Clinical Trials /

Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC

NCT04413123

Description:

This research study will assess whether cabozantinib, nivolumab and ipilimumab in combination are safe and effective in slowing down the growth of kidney cancer(renal cell carcinoma or RCC) that has advanced or spread to other areas the body.

Related Conditions:
  • Chromophobe Renal Cell Carcinoma
  • Collecting Duct Carcinoma
  • Kidney Medullary Carcinoma
  • Non-Clear Cell Renal Cell Carcinoma
  • Papillary Renal Cell Carcinoma
  • Translocation-Associated Renal Cell Carcinoma
  • Unclassified Renal Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC
  • Official Title: A Phase 2 Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Advanced Non-Clear Cell Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 19-789
  • NCT ID: NCT04413123

Conditions

  • Papillary Renal Cell Carcinoma
  • Unclassified Renal Cell Carcinoma
  • Translocation Renal Cell Carcinoma
  • Chromophobe Renal Cell Carcinoma
  • Collecting Duct Renal Cell Carcinoma
  • Medullary Renal Cell Carcinoma
  • Renal Cell Carcinoma
  • Unresectable Advanced Renal Cell Carcinoma
  • Metastatic Ncc Renal Cell Carcinoma

Interventions

DrugSynonymsArms
CabozantinibCOMETRIQ™, CABOMETYX™Cabozantinib
NivolumabOpdivo®Cabozantinib
IpilimumabYervoyCabozantinib

Purpose

This research study will assess whether cabozantinib, nivolumab and ipilimumab in combination are safe and effective in slowing down the growth of kidney cancer(renal cell carcinoma or RCC) that has advanced or spread to other areas the body.

Detailed Description

      This research study involves an investigational drug combination not approved by the FDA (the
      U.S. Food and Drug Administration) for your kidney cancer.

      The names of the study drugs in this investigational combination are:

        -  Cabozantinib

        -  Nivolumab

        -  Ipilimumab

      The research study procedures include screening for eligibility, study treatment, participant
      evaluations and safety follow-up visits, in addition to general health status follow-up after
      study treatment.

      It is expected that about 40 people will take part in this research study.
    

Trial Arms

NameTypeDescriptionInterventions
CabozantinibExperimentalEligible patients will be enrolled and receive treatment with Cycle 1-4 (cycles of 21 days) Cabozantinib predetermined protocol dosage po daily Nivolumab predetermined protocol dosage via IV every 3 weeks Ipilimumab predetermined protocol dosage via IV every 3 weeks After the first four cycles of therapy, Cabozantinib determined protocol dosage po daily Nivolumab predetermined protocol dosage via IV every 3 weeks (cycles of 28 days)
  • Cabozantinib
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  histologically or cytologically confirmed unresectable advanced or metastatic nccRCC,
             including but not limited to:

               -  Papillary RCC, any type

               -  Unclassified RCC

               -  Translocation RCC

               -  Chromophobe RCC

               -  Collecting duct RCC

               -  Medullary RCC

               -  Renal cell carcinoma with 80% or more sarcomatoid features on primary nephrectomy
                  specimen or a biopsy

               -  Other nccRCC histologies

          -  Measurable disease as per RECIST 1.1. See Section 11 for the evaluation of measurable
             disease.

          -  Age ≥ 18 years

          -  ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A)

          -  Participants must undergo fresh tumor biopsy after registration but prior to the start
             of treatment unless medically unsafe or not feasible. If a fresh tumor biopsy is not
             medically safe or not feasible, confirmation of the availability of archival tumor
             tissue is required. For archival tissue, a recommended minimum of 20 unstained slides
             should be obtained.

          -  Normal organ and marrow function as defined below:

               -  absolute neutrophil count ≥1,500/mcL

               -  platelets ≥100,000/mcL

               -  hemoglobin ≥9g/dL (transfusions allowed)

               -  total bilirubin ≤2.0 x institutional upper limit of normal with the following
                  exception: patients with known Gilbert disease should have a serum bilirubin ≤ 3
                  x ULN

          -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal with the following
             exception: patients with known liver metastases should have AST and ALT ≤ 5 x ULN

          -  creatinine clearance ≥30 mL/min/1.73 m2 according to the Cockcroft-Gault equation.

          -  Normal coagulation INR ≤ 1.5

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             5 months after the duration of study participation. Should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             should inform her treating physician immediately. Men treated or enrolled on this
             protocol must also agree to use adequate contraception prior to the study, for the
             duration of study participation, and 7 months after completion of cabozantinib,
             nivolumab or ipilimumab administration.

          -  Ability to understand and willingness to sign a written informed consent document

        Exclusion Criteria:

        - Patients could be untreated or have received prior lines of therapies. Patients who
        receive prior therapy may receive only one VEGF based therapy. A combination therapy (e.g.

        lenvatinib+everolimus) is considered 1 line of therapy.

          -  Previous therapy with CD137 agonists and immune checkpoint inhibitors, including but
             not limited to inhibitors of the PD-1/PD-L1 and/or CTLA-4 axes. Previous treatment
             with IFNα or IL-2 is allowed if received > 4 weeks from enrollment.

          -  Treatment with small molecule tyrosine kinase inhibitors within 2 weeks of enrollment,
             or any other anticancer agent within 4 weeks of enrollment.

          -  Prior therapy with cabozantinib

          -  Patients receiving any other therapeutic investigational agents.

          -  Treatment with hydroxychloroquine within two weeks of treatment start.

          -  Radiotherapy for nccRCC within 14 days of first study treatment with the exception of
             a single fraction of radiation administered for palliation of symptoms.

          -  Untreated brain metastases. Patients might be included if they underwent radiation
             therapy or surgery at least 4 weeks prior enrollment. Stability of the central nervous
             system disease should be confirmed by brain MRI or CT-scan or as determined by
             treating investigator. Patients should not be receiving prednisone dose >10 mg/d at
             C1D1.

          -  Other malignancy diagnosed within 2 years of first study treatment unless negligible
             risk of metastases or death (included but not limited to carcinoma in situ of the
             cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal
             carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma, or other
             malignancy not deemed to impact patients 5-year life expectancy).

          -  Significant cardiovascular disorders including:

               -  Significant cardiovascular disease including dyspnea of New York Heart
                  Association (NYHA) class II or greater, myocardial infarction within the previous
                  3 months of first study treatment, unstable arrhythmias, unstable angina.
                  Patients with known coronary artery disease or congestive heart failure not
                  meeting the above criteria, or left ventricular ejection fraction < 50%, must be
                  on a stable and optimized in the opinion of the treating physician, in
                  consultation with a cardiologist when appropriate.

               -  Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or
                  diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy is allowed.

               -  Personal history of hypertensive crisis or hypertensive encephalopathy within the
                  previous 3 months of registration.

               -  Personal history of stroke or transient ischemic attack within 3 months of
                  registration.

               -  Significant vascular disease, such as but not limited to aortic aneurysm
                  requiring surgical repair or recent peripheral arterial thrombosis, within 6
                  months of registration.

          -  Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
             electrocardiogram (ECG). Furthermore, subjects with a history of additional risk
             factors for torsades de pointes (eg, long QT syndrome) are also excluded.

          -  Known history of severe allergic reactions attributed to compounds of similar chemical
             or biologic composition human antibodies, or known hypersensitivity to any component
             of cabozantinib, nivolumab or ipilimumab products.

          -  Systemic immunosuppressive medications including but not limited to: Corticosteroids
             at a dose > 10mg equivalent prednisone daily, cyclosporin, azathioprine, methotrexate,
             thalidomide, anti-tumor necrosis factor (TNF) agents, hydroxychloroquine, within 2
             weeks of first study dose.

               -  Patients who have received acute, low-dose systemic immunosuppressant medications
                  may be enrolled.

               -  Patients with adrenal insufficiency on physiologic replacement doses of steroids
                  may be enrolled.

               -  The use of inhaled, topical, intraocular, or intraarticular corticosteroids or
                  mineralocorticoids are allowed

          -  Prior allogenic stem cell or solid organ transplant.

          -  Personal history of autoimmune disease including: myasthenia gravis, myositis,
             autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
             bowel disease, vascular thrombosis associated with anti-phospholipid syndrome,
             Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple
             sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis. Patients with
             a history of autoimmune-related hypothyroidism on thyroid replacement hormone, or
             those with autoimmune dermatologic conditions not requiring the use of prednisone > 10
             mg or equivalent are eligible.

          -  History of idiopathic pulmonary fibrosis, organized pneumonia, or evidence of active
             pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in
             the radiation field is permitted.

          -  History of following infectious diseases:

               -  Active or chronic hepatitis B (defined as having a positive hepatitis B surface
                  antigen [HBsAg] test at screening).

               -  Active hepatitis C infection. Patients with positive hepatitis C antibody test
                  are eligible if PCR is negative for hepatitis C viral DNA.

               -  Infection requiring therapeutic oral or IV anti-microbials within 2 weeks of
                  first study treatment. Patients receiving routine antimicrobial prophylaxis for
                  dental procedures are eligible.

               -  Known positive test for HIV.

          -  Administration of a live, attenuated vaccine within 3 weeks for first study treatment.

          -  Bleeding diathesis, or significant coagulopathy in the absence of therapeutic
             anticoagulation.

          -  Use of strong inhibitors and inducers of CYP3A4

          -  Significant bleeding, including but not limited to hematemesis, hematuria, hemoptysis
             of > 0.5 teaspoon (2.5 mL), within 3 months before registration.

          -  Invasion of major pulmonary blood vessels. A discussion with PI may be needed if
             invading lesions are suspected.

          -  Concomitant use of dipyramidole, ticlopidine, clopidogrel, cilostazol is excluded.
             Aspirin (≤ 325 mg per day) is allowed. Prophylactic anticoagulation with oral or
             parenteral anticoagulants for the patency of venous access devices or other
             indications is allowed.

        Therapeutic use of low-molecular weight heparin (such as enoxaparin) and subcutaneous or
        oral Factor Xa inhibitors are allowed. Use of warfarin is prohibited.

          -  Significant GI conditions at risk of perforation or bleeding, including but not
             limited to:

               -  Active GI obstruction or requirement of routine parenteral nutrition or tube
                  feedings.

               -  Personal history of abdominal or tracheoesophageal fistula or GI perforation
                  within 6 months of registration.

               -  Evidence of abdominal free air not explained by paracentesis or recent surgical
                  procedure.

               -  Serious, non-healing or dehiscing wound or active ulcer.

          -  Major surgical procedure to include major dental, oral or maxillofacial procedures
             within 14 days of first study treatment.

          -  Proteinuria as demonstrated by > 1.5 gram of protein in a 24-hour urine collection.
             All patients with ≥ 2+ protein on urinalysis must undergo 24-hour urine collection for
             protein.

          -  Unable to swallow pills.

          -  Malabsorption syndrome.

          -  Inability to receive IV medications

          -  Pregnant or lactating women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:tart of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started up to 21 Months
Safety Issue:
Description:Percent of patients who achieve overall response (CR or PR) by RECIST 1.1 will be summarized with 80% two-sided exact binomial confidence intervals (CI)

Secondary Outcome Measures

Measure:Duration of response (DOR)
Time Frame:first documentation of response, to the earlier of the first documentation of disease progression or death from any cause, and calculated for patients with a best confirmed response of CR up to 21 Months
Safety Issue:
Description:will be estimated using the method of Kaplan-Meier, for all patients and by histology subtypes. M
Measure:Progression-free survival (PFS)
Time Frame:trial treatment start to the earlier of progression or death due to any cause per investigator assessment. Participants alive without disease progression are censored at date of last disease evaluation up to 21 Months
Safety Issue:
Description:the method of Kaplan-Meier, for all patients and by histology subtypes evaluation.
Measure:Overall survival (OS)
Time Frame:from trial treatment start to death due to any cause or censored at date last known alive up to 21 Months
Safety Issue:
Description:the method of Kaplan-Meier, for all patients and by histology subtypes
Measure:"Number of Participants with TreatmentRelated Adverse Events as Assessed by CTCAE version 5.
Time Frame:Baseline, day 1 of every cycle (21 days for first 4 cycles and then 28 days for each cycle tehreafter) and End of Treatment up 21 months
Safety Issue:
Description:For toxicity reporting, all adverse events will be graded and analyzed using CTCAE version 5.
Measure:Quality of life- FKSI-19 Scale
Time Frame:12 weeks for the first assessment, then every 8 weeks (+/- 7 days) for the first 6 months. Then take place every 12 weeks (+/- 7 days)
Safety Issue:
Description:The Functional Assessment of Cancer Therapy-Kidney Symptom (FKSI-19) is a 19 item questionnaire with each item scored on a scale of 0-4 for a total score of 0-76 with higher scores indicating fewer symptom
Measure:Quality of life-BFI Questionaire
Time Frame:2 weeks for the first assessment, then every 8 weeks (+/- 7 days) for the first 6 months. Then take place every 12 weeks (+/- 7 days)
Safety Issue:
Description:The Brief Fatigue Inventory (BFI) is a 9-item questionnaire with each item scored on a scale of 0-10. Scores are categorized as mild (1-3), moderate (4-6), or severe (7-10). A global fatigue score can be found by averaging the score obtained on each test item completed
Measure:Objective response rate (ORR)
Time Frame:defined as the percentage of patients with partial (PR) or complete response (CR) as best overall response according to RECIST 1.1 by investigator assessment up to 21 Months
Safety Issue:
Description:ORR by RECIST 1.1 according to histology subtypes (Papillary RCC versus other histology types) will be summarized with 80% two-sided exact CIs.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Bradley A. McGregor

Trial Keywords

  • Papillary Renal Cell Carcinoma
  • Unclassified Renal Cell Carcinoma
  • Translocation Renal Cell Carcinoma
  • Chromophobe Renal Cell Carcinoma
  • Collecting duct Renal Cell Carcinoma
  • Medullary Renal Cell Carcinoma
  • Renal Cell Carcinoma
  • Unresectable Advanced Renal Cell Carcinoma
  • Metastatic ncc Renal Cell Carcinoma

Last Updated

May 28, 2020