Clinical Trials /

Lenvatinib With Everolimus Versus Cabozantinib for Second-Line or Third-Line Treatment of Metastatic Renal Cell Cancer

NCT05012371

Description:

This phase II trial compares the effects of lenvatinib given in combination with everolimus to the effects of cabozantinib given alone in treating patients with renal cell cancer (RCC) that has spread to other parts of the body (metastatic) and that got worse on a previous PD-1/PD-L1 checkpoint inhibitor. Lenvatinib, everolimus, and cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lenvatinib With Everolimus Versus Cabozantinib for Second-Line or Third-Line Treatment of Metastatic Renal Cell Cancer
  • Official Title: A Phase II Study of Lenvatinib Plus Everolimus Versus Cabozantinib in Patients With Metastatic Renal Cell Carcinoma That Progressed on A PD-1/PD-L1 Checkpoint Inhibitor

Clinical Trial IDs

  • ORG STUDY ID: 2021-0400
  • SECONDARY ID: NCI-2021-07429
  • SECONDARY ID: 2021-0400
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT05012371

Conditions

  • Advanced Clear Cell Renal Cell Carcinoma
  • Metastatic Clear Cell Renal Cell Carcinoma
  • Stage III Renal Cell Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v8

Interventions

DrugSynonymsArms
CabozantinibArm B (cabozantinib)
Everolimus42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, ZortressArm A (lenvatinib, everolimus)
LenvatinibE7080, ER-203492-00, Multi-Kinase Inhibitor E7080Arm A (lenvatinib, everolimus)

Purpose

This phase II trial compares the effects of lenvatinib given in combination with everolimus to the effects of cabozantinib given alone in treating patients with renal cell cancer (RCC) that has spread to other parts of the body (metastatic) and that got worse on a previous PD-1/PD-L1 checkpoint inhibitor. Lenvatinib, everolimus, and cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare the efficacy of lenvatinib plus everolimus versus cabozantinib in patients with
      mRCC who developed progressive disease after 1-2 lines of therapy, including a PD-1/PD-L1
      checkpoint inhibitor.

      SECONDARY OBJECTIVES:

      I. To compare tumor responses to lenvatinib plus everolimus versus cabozantinib in patients
      with mRCC who developed progressive disease after 1-2 lines of therapy, including a
      PD-1/PD-L1 checkpoint inhibitor.

      II. To compare health-related quality of life (HRQoL) and safety of lenvatinib plus
      everolimus versus cabozantinib in patients with mRCC who developed progressive disease after
      1-2 lines of therapy, including a PD-1/PD-L1 checkpoint inhibitor.

      III. To compare overall survival (OS) with lenvatinib plus everolimus versus cabozantinib in
      patients with mRCC who developed progressive disease after 1-2 lines of therapy, including a
      PD-1/PD-L1 checkpoint inhibitor.

      EXPLORATORY OBJECTIVE:

      I. To assess whether alterations to c-MET, VEGF, mTOR, and FGFR are associated with response
      to therapy.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive lenvatinib orally (PO) once daily (QD) and everolimus PO QD. Cycles
      repeat every 30 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive cabozantinib PO QD. Cycles repeat every 30 days in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (lenvatinib, everolimus)ExperimentalPatients receive lenvatinib PO QD and everolimus PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
  • Everolimus
  • Lenvatinib
Arm B (cabozantinib)Active ComparatorPatients receive cabozantinib PO QD. Cycles repeat every 30 days in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with histologically or cytologically confirmed metastatic/advanced clear cell
             renal cell cancer (RCC), or RCC with a clear cell component, who have received 1 or 2
             prior lines of treatment in the advanced or metastatic setting, and the most recent
             treatment must include a PD-1/PD-L1 checkpoint inhibitor.

          -  There must be evidence of progression on or after treatment (at any point after
             completing prior therapy) with a PD-1/PD-L1-containing regimen as the last treatment
             received within 6 months of enrollment.

          -  Patients must have at least one measurable site of disease, defined as a lesion that
             can be accurately measured in at least one dimension (longest diameter to be recorded)
             and measures >= 15 mm with conventional techniques or >= 10 mm with more sensitive
             techniques such as magnetic resonance imaging (MRI) or spiral computed tomography (CT)
             scan. If the patient has had previous radiation to the marker lesion(s), there must be
             evidence of progression since the radiation.

          -  Karnofsky performance status >= 70

          -  Age >= 18 years

          -  Hemoglobin >= 9 g/dL (treatment/transfusion allowed)

          -  Absolute neutrophil count (ANC) >= 1,000/microliter

          -  Platelets >= 75,000/microliter

          -  Total bilirubin =< 1.5 mg/dL (for patients with Gilbert's disease, total bilirubin
             should be =< 3 mg/dL [=< 51.3 micromoles/L])

          -  Aspartate aminotrasferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) or
             alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             institutional upper limit of normal (ULN), except in known hepatic metastasis, wherein
             may be =< 5 x ULN

          -  Serum creatinine =< 1.5 x ULN (as long as patient does not require dialysis); if
             creatinine is not < 1.5 x ULN, then calculate by Cockcroft-Gault methods or local
             institutional standard and creatinine clearance must be >= 30 mL/kg/1.73 m^2

          -  International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x
             ULN prior to study entry. Therapeutic anticoagulation is permitted if: on a stable
             dose of low molecular weight heparin (LMWH) for > 2 weeks (14 days) at the time of
             enrollment or on a direct oral anticoagulant (DOAC) for > 2 weeks at time of
             enrollment.

          -  Female patients of childbearing potential (not postmenopausal for at least 12 months
             and not surgically sterile) must have a negative serum or urine pregnancy test
             (minimum sensitivity 25 international units/L or equivalent units of human chorionic
             gonadotropin [HCG]) before study entry. Pregnancy test must be repeated if performed >
             14 days before starting study drug.

          -  Women must not be breastfeeding

          -  Patients with a history of major psychiatric illness must be judged (by the treating
             physician) able to fully understand the investigational nature of the study and the
             risks associated with the therapy.

          -  Patients with treated/stable brain metastases are allowed on protocol if they had
             brain metastases that received central nervous system (CNS)-directed therapy, such as
             surgery or treatment with radiosurgery or gamma knife, without recurrence or edema for
             1 month (4 weeks).

        Exclusion Criteria:

          -  Prior receipt of lenvatinib, a c-MET inhibitor, such as cabozantinib or sitravatinib,
             or an mTOR inhibitor, such as everolimus or temsirolimus.

          -  Patients must not have any other malignancies within the past 3 years except for in
             situ carcinoma of any site, adequately treated (without recurrence post-resection or
             post- radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of
             the skin, or active non-threatening second malignancy that would not, in the
             investigator's opinion, potentially interfere with the patient's ability to
             participate and/or complete this trial. Examples include but are not limited to:
             urothelial cancer grade Ta/T1 or adenocarcinoma of the prostate treated with active
             surveillance.

          -  Patients currently receiving anticancer therapies or who have received anticancer
             therapies within 2 weeks (14 days) from enrollment into this study (including
             chemotherapy and targeted therapy) are excluded. Also, patients who have completed
             palliative radiation therapy more than 14 days prior to the first dose of lenvatinib
             plus everolimus or cabozantinib are eligible.

          -  Patients who had a major surgery or significant traumatic injury (injury requiring >
             28 days to heal) within 28 days of start of study drug, patients who have not
             recovered from the side effects of any major surgery (defined as requiring general
             anesthesia), or patients that are expected to require major surgery during the course
             of the study.

          -  Active or documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative
             colitis)

          -  Immunocompromising conditions, as follows:

               -  Known acute or chronic human immunodeficiency virus (HIV) infection with CD4+ T
                  cell count < 350 cells/microliter. Patients with a history of an acquired
                  immunodeficiency syndrome (AIDS)-defining infection can be included if their CD4+
                  T cell count > 350 cells/microliter and have not had an AIDS-defining infection
                  within prior 12 months. If patients are on antiretroviral therapy (ART), it must
                  be started at least 4 weeks prior to trial enrollment and the HIV viral load
                  should be < 400 copies/mL. Medication interactions with ART should be screened
                  prior to enrollment.

               -  History of primary immunodeficiency

               -  History or allogeneic transplant

               -  Current or prior use of immunosuppressive medication within 28 days before the
                  first dose of study treatment, with the exception of topical, ocular, intranasal,
                  and inhaled corticosteroids, or systemic corticosteroids

          -  Any underlying medical condition, which in the opinion of the investigator, will make
             the administration of study drug hazardous or obscure the interpretation of adverse
             events, such as a condition associated with frequent diarrhea, uncontrolled nausea,
             vomiting, malabsorption syndrome or small bowel resection that may significantly alter
             the absorption of lenvatinib, everolimus, or cabozantinib.

          -  Patients receiving any concomitant systemic therapy for renal cell cancer are
             excluded.

          -  Patients must not be scheduled to receive another experimental drug while on this
             study.

          -  Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation in the study such as:

               -  Symptomatic congestive heart failure of New York Heart Association class III or
                  IV

               -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction within 6 months of start of study drug, serious uncontrolled cardiac
                  arrhythmia, or any other clinically significant cardiac disease

               -  Severely impaired lung function as defined as oxygen saturation that is 88% or
                  less at rest on room air

               -  Uncontrolled diabetes as defined by a hemoglobin A1C >= 8%

               -  Systemic fungal, bacterial, viral, or other infection that is not controlled
                  (defined as exhibiting ongoing signs/symptoms related to the infection and
                  without improvement) despite appropriate antibiotics or other treatment.

               -  Liver disease, such as cirrhosis or chronic active hepatitis as defined here. For
                  hepatitis B virus (HBV), a positive test using HBV surface antigen (HBsAg) test.
                  For hepatitis C virus (HCV), patients with a positive HCV antibody test and HCV
                  ribonucleic acid (RNA) positive are excluded. If a patient is receiving HCV
                  curative treatment, they must complete therapy and have HCV RNA below level of
                  detection. For patients with a history of HCV infection, they are eligible if
                  they have completed curative therapy and have HCV viral load below the level of
                  detection.

               -  Uncontrolled blood pressure (systolic blood pressure > 140 mmHg or diastolic
                  blood pressure > 90 mmHg) in spite of optimized regimen of antihypertensive
                  medications.

               -  Subjects having > 1+ proteinuria on urine dipstick testing unless a spot urine
                  protein to creatinine ratio is =< 1 mg/mg

          -  Patients must not have history of other diseases, metabolic dysfunction, physical
             examination finding, or clinical laboratory finding giving reasonable suspicion of a
             disease or condition that contraindicates the use of lenvatinib, everolimus, or
             cabozantinib or that might affect the interpretation of the results of the study or
             render the subject at high risk from treatment complications.

          -  Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree
             of tumor invasion/infiltration of blood vessels should be considered because of the
             risk of severe hemorrhage associated with tumor shrinkage/necrosis following
             lenvatinib treatment.

          -  Any patients who cannot be compliant with the appointments required in this protocol
             must not be enrolled in this study.

          -  Severe hypersensitivity (>= grade 3) to lenvatinib and/or any of its excipients.

          -  Patients with left ventricular ejection fraction < 40%.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:Time from start of study drug until disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed up to 2 years
Safety Issue:
Description:To be compared between lenvatinib + everolimus versus cabozantinib. Monitored using Bayesian optimal phase 2 (BOP2) design with time-to-event endpoint.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:ORR is defined as complete response (CR) plus partial response (PR).
Measure:Disease Control Rate (DCR)
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as CR + PR + stable disease.
Measure:Health-Related Quality of Life (HRQoL)
Time Frame:Up to 2 years
Safety Issue:
Description:Evaluated using standardized questionnaires, including Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (FKSI-19), Patient-Reported Outcomes Measurement Information System (PROMIS)-10, Center for Epidemiologic Studies Depression Scale (CES-D), Social Provisions Scale, and the Finding Meaning in Cancer Scale (FMCS).
Measure:Incidence of grade 3 or 4 adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Measure:Overall survival (OS)
Time Frame:Start of study drug to death due to any cause, assessed up to 2 years
Safety Issue:
Description:OS is compared between lenvatinib + everolimus versus cabozantinib in patients with metastatic renal cell carcinoma who developed progressive disease after 1-2 lines of therapy, including a PD-1/PD-L1 checkpoint inhibitor.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

August 25, 2021