Unresectable, Locally Advanced or Metastatic Renal Cell Carcinoma with a Clear-Cell Component Who Progressed After 1st Line Treatment with Checkpoint Inhibitors MedDRA version: 21.1 Level: PT Classification code 10067946 Term: Renal cell carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: CABOMETYX 20 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: CABOZANTINIB
CAS Number: 849217-68-1
Current Sponsor code: XL184
Concentration unit: mg mil
Sponsors
Ipsen Pharma
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: (1) Subjects must provide a signed informed consent prior to any study-related procedures; (2) Male or female subjects must be aged =18 years on the day the informed consent is signed; (3) Subjects must have histologically confirmed unresectable, locally advanced (defined as disease not eligible for curative surgery or radiation therapy) or metastatic RCC with a clear-cell carcinoma component; (4) Subjects must have radiographic disease progression, according to Investigator’s judgement, following 1st line treatment with CPI (ipilimumab plus nivolumab) (Cohort A) or CPI in combination with VEGF-targeted therapy (Cohort B); (5) Subjects present =1 target lesion according to RECIST 1.1 per investigator; (6) Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1; (7) Subjects with treated brain metastases are eligible if metastases have been shown to be stable as per Investigator’s judgement; (8) Subjects must have adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 15 days before baseline: (a) Absolute neutrophil count (ANC) = 1500/mm3 (= 1.5 GI/L). (b) Platelets = 100,000/mm3 (= 100 GI/L). (c) Hemoglobin = 9 g/dL (= 90 g/L). (d) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal. (e) Total bilirubin = 1.5 × the upper limit of normal. For subjects with Gilbert’s disease = 3 mg/dL (= 51.3 µmol/L). (f) Serum creatinine = 2.0 × upper limit of normal or calculated creatinine clearance = 30 mL/min (= 0.5 mL/sec) using the Cockcroft-Gault equation (g) Urine protein-to-creatinine ratio (UPCR) = 1 mg/mg (= 113.2 mg/mmol) creatinine or 24-hour urine protein < 1 g. (9) Subject must have recovered to baseline or = Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy as determined by the investigator; (10) Subjects must have completed a steroid taper, if he/she experienced an immunerelated adverse event associated with previous CPI treatment; (11) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and not surgically sterile) must provide a negative pregnancy test within 7 days prior to the start of study treatment. If a urine test cannot be confirmed as negative, a negative serum pregnancy test is required; (12) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and not surgically sterile) and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 120 days after the last dose of study treatment; (13) All male participants must agree to refrain from donating sperm and unprotected sexual intercourse with female partners during the study and for 120 days after the last dose of study treatment; (14) Subjects must be willing and able to comply with study requirements, remain at the investigational site for the required duration of each study visit and be willing to return to the investigational site for the follow up evaluation, as specified in the protocol. (15) Subjects must be covered by social security or be the beneficiary of such a system (only applicable for French subjects). Are the trial subjects under 18? no Number of subjects for
Exclusion criteria
Exclusion criteria: (1)Inability to swallow tablets; (2)treated with any other investigational medicinal product (IMP) during a clinical trial within the last 30 days before baseline; (3)previously treated with cabozantinib; (4)Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast medium used for Contrast Tomography (CT)-scan; (5)Presents untreated brain or leptomeningeal metastases, or current clinical or radiographic progression of known brain metastases; (6)diagnosis of a serious cardiovascular disorder: (a)Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, or serious cardiac arrhythmias; (b)Uncontrolled hypertension, defined as sustained blood pressure (BP) (>140 mm Hg systolic or>90 mm Hg diastolic pressure) despite optimal antihypertensive treatment; (c)Stroke (including transient ischaemic attack (TIA)), myocardial infarction (MI) or other ischaemic event, or thromboembolic event (e.g. deep venous thrombosis, pulmonary embolism) within 6 months before screening; (d)History of risk factors for torsades de pointes (eg, long QT syndrome); (7)Is receiving a concomitant anticoagulation with coumarin agents (e.g. warfarin), direct thrombin inhibitor dabigatran, direct Factor Xa inhibitor betrixaban or platelet inhibitors (e.g. clopidogrel) (8)gastrointestinal (GI) disorder including those associated with a high risk of perforation or fistula formation: (a)Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction; (b)Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before screening; Note: Complete healing of an intra-abdominal abscess must have been confirmed before screening. (9)Presents a corrected QT (QTc) interval calculated by the Fridericia formula (QTcF)>500 msec within 1 month prior to baseline; Note: If a single ECG shows a QTcF with an absolute value>500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility (10)clinically significant haematuria, hematemesis, or haemoptysis of >0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding within 3 months before screening; (11)cavitating pulmonary lesion(s) or known endobronchial disease manifestation; (12)lesions invading major pulmonary blood vessels; (13)diagnosed with other clinically significant disorders such as: (a)Serious nonhealing wound/ulcer/bone fracture; (b)Malabsorption syndrome; (c)Uncompensated/symptomatic hypothyroidism (subject with a history of autoimmune-related hypothyroidism on thyroid-replacement hormone are eligible for the study); (d)Moderate to severe hepatic impairment (e)Requirement for haemodialysis or peritoneal dialysis (f)History of solid organ transplantation; (14)predicted life expectancy of less than 3 months; (15)prior surgery within 4 weeks prior to baseline. Note: If the subject has undergone major surgery, complete wound healing must have occurred 1 month prior to baseline. (16)palliative radiation therapy for bone within 2 weeks or for radiation fields including viscera within 4 weeks prior to baseline. Note: Resolution/healing of side effects must be complete prior to baselin
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The overall objective of this study is to evaluate the efficacy and safety of cabozantinib as 2nd line treatment in subjects with unresectable, locally advanced or metastatic RCC with a clear-cell component, who progressed after prior CPI therapy with ipilimumab and nivolumab in combination or CPI combined with VEGF-targeted therapy. To assess the efficacy of cabozantinib by the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by independent central review in cohort A;Secondary Objective: • To assess other efficacy criteria of cabozantinib such as time to response (TTR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) by independent central review and Investigator’s review; • To assess objective response rate (ORR) by independent central review and Investigator’s review in cohort B; • To assess ORR by Investigator’s review in cohort A; • To assess overall survival (OS); • To assess the ORR and PFS by Investigator’s review and OS in overall population (cohorts A+B); • To assess the change in disease-related symptoms as assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire; • To assess the safety and tolerability of cabozantinib.;Primary end point(s): Objective response rate (ORR) in cohort A per RECIST 1.1 evaluated by independent central review. ;Timepoint(s) of evaluation of this end point: Objective response rate (ORR) defined as the proportion of subjects who achieved a partial response (PR) or complete response (CR) at any timepoint as determined by independent central review per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, confirmed by a subsequent visit =28 days later. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Time-to-event endpoints (TTR, DOR, PFS and OS) will be analysed using the Kaplan-Meier method. Median durations and associated 2-sided 95% CIs will be provided. Event rates at timepoints from either first dose of study treatment or first documented response will also be estimated with associated 2-sided 95% CIs. ;Secondary end point(s): •Time to response (TTR) defined as the time from start of study treatment to the date of first evidence of response (PR or CR as determined by independent central review per RECIST 1.1); •Duration of response (DOR) defined as the time from first documented response (PR or CR as determined by independent central review per RECIST 1.1) to either disease progression (as determined by independent central review per RECIST 1.1) or death due to any cause, whichever occurs first. Censoring rules will be similar to those applied for progression-free survival (PFS); •Disease control rate (DCR), defined as the proportion of subjects who achieved a PR, CR or SD as determined by independent central review per RECIST 1.1; •PFS defined as the time from start of study treatment to either disease progression (as determined by independent central review per RECIST 1.1) or death due to any cause, whichever occurs first; •Objective response rate (ORR) in cohort B defined as the proportion of subjects who achieved a partial response (PR) or complete response (CR) at any timepoint as determined by independent central review per RECIST 1.1; •Overall survival (OS) defined as the time from the start of treatment until death due to any cause; •ORR, TTR, DOR, DCR and PFS according to local Investigator's review per RECIST 1.1; •Change in disease-related symptoms as assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSIDRS). All these secondary endpoints will be presented in each cohort separately. In addition, ORR and PFS according to local Investigator's review per RECIST 1.1 a | — |
Countries
Austria, France, Germany, Netherlands, Spain, Switzerland, United Kingdom
Contacts
Public ContactGlobal Medical Affairs Director.
Ipsen Pharma
Outcome results
None listed