Study of Cabozantinib as 2nd Line Treatment in Subjects With Locally Advanced or Metastatic Renal Cell Carcinoma (RCC) With a Clear-Cell Component Who Progressed After 1st Line Treatment With Checkpoint Inhibitors

Phase 2

Active, not recruiting

Conditions: Locally Advanced or Metastatic Renal Cell Carcinoma

Interventions: Drug: Cabozantinib

Registration Number: NCT03945773

Lead Sponsor: Ipsen

Brief Summary: 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 Checkpoint Inhibitors (CPI) therapy with ipilimumab and nivolumab in combination or CPI combined with Vascular Endothelial Growth Factor (VEGF)-targeted therapy.

Detailed Description: Not available

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 127

Inclusion Criteria

All subjects must fulfil all the following criteria to be included in the study:

Subjects must provide a signed informed consent prior to any study-related procedures;
Male or female subjects must be aged ≥18 years on the day the informed consent is signed;
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;
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);
Subjects present ≥1 target lesion according to RECIST 1.1 per Investigator;
Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1;
Subjects with treated brain metastases are eligible if metastases have been shown to be stable as per Investigator's judgement;
Subjects must have adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 15 days before baseline:
1. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L).
2. Platelets ≥ 100,000/mm3 (≥ 100 GI/L).
3. Haemoglobin ≥ 9 g/dL (≥ 90 g/L).
4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal (ULN).
5. Total bilirubin ≤ 1.5 × ULN. For subjects with Gilbert's disease ≤ 3 mg/dL (≤ 51.3 μmol/L).
6. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation
7. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine or 24-hour urine protein < 1 g.
Subject must have recovered to baseline or ≤ Grade 1 per CTCAE v5 from toxicities related to any prior treatments, unless Adverse Events (AE(s)) are clinically nonsignificant and/or stable on supportive therapy as determined by the Investigator;
Subject must have completed a steroid taper if he/she had an immune-related adverse event associated with immune CPI;
Female subjects of childbearing potential (i.e. less than or equal to 2 years postmenopause 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;
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 4 months after the last dose of study treatment;
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;
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
Subjects must be covered by social security or be the beneficiary of such a system (only applicable for French subjects).

Exclusion Criteria

Subjects will not be included in the study if the subject:

Inability to swallow tablets;
Was treated with any other investigational medicinal product (IMP) within the last 30 days before baseline;
Was previously treated with cabozantinib;
Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast medium used for Contrast Tomography (CT)-scan;
Presents untreated brain or leptomeningeal metastases, or current clinical or radiographic progression of known brain metastases;
Has a diagnosis of a serious cardiovascular disorder:
1. Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, or serious cardiac arrhythmias;
2. Uncontrolled hypertension, defined as sustained blood pressure (BP) (>140 mm Hg systolic or >90 mm Hg diastolic pressure) despite optimal antihypertensive treatment;
3. 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;
4. History of risk factors for torsades de pointes (e.g., long QT syndrome);
Is receiving concomitant anticoagulation with coumarin agents (e.g. warfarin), direct thrombin inhibitor dabigatran, Direct Factor Xa inhibitors betrixaban or platelet inhibitors (e.g. clopidogrel); Note: The following are allowed anticoagulants: prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparin (LMWH) are permitted. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in patients without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before baseline without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumour.
Has a 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
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
Presents clinically significant haematuria, hematemesis, or haemoptysis of >0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g.

pulmonary haemorrhage) within 3 months before screening;
Presents cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
Presents lesions invading major pulmonary blood vessels;
Has been diagnosed with other clinically significant disorders such as:
1. Serious nonhealing wound/ulcer/bone fracture;
2. Malabsorption syndrome;
3. Uncompensated/symptomatic hypothyroidism;
4. Moderate to severe hepatic impairment (Child-Pugh B or C);
5. Requirement for haemodialysis or peritoneal dialysis;
6. History of solid organ transplantation;
Has a predicted life expectancy of less than 3 months;
Has had 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
Has had 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;
Has a 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 (Gleason Grade ≤6), 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;
Has a 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 Summary of Product Characteristics (SmPC) document;
Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded;
Has a serious medical or psychiatric condition that renders the subject unable to understand the nature, scope and possible consequences of the study, and/or presents an uncooperative attitude;
Is 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 (i.e. less than or equal to 2 years post-menopause and not surgically sterile);
Is likely to require treatment during the study with drugs that are not permitted by the study protocol;
Has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the subject's safety

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A	Cabozantinib	Subjects who radiographically progressed after one prior line by CPI therapy with ipilimumab and nivolumab.
Cohort B	Cabozantinib	Subjects who radiographically progressed after one prior line by CPI therapy combined with VEGF-targeted therapy.

Primary Outcome Measures

Name	Time	Method
Cohort A: Objective Response Rate (ORR) Assessed by Independent Central Review	Tumour assessments performed at Screening/Baseline (within 28 days prior start of study treatment) and every 12 weeks, up to approximately 40 months	ORR was defined as the percentage of participants 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. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. The confidence interval of the ORR was calculated using Clopper-Pearson exact method.

Secondary Outcome Measures

Name	Time	Method
Time to Response (TTR) Assessed by Independent Central Review and Investigator	Tumour assessments performed at Screening/Baseline (within 28 days prior start of study treatment) and every 12 weeks, up to approximately 40 months	TTR was 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 and Investigator per RECIST 1.1). The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
Duration of Response (DOR) Assessed by Independent Central Review and Investigator	Tumour assessments performed at Screening/Baseline (within 28 days prior start of study treatment) and every 12 weeks, up to approximately 40 months	DOR was defined as the time from first documented response (PR or CR as determined by independent central review and Investigator per RECIST 1.1) to either disease progression (as determined by independent central review and Investigator per RECIST 1.1) or death due to any cause, whichever occurs first. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. The progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 millimeters (mm). DOR was calculated using the Kaplan-Meier method.
Disease Control Rate (DCR) Assessed by Independent Central Review and Investigator	Tumour assessments performed at Screening/Baseline (within 28 days prior start of study treatment) and every 12 weeks, up to approximately 40 months	DCR was defined as the percentage of participants who achieved a PR, CR or stable disease (SD) as determined by independent central review and Investigator per RECIST 1.1. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. The SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. The PD was defined at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 mm.
Progression-free Survival (PFS) Assessed by Independent Central Review and Investigator	Tumour assessments performed at Screening/Baseline (within 28 days prior start of study treatment) and every 12 weeks, up to approximately 40 months	PFS was defined as the time from start of study treatment to either disease progression (as determined by independent central review and Investigator per RECIST 1.1) or death due to any cause, whichever occurs first. The PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of ≥ 5 mm. PFS was calculated using the Kaplan-Meier method.
Cohort B: Objective Response Rate Assessed by Independent Central Review	Tumour assessments performed at Screening/Baseline (within 28 days prior start of study treatment) and every 12 weeks, up to approximately 40 months	ORR was defined as the percentage of participants who achieved a PR or CR at any timepoint as determined by independent central review per RECIST 1.1. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. The CI of the ORR was calculated using Clopper-Pearson exact method.
Objective Response Rate Assessed by Investigator	Tumour assessments performed at Screening/Baseline (within 28 days prior start of study treatment) and every 12 weeks, up to approximately 40 months	ORR was defined as the percentage of participants who achieved a PR or CR at any timepoint as determined by Investigator per RECIST 1.1. The CR was defined as disappearance of all target lesions. The PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. The CI of the ORR was calculated using Clopper-Pearson exact method.
Overall Survival (OS) Assessed by Investigator	From the start of study treatment (Day 1) up to end of study, 45 months	OS was defined as the time from the start of treatment until death due to any cause. OS was calculated using the Kaplan-Meier method.
Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) Score at Month 40	Baseline (Day 1) and Month 40	The FKSI-DRS questionnaire consisted of 9-items to evaluate participant's symptoms in the past 7 days such as lack of energy, pain, weight-loss, bone-pain, shortness of breath, fatigue, fever, blood in urine etc. Participants rated each question from 0 (not at all) to 4 (very much). Total score was calculated as the sum of the item responses divided by the number of items completed and multiplied by the total number of items in the scale. Total score ranged from 0 to 36. Higher scores indicated less symptoms. Baseline was defined as the last questionnaire answered prior to the first dose of study drug. A negative change from baseline indicated worse outcome.

Trial Locations

Locations (40): Maxima Medisch Centrum
🇳🇱
Eindhoven, Netherlands
Kantonsspital St. Gallen
🇨🇭
Saint Gallen, Switzerland
The Christie NHS Foundation Trust
🇬🇧
Manchester, United Kingdom
Institut Claudius Régaud
🇫🇷
Toulouse, France
Institut de Cancérologie de l'Ouest
🇫🇷
Saint-Herblain, France
Centre Léon Bérard
🇫🇷
Lyon, France
University Hospital Carl Gustav Carus Dresden
🇩🇪
Dresden, Germany
Universitätsmedzin Charité
🇩🇪
Berlin, Germany
CHU Strasbourg
🇫🇷
Strasbourg, France
University Hospital Tuebingen
🇩🇪
Tübingen, Germany
CHRU Besançon
🇫🇷
Besançon, France
Otto-von-Guericke-Universität University hospital Magdeburg
🇩🇪
Magdeburg, Germany
Klinikum Der Friedrich-Schiller-Universitaet Jena
🇩🇪
Jena, Germany
The Netherlands Cancer Institute - Oncology
🇳🇱
Amsterdam, Netherlands
Universitair Medisch Centrum Utrecht
🇳🇱
Utrecht, Netherlands
Institut Paoli Calmettes
🇫🇷
Marseille, France
Gustave Roussy
🇫🇷
Villejuif, France
Institut Mutualiste Montsouris
🇫🇷
Paris, France
Caritas Krankenhaus St.Josef Klinik für Urologie
🇩🇪
Regensburg, Germany
Hospital Universitario 12 de Octubre
🇪🇸
Madrid, Spain
Centre Jean Perrin
🇫🇷
Clermont-Ferrand, France
CHU de Nîmes - Institut de Cancérologie du Gard
🇫🇷
Nîmes, France
SALK - Salzburger Landesklinik
🇦🇹
Salzburg, Austria
Institut de Cancérologie de Lorraine
🇫🇷
Nancy, France
Centre Hospitalier Lyon Sud
🇫🇷
Pierre-Bénite, France
University Cancer Center Hamburg Eppendorf
🇩🇪
Hamburg, Germany
Medizinische Hochschule Hannover
🇩🇪
Hannover, Germany
Universitätsklinikum Essen
🇩🇪
Essen, Germany
Universitätsklinikum Schleswig-Holstein
🇩🇪
Lübeck, Germany
University, Hospital Münster
🇩🇪
Münster, Germany
Leiden University Medical Center
🇳🇱
Leiden, Netherlands
Hospital Lucus Augusti
🇪🇸
Lugo, Spain
Hospital de La Santa Creu i Sant Pau
🇪🇸
Barcelona, Spain
M.D. Anderson Center Madrid
🇪🇸
Madrid, Spain
Universitätsspital Bern, Inselspital
🇨🇭
Bern, Switzerland
Centre Hospitalier Universitaire Vaudois
🇨🇭
Lausanne, Switzerland
Beatson West of Scotland Cancer Centre
🇬🇧
Glasgow, United Kingdom
Mount Vernon Hospital
🇬🇧
Northwood, United Kingdom
Western General Hospital - Edinburgh Cancer Centre
🇬🇧
Edinburgh, United Kingdom
Royal Cornwall Hospital (RCH) - Sunrise Centre
🇬🇧
Truro, United Kingdom