Clinical Trials /

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

NCT03945773

Description:

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.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Phase II, Multicentre, 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 With Checkpoint Inhibitors.

Clinical Trial IDs

  • ORG STUDY ID: F-FR-60000-023
  • SECONDARY ID: 2018-002820-18
  • NCT ID: NCT03945773

Conditions

  • Locally Advanced or Metastatic Renal Cell Carcinoma

Interventions

DrugSynonymsArms
CabozantinibCabometyxCohort A

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalSubjects who radiographically progressed after one prior line by CPI therapy with ipilimumab and nivolumab.
  • Cabozantinib
Cohort BExperimentalSubjects who radiographically progressed after one prior line by CPI therapy combined with VEGF-targeted therapy.
  • Cabozantinib

Eligibility Criteria

        Inclusion Criteria:

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

          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:

               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. Fasting serum triglycerides ≤ 2.5 × ULN AND total cholesterol ≤ 300 mg/dL (≤ 7.75
                  mmol/L). Lipid-lowering medication is allowed.

               7. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥
                  0.5 mL/sec) using the Cockcroft-Gault equation

               8. 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 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;

         10. Subject must have completed a steroid taper if he/she had an immune-related adverse
             event associated with immune CPI;

         11. 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;

         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 4 months 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).

        Exclusion Criteria:

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

          1. Inability to swallow tablets;

          2. Was treated with any other investigational medicinal product (IMP) 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. 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);

          7. Is receiving concomitant anticoagulation with oral anticoagulants (e.g. warfarin,
             direct thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g. clopidogrel);
             Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and low
             dose, low molecular weight heparin (LMWH) are permitted.

          8. 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

          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. 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;

         11. Presents cavitating pulmonary lesion(s) or known endobronchial disease manifestation;

         12. Presents lesions invading major pulmonary blood vessels;

         13. Has been diagnosed with other clinically significant disorders such as:

               1. Serious nonhealing wound/ulcer/bone fracture;

               2. Malabsorption syndrome;

               3. Free thyroxine 4 (FT4) outside the laboratory normal reference range;

               4. Uncompensated/symptomatic hypothyroidism;

               5. Moderate to severe hepatic impairment (Child-Pugh B or C);

               6. Requirement for haemodialysis or peritoneal dialysis;

               7. History of solid organ transplantation;

         14. Has a predicted life expectancy of less than 3 months;

         15. 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

         16. 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;

         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;

         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 Summary
             of Product Characteristics (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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:up to 42 months
Safety Issue:
Description:Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by Independent Central review

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:up to 42 months
Safety Issue:
Description:Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator
Measure:Time to response (TTR)
Time Frame:Every 12 weeks up to 42 months
Safety Issue:
Description:Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
Measure:Duration of response (DOR)
Time Frame:Every 12 weeks up to 42 months
Safety Issue:
Description:Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
Measure:Disease control rate (DCR)
Time Frame:Every 12 weeks up to 42 months
Safety Issue:
Description:Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
Measure:Progression-free survival (PFS)
Time Frame:Every 12 weeks up to 42 months
Safety Issue:
Description:Assesses by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 assessed by the Investigator and Independent Central review
Measure:Change in disease-related symptoms
Time Frame:Every 12 weeks up to 42 months
Safety Issue:
Description:Assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire.
Measure:Overall survival (OS)
Time Frame:Every 12 weeks starting after End of Study Treatment visit (30 days after the last dose) until the subject expires or the end of the study (18 months after the last subject received the first cabozantinib dose), whichever occurs first.
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ipsen

Last Updated

November 27, 2020