11. 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.
12. 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.
13. 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.
14. 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:
- - A potential subject who meets any of the following criteria will be excluded from
participation in this study:
1.
Leptomeningeal metastasis (based on MRI or CSF cytology, if strong suspicion
despite negative MRI, CSF analysis should be done).
2. Previous treatment with TROP2 inhibitor or angiogenesis inhibitor.
3. Known hypersensitivity to the study drugs, its metabolites, or formulation
excipient.
4. Positive serum pregnancy test or women who are breastfeeding.
5. Contra-indication for MRI.
6. History of allogeneic bone marrow or solid organ transplant.
7. 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.
8. Have not recovered (ie, ≥ Grade 2 is considered not recovered) from AEs due to a
previously administered agent.
1. Note: patients with any grade vitiligo or alopecia are an exception to this
criterion and will qualify for the study.
2. Note: if patients received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention
prior to starting therapy.
9. 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.
10. Met any of the following criteria for cardiac disease:
1. Myocardial infarction or unstable angina pectoris within 6 months of
enrollment.
2. 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.
3. New York Heart Association (NYHA) class III or greater congestive heart
failure or left ventricular ejection fraction of < 40%.
11. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's
disease) or GI perforation within 6 months of enrolment.
12. Have active serious infection requiring antibiotics.
13. 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.
14. 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.
15. 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.
16. Any medical condition that, in the investigator's or sponsor's opinion, poses an
undue risk to the patient's participation in the study. 17. 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.
18. 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.
19. Contra-indications specific to bevacizumab. 1. 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.
2. Prior history of hypertensive crisis or hypertensive encephalopathy.
3. Significant vascular disease (e.g., aortic aneurysm requiring surgical
repair or recent peripheral arterial thrombosis) within 6 months prior to
start of treatment.
4. History of hemoptysis (≥ one-half teaspoon of bright red blood per episode)
within 1 month prior to start of treatment.
5. Evidence of bleeding diathesis or coagulopathy (in the absence of
therapeutic anticoagulation).
6. Current or recent (within 10 days of start of treatment) use of aspirin (>
325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, and
cilostazol.
7. 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.
8. 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.
9. Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40
mg/day) is permitted.
10. Core biopsy or other minor surgical procedure, excluding placement of a
vascular access device, within 7 days prior to the first dose of
bevacizumab.
11. History of abdominal or tracheoesophageal fistula or gastrointestinal
perforation within 6 months prior to start of treatment.
12. Clinical signs of gastrointestinal obstruction or requirement for routine
parenteral hydration, parenteral nutrition, or tube feeding.
13. Evidence of abdominal free air not explained by paracentesis or recent
surgical procedure.
14. Serious, non-healing wound, active ulcer, or untreated bone fracture.
15. 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.
16. Clear tumour infiltration into the thoracic great vessels is seen on
imaging.
17. Clear cavitation of pulmonary lesions is seen on imaging.
