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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03967522
Recruitment Status : Recruiting
First Posted : May 30, 2019
Last Update Posted : December 20, 2019
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard

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).

Condition or disease Intervention/treatment Phase
Metastatic Renal Cell Carcinoma Drug: Cabozantinib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 77 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CABRAMET: A Phase 2 Study of Cabozantinib in Metastatic Renal Cell Carcinoma (mRCC) With Brain Metastases
Actual Study Start Date : November 29, 2019
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : March 2024


Arm Intervention/treatment
Experimental: Cabozantinib treatment
All participants will be treated by 60 mg of cabozantinib once daily.
Drug: Cabozantinib
All participants will be treated by 60 mg of cabozantinib once daily. Temporary or permanent discontinuation and/or dose reduction of cabozantinib therapy may be required for the management of some adverse reactions. When dose reduction is necessary, it is recommended to reduce to 40 mg daily, and then to 20 mg daily.




Primary Outcome Measures :
  1. The non progression rate in brain metastases at 3 months [ Time Frame: At 3 months for each patient ]
    Tumor assessment in brain will be performed by cerebral MRI at baseline, 1.5 months and 3 months. These cerebral MRI will be reviewed by central review according to the RANO-BM criteria.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 54 months ]
    Assessed using the National Cancer Institute - Common Terminology Criteria for Adverse Event (NCI-CTCAE) v5 grading scale, specific registration of neurological event during study duration.

  2. Best response in brain metastases [ Time Frame: Up to follow-up visit month 18 for each patient ]
    Evaluated according to RANDO-BM criteria.

  3. Duration of response in brain [ Time Frame: Up to 18 months for each patient ]
    From the date of inclusion to the date of first documented disease progression.

  4. Progression-free survival [ Time Frame: Up to 18 months for each patient ]
    Measured from the date of inclusion to the date of first documented disease progression or death from any cause.

  5. Overall survival [ Time Frame: Up to 54 months ]
    Measured from the date of inclusion to the date of death from any cause.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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, 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03967522


Contacts
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Contact: Sylvie NEGRIER, MD, PhD 0478782751 ext +33 sylvie.negrier@lyon.unicancer.fr

Locations
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France
Institut de Cancérologie de l'Ouest-Site Paul Papin Not yet recruiting
Angers, France, 49005
Contact: Remy DELVA, MD    +332.41.35.27.00    remy.delva@ico.unicancer.fr   
CHU Besancon Not yet recruiting
Besançon, France, 25030
Contact: Fabien CALCAGNO, MD    +33381668705    f.calcagno@chu-besancon.fr   
Centre Georges François Leclerc Not yet recruiting
Dijon, France, 21079
Contact: Sylvain LADOIRE, MD    +333 80 73 75 28    sladoire@cgfl.fr   
Centre Leon Berard Recruiting
Lyon, France, 69373
Contact: Sylvie NEGRIER, MD, PhD    +334 78 78 27 51    sylvie.negrier@lyon.unicancer.fr   
Centre Val d'Aurelle Not yet recruiting
Montpellier, France, 34928
Contact: Diego TOSI, MD    +334.67.61.23.04    diego.tosi@icm.unicancer.fr   
Institut de Cancérologie de la Lorraine Not yet recruiting
Nancy, France, 54519
Contact: Lionnel GEOFFROIS, MD    +333 83 59 83 31    l.geoffrois@nancy.unicancer.fr   
Institut de Cancérologie de l'Ouest-site René Gauducheau Not yet recruiting
Saint-Herblain, France, 44805
Contact: Frédéric ROLLAND, MD    +332.40.67.99.76    frederic.rolland@ico.unicancer.fr   
IUCT-Institut Claudius Regaud Recruiting
Toulouse, France, 31059
Contact: Christine CHEVREAU, MD    +335 31 15 51 51    chevreau.christine@iuct-oncopole.fr   
Institut Gustave Roussy Not yet recruiting
Villejuif, France, 94805
Contact: Laurence ALBIGES, MD    +331 42 11 62 64    laurence.albiges@gustaveroussy.fr   
Sponsors and Collaborators
Centre Leon Berard
Investigators
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Principal Investigator: Sylvie NEGRIER, MD,PhD Centre Leon Berard

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Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT03967522    
Other Study ID Numbers: ET19-006 - CABRAMET
First Posted: May 30, 2019    Key Record Dates
Last Update Posted: December 20, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Leon Berard:
mRCC
cabozantinib
brain metastases
Additional relevant MeSH terms:
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Carcinoma
Neoplasm Metastasis
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplastic Processes
Pathologic Processes
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases