| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable, Locally Advanced or Metastatic Renal Cell Carcinoma with a Clear-Cell Component Who Progressed After 1st Line Treatment with Checkpoint Inhibitors |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067946 |
| E.1.2 | Term | Renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
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| E.2.2 | Secondary objectives of the trial |
•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 objective response rate (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 |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| At selected sites, tumour tissue (archived before 1st line treatment) may be obtained at any time (archived biopsy) for a biomarker sub-study (exploratory analysis) of MET and PD-L1 expression (status) associated with RCC prognosis or the mechanism(s) of action of study treatment. Details regarding the preparation, processing, and shipping of samples can be found in the biomarkers manual. |
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| E.3 | Principal 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) Fasting serum triglycerides ≤ 2.5 × upper limit of normal and total cholesterol ≤ 300 mg/dL (≤ 7.75 mmol/L). Lipid-lowering medication is allowed.
(g) Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation
(h) 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) Subject must have completed a steroid taper if he/she experienced an immune-related 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).
Treatment Extension Phase:
(16) Provision of signed informed consent form specific for Treatment Extension Phase.
(17) Subject having participated to the main study.
(18) Subject still benefiting from cabozantinib treatment at the end of the main study (i.e. not progressing) and not experiencing any
unacceptable safety issues.
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| E.4 | Principal exclusion criteria |
(1)Inability to swallow tablets;
(2)Was treated with any other investigational medicinal product (IMP) during a clinical study within the last 30 days before baseline;
(3)Was 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)receiving a concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors
Note: Low dose aspirin for cardioprotection (per local applicable guidelines), and low dose LMWH are permitted.
(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 baseline;
(17)history of another active malignancy within 3 years from screening except for locally curable cancers that have been apparently cured, such as low-grade thyroid carcinoma, prostate cancer not requiring treatment , basal or squamous cell skin cancer, superficial bladder cancer, in situ melanoma, in situ prostate, cervix or breast carcinoma or other treated malignancies with <5% chance of relapse according to the Investigator;
(18)history of allergy to study treatment components or agents with a similar chemical structure or any excipient used in the formulation as listed in the SmPC document;
(19)rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption;
(20)serious medical or psychiatric condition that render the subject unable to understand the nature, scope and possible consequences of the study, and/or presents an uncooperative attitude;
(21)pregnant or breastfeeding. A β-human chorionic gonadotrophin (HCG) serum pregnancy test will be performed up to 7 days prior to baseline for all female subjects of childbearing potential ;
(22)likely to require treatment during the study with drugs that are not permitted by the study protocol;
(23)abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the subject’s safety.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Objective response rate (ORR) in cohort A per RECIST 1.1 evaluated by independent central review.
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| E.5.1.1 | 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. |
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| E.5.2 | Secondary end point(s) |
• Time to response (TTR) per RECIST 1.1 evaluated by independent central review;
• Duration of response (DOR) per RECIST 1.1 evaluated by independent central review;
• Disease control rate (DCR) per RECIST 1.1 by independent central review;
• Progression-free survival (PFS) per RECIST 1.1 by independent central review;
•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);
• ORR, TTR, DOR, DCR and PFS per RECIST 1.1 according to local Investigator’s review;
• Change in disease-related symptoms as assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire.
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| E.5.2.1 | 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.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Austria |
| Belgium |
| France |
| Germany |
| Netherlands |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will end 18 months after the last subject included in the study received the first cabozantinib dose.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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