Open-Label Study of Cabozantinib as 2nd Line Treatment in Subjects with Unresectable, Locally Advanced or Metastatic Renal Cell Carcinoma with a Clear-Cell Component Who Progressed After 1st Line Treatment.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ipsen Pharma

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Oct 2019 → 12 Feb 2026

Decision date (initial)

2024-08-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Ipsen Phama (France)

External identifiers

EU CT number

2024-514479-16-00

EudraCT number

2018-002820-18

ClinicalTrials.gov

NCT03945773

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety

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 objectives 7

1. 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.
2. To assess objective response rate (ORR) by independent central review and Investigator's review in cohort B
3. To assess objective response rate (ORR) by Investigator's review in cohort A
4. To assess overall survival (OS)
5. To assess the ORR and PFS by Investigator's review and OS in overall population (cohorts A+B)
6. To assess the change in disease-related symptoms as assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire
7. To assess the safety and tolerability of cabozantinib

Conditions and MedDRA coding

Unresectable, Locally Advanced or Metastatic Renal Cell Carcinoma with a Clear-Cell Component Who Progressed After 1st Line Treatment with Checkpoint Inhibitors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Subjects must provide a signed informed consent prior to any study - related procedures
2. 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)
3. Subjects present >/=1 target lesion according to RECIST 1.1 per investigator
4. Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1
5. Subjects with treated brain metastases are eligible if metastases have been shown to be stable as per Investigator's judgement
6. 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 × ULN. For subjects with Gilbert’s disease ≤ 3 mg/dL (≤ 51.3 μmol/L). (f) Serum creatinine ≤ 2.0 × ULN 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.
7. 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
8. Subject must have completed a steroid taper if he/she experienced an immune-related adverse event associated with previous CPI treatment
9. 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
10. 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
11. 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
12. 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
13. Subjects must be covered by social security or be the beneficiary of such a system (only applicable for French subjects)
14. Male or female subjects must be aged >/=18 years on the day the informed consent is signed
15. 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

Exclusion criteria 23

1. Inability to swallow tablets
2. 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
3. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation
4. Lesions invading major pulmonary blood vessels
5. Diagnosed with other clinically significant disorders such as: (a)Serious nonhealing wound/ulcer/bone fracture; (b)Malabsorption syndrome; (c)Uncompensated/symptomatic hypothyroidism (d)Moderate to severe hepatic impairment (e)Requirement for haemodialysis or peritoneal dialysis (f)History of solid organ transplantation
6. Predicted life expectancy of less than 3 months
7. 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
8. 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
9. 17 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
10. treated with any other investigational medicinal product (IMP) during clinical study within the last 30 days before baseline
11. Previously treated with cabozantinib
12. Has a contraindication to Magnetic Resonance Imaging or contrast medium used for Contrast Tomography (CT)-scan
13. Presents untreated brain or leptomeningeal metastases, or current clinical or radiographic progression of known brain metastases
14. 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)
15. 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
16. 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
17. 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
18. 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 SmPC document.
19. Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded.
20. 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.
21. 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.
22. Is likely to require treatment during the study with drugs that are not permitted by the study protocol.
23. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective response rate (ORR) in cohort A per RECIST 1.1 evaluated by independent central review

Secondary endpoints 8

1. Time to response (TTR) per RECIST 1.1 evaluated by independent central review
2. Duration of response (DOR) per RECIST 1.1 evaluated by independent central review
3. Disease control rate (DCR) per RECIST 1.1 by independent central review
4. Progression-free survival (PFS) per RECIST 1.1 by independent central review
5. 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
6. Overall survival (OS)
7. ORR, TTR, DOR, DCR and PFS per RECIST 1.1 according to local Investigator's review
8. Change in disease-related symptoms as assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI- DRS) questionnaire

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ipsen Pharma

Sponsor organisation

Ipsen Pharma

Address

70 Rue Balard

City

Paris

Postcode

75015

Country

France

Scientific contact point

Organisation

Ipsen Pharma

Contact name

Medical Development Director

Public contact point

Organisation

Ipsen Pharma

Contact name

Ipsen Clinical Study Enquiries

Third parties 3

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications