Overview
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.
Eligibility
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 Group (ECOG)
Performance Status (PS) ≤ 1. I7.Life expectancy ≥ 3 months
I8.Adequate organ function as defined by the following criteria:
- 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.