Evaluation of Cabozantinib in Metastatic Renal Cell Carcinoma (mRCC) With Brain Metastases (CABRAMET)

  • STATUS
    Recruiting
  • End date
    Mar 15, 2024
  • participants needed
    77
  • sponsor
    Centre Leon Berard
Updated on 21 February 2022
metastasis
neutrophil count
cabozantinib
brain metastases

Summary

This is a multicenter, open-label, exploratory, single-arm, prospective phase II study to assess the efficacy and safety profile of cabozantinib in patients with brain metastases from metastatic renal cell carcinoma (mRCC).

Description

Cabozantinib is a small molecule inhibitor of tyrosine kinases which include MET (hepatocyte growth factor receptor protein), VEGFR (vascular endothelial growth factor receptors), AXL, RET (Rearranged during transfection), FLT3 (Fms-like tyrosine kinase-3), KIT (mast/stem cell factor receptor), ROS1, MER, TYRO3, TRKB (Tropomyosin receptor kinase B) and TIE-2 (angiopoietins receptor). Similar to other TKIs, cabozantinib is a reversible, ATP-competitive inhibitor. Cabozantinib has thus demonstrated significant activity in metastatic clear cell renal cell carcinoma after failure of one or 2 tyrosine kinase inhibitors and is now approved in the second line setting in Europe. Some efficacy was also demonstrated in patients in first line treatment when compared to sunitinib.

Brain metastasis in renal cancer are difficult to treat and cytotoxic systemic therapies are still not used, given by the more or less impermeable blood-brain barrier. The interest of cabozantinib in brain renal cell carcinoma metastases is encouraged by 3 recent cases reports of significant responses of brain metastases including a complete response of brain metastases in one case. Moreover MET receptor surexpression appear more frequent in brain metastases than in other renal cell carcinoma tumor sites. Cabozantinib as multitarget inhibitor including VEGF and MET receptors suggest that it could be a good option. Its efficacy in brain metastases from renal cell carcinoma requires further evaluation.

On this basis, the investigators propose to conduct an open-label exploratory single arm, multicenter prospective phase II trial to assess the efficacy of cabozantinib on brain metastases in metastatic renal cell carcinoma patients.

Ancillary studies:

The relationship between serum markers and efficacy data will be investigated. Serum and plasma sample will be collected at Baseline. MET expression and MET sequencing will be also performed on available tumor tissues.

Details
Condition Metastatic Renal Cell Carcinoma
Treatment Cabozantinib
Clinical Study IdentifierNCT03967522
SponsorCentre Leon Berard
Last Modified on21 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

I1. Age 18 years. I2. Histologically proven metastatic Renal Cell Carcinoma
I3. Brain metastases not requiring corticosteroids at dose > 40 mg/day. I4.At
least 1 locally untreated brain lesion 8mm in longest diameter or >5mm if > 1
lesion
I5.Not previously treated by cabozantinib. I6.Eastern Cooperative Oncology
I8.Adequate organ function as defined by the following criteria
Group (ECOG) Performance Status (PS) 1. I7.Life expectancy 3 months
Total serum bilirubin 2 x ULN (Gilbert's disease exempted)
Serum transaminases and alkaline phosphatases 2.5 x ULN, or in case of liver or bone metastasis 5.0 x ULN
Serum creatinine 2 x ULN OR creatinine clearance 50 ml/min
Absolute neutrophil count (ANC) 1 500/mm3
Platelets 100 000/mm3 (100 G/l)
Hemoglobin 9.0 g/dl. I9. Covered by a medical/health insurance. I10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
I11. Signed and dated IRB/ICE approved informed consent form. I12. Accepting
to use effective contraception (barrier contraceptives) during study treatment
and within at least 4 months after final dose of study therapy. Oral
contraceptives are not acceptable

Exclusion Criteria

E1. Any local previous treatment of current brain metastases. E2. Any anti-
coagulation therapy (except preventive treatment at low dose). E3. Contra-
indication of Magnetic Resonance Imaging (MRI) (i.e. : pace-maker). E4
Uncontrolled seizures. E5. Any symptoms of intracranial hypertension. E6. Any
of the following within 12 months prior to treatment initiation
severe/unstable angina, myocardial infarction, coronary artery bypass graft
symptomatic congestive heart failure, ischemic or hemorrhagic stroke including
transient ischemic attack
E7. Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or
diastolic pressure >90 mmHg, despite optimal medical treatment
E8. Ongoing cardiac dysrhythmia of grade 2, atrial fibrillation of any grade
QTc interval > 0.43
E9. Pregnant or breast feeding woman (mandatory negative serum or urinary
pregnancy test at study entry for all women of childbearing potential)
E10. Any acute or chronic medical or psychiatric condition or laboratory
abnormality that would make the patient unsuited to study participation
E11. Any second malignancy within the last 3 years with the exception of basal
cell carcinoma, in situ cervical cancer and pT1/a bladder cancer with no
evidence of recurrent disease for 12 months
E12. Patients receiving strong inhibitor or inducer of CYP3A4 especially some
anti-epileptic drugs
E13. Psychological, familial, sociological, geographical conditions that would
limit compliance with study protocol requirements
E14. Participation to another clinical trial that might interfere with the
evaluation of the main criterion
E15. Known hypersensitivity to the active substance or to any of the
excipients of cabozantinib
E16. Patient requiring tutorship or curatorship
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