Clinical trial NCT03967522: Evaluation of Cabozantinib in Metastatic Renal Cell Carcinoma (mRCC) With Brain Metastases
Official title: CABRAMET: A Phase 2 Study of Cabozantinib in Metastatic Renal Cell Carcinoma (mRCC) With Brain Metastases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Renal Cell Carcinoma
Keywords: mRCC
cabozantinib
brain metastases
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
First posted: 2019-05-30
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

Detailed 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 criteria: 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.

Primary outcomes:
measure: The non progression rate in brain metastases at 6 months
timeFrame: At 6 months for each patient
Secondary outcomes:
measure: Incidence of adverse events
timeFrame: Up to 54 months
measure: Best response in brain metastases
timeFrame: Up to follow-up visit month 18 for each patient
measure: Duration of response in brain
timeFrame: Up to 18 months for each patient
measure: Progression-free survival
timeFrame: Up to 18 months for each patient
measure: Overall survival
timeFrame: Up to 54 months
measure: Response rate on the extracranial disease at 3 and 6 months
timeFrame: From baseline to 3 months and 6 months for each patients
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest-Site Paul Papin
city: Besançon
country: France
facility: CHU Besancon
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Lyon
country: France
facility: Centre Leon Berard
city: Nancy
country: France
facility: Institut de Cancérologie de la Lorraine
city: Paris
country: France
facility: Hopital Européen Georges Pompidou
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest-site René Gauducheau
city: Strasbourg
country: France
facility: ICANS
city: Suresnes
country: France
facility: Hopital Foch
city: Toulouse
country: France
facility: IUCT-Institut Claudius Regaud
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Leon Berard
name: Sylvie NEGRIER, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: