Clinical Trials /

Lenvatinib and Pembrolizumab Before Surgery for the Treatment of Locally Advanced Non-Metastatic Kidney Cancer

NCT04393350

Description:

This phase II trial studies how well lenvatinib and pembrolizumab before surgery work in treating patients with kidney cancer that has spread from its original site of growth to nearby tissues or lymph nodes but has not spread to other places in the body (non-metastatic). Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving lenvatinib and pembrolizumab before surgery may kill more tumor cells.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lenvatinib and Pembrolizumab Before Surgery for the Treatment of Locally Advanced Non-Metastatic Kidney Cancer
  • Official Title: WINSHIP4955-20:Neoadjuvant Lenvatinib With Pembrolizumab in Patients With Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: STUDY00000009
  • SECONDARY ID: NCI-2020-01064
  • SECONDARY ID: Winship4955-20
  • SECONDARY ID: P30CA138292
  • NCT ID: NCT04393350

Conditions

  • Kidney Cancer
  • Stage III Renal Cell Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v8

Interventions

DrugSynonymsArms
LenvatinibE7080, ER-203492-00, Multi-Kinase Inhibitor E7080Treatment (lenvatinib, pembrolizumab)
Lenvatinib Mesylate4-[3-Chloro-4-(N''-cyclopropylureido)phenoxy]7-methoxyquinoline-6-carboxamide Mesylate, E7080, Lenvima, Multi-Kinase Inhibitor E7080Treatment (lenvatinib, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (lenvatinib, pembrolizumab)

Purpose

This phase II trial studies how well lenvatinib and pembrolizumab before surgery work in treating patients with kidney cancer that has spread from its original site of growth to nearby tissues or lymph nodes but has not spread to other places in the body (non-metastatic). Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving lenvatinib and pembrolizumab before surgery may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the objective response rate (complete and partial responses), following the
      administration of lenvatinib and pembrolizumab for a total of 4 cycles (12 weeks) in patients
      with locally-advanced, biopsy-proven non-metastatic clear cell renal cell carcinoma (ccRCC)
      prior to undergoing nephrectomy (partial or radical).

      SECONDARY OBJECTIVES:

      I. To assess the safety and tolerability of neoadjuvant lenvatinib plus pembrolizumab in a
      presurgical population.

      II. To determine the clinical outcomes including disease-free survival (DFS) and overall
      survival (OS) of patients with non-metastatic ccRCC treated with neoadjuvant lenvatinib and
      pembrolizumab.

      III. To evaluate surgery-related complications and outcomes as per the Clavien-Dindo
      classification system.

      EXPLORATORY OBJECTIVES:

      I. To evaluate changes in biomarkers of immune activation and gene expression before, during
      and after treatment.

      II. To assess the quality of life, frailty and sarcopenia of patients before and after
      treatment.

      OUTLINE:

      Patients receive lenvatinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab
      intravenously (IV) over 30 minutes on day 1. Treatments repeat every 21 days for up to 4
      cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up within 14 days, then every 12
      weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lenvatinib, pembrolizumab)ExperimentalPatients receive lenvatinib PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatments repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Lenvatinib
  • Lenvatinib Mesylate
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a renal mass consistent with a clinical stage >= T3Nx or TanyN+ or
             deemed unresectable by surgeon

          -  Renal cell carcinoma with clear cell component on pre-treatment biopsy of the primary
             tumor

          -  The participant (or legally acceptable representative if applicable) provides written
             informed consent and the willingness and ability to comply with all aspects of the
             protocol

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Absolute neutrophil count (ANC) >= 1500/uL (specimens must be collected within 72
             hours prior to the start of study treatment)

          -  Platelets >= 100 000/uL (specimens must be collected within 72 hours prior to the
             start of study treatment)

          -  Hemoglobin >= 9.0 g/dL (specimens must be collected within 72 hours prior to the start
             of study treatment)

               -  Criteria must be met without erythropoietin dependency and without packed red
                  blood cell (pRBC) transfusion within last 4 weeks

          -  International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x upper limit of
             normal (ULN) unless participant is receiving anticoagulant therapy as long as PT or
             activated partial thromboplastin time (aPTT) is within therapeutic range of intended
             use of anticoagulants (specimens must be collected within 72 hours prior to the start
             of study treatment)

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is
             receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
             intended use of anticoagulants (specimens must be collected within 72 hours prior to
             the start of study treatment)

          -  Serum creatinine =< 1.5 x ULN OR measured or calculated creatinine clearance
             (glomerular filtration rate [GFR] can also be used in place of creatinine or
             creatinine clearance [CrCl]) >= 40 mL/min (>= 0.67 mL/sec) for participant with
             creatinine levels > 1.5 x institutional ULN (specimens must be collected within 72
             hours prior to the start of study treatment)

               -  Creatinine clearance (CrCl) calculated per the Cockcroft and Gault formula

          -  Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
             bilirubin levels > 1.5 x ULN (specimens must be collected within 72 hours prior to the
             start of study treatment)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x
             ULN for participants with liver metastases) (specimens must be collected within 72
             hours prior to the start of study treatment)

          -  All females must have a negative serum or urine pregnancy test (minimum sensitivity 25
             IU/L or equivalent units of beta-human chorionic gonadotropin [beta-hCG]) at the
             screening visit and the baseline visit. A pregnancy test needs to be performed within
             72 hours of the first dose of study drug. Women of childbearing potential (WOCBP) must
             agree to use a highly effective method of contraception for the entire study period
             and for 120 days after study discontinuation

          -  Male subjects who are partners of women of childbearing potential must use a condom
             and their female partners of childbearing potential must use a highly effective method
             of contraception beginning at least 1 menstrual cycle prior to starting study drugs,
             throughout the entire study period, and for 120 days after the last dose of study
             drug, unless the male subjects are totally sexually abstinent or have undergone a
             successful vasectomy with confirmed azoospermia or unless the female partners have
             been sterilized surgically or are otherwise proven sterile

        Exclusion Criteria:

          -  Evidence of metastatic disease on pre-treatment imaging

          -  The subject has received of any type of cytotoxic, biologic or other systemic
             anticancer therapy for kidney cancer

          -  The subject has received any other type of investigational agent within 28 days before
             the first dose of study treatment

          -  Excluding the primary tumor leading to enrollment in this study, any other active
             malignancy (except for localized prostate cancer, definitively treated melanoma
             in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the
             bladder or cervix) within the past 24 months

          -  Prior treatment with lenvatinib or any agent directed against PD-1, PD-L1 or PD-L2, or
             another stimulatory or co inhibitory T-cell receptor (e.g. CTLA-4, OX 40, CD137)

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of trial treatment

          -  Subjects having > 1+ proteinuria on urinalysis will undergo 24-hour urine collection
             for quantitative assessment of proteinuria. Subjects with urine protein >= 1 g/24-hour
             will be ineligible

          -  Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition
             that might affect the absorption of lenvatinib

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

               -  Cardiovascular disorders:

                    -  New York Heart Association congestive heart failure of grade II or above,
                       unstable angina, myocardial infarction within the past 6 months, or serious
                       cardiac arrhythmia associated with significant cardiovascular impairment
                       within the past 6 months

                    -  Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm
                       Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
                       treatment

                    -  Prolongation of corrected QT (QTc) interval to > 480 msec per
                       electrocardiogram (ECG) within 28 days before first dose of study treatment

               -  Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of
                  red blood, or other history of significant bleeding (e.g. pulmonary hemorrhage)
                  within 3 weeks prior to the first dose of study drug

               -  Serious non-healing wound/ulcer/bone fracture

               -  History of organ allograft (subject has had an allogenic tissue/solid organ
                  transplant)

          -  Biologic response modifiers (e.g. granulocyte colony-stimulating factor) within 4
             weeks before study entry. Chronic erythropoietin therapy is permitted provided that no
             dose adjustments were made within 2 months before first dose of study treatment

          -  Subjects must have recovered adequately from any toxicity and/or complications from
             major surgery prior to starting therapy

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g. FluMist are live attenuated vaccines and are not allowed

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a known history of active Hepatitis B (e.g., hepatitis B surface antigen [HBsAg])
             or hepatitis C (e.g., HCV RNA qualitative is detected)

          -  Has uncontrolled HIV defined by a CD4+ count < 350 cells/uL, an AIDS-defining
             opportunistic infection within the last 12 months prior to study enrollment or
             documented multidrug resistance that prevents effective HIV therapy

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (complete and partial responses)
Time Frame:Baseline until end of Cycle 1 (4 Cycles (12 weeks)
Safety Issue:
Description:Will assess the proportion of patients with a reduction in overall tumor burden from baseline after 12 weeks of treatment with neoadjuvant lenvatinib and pembrolizumab.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs)
Time Frame:From treatment phase up to 14 day post treatment
Safety Issue:
Description:Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The safety profile of the treatment will be documented and summarized by summary statistics as frequency and percentage for each AE.
Measure:Overall survival (OS)
Time Frame:Up to 4 years after study start
Safety Issue:
Description:OS will be estimated with the Kaplan-Meier method. The OS of each patient group at specific time points such as 6 months, 1 year, 3 years, etc. and will be also estimated alone with 95% confidence interval (CI).
Measure:Disease free survival (DFS)
Time Frame:From time of surgery to the first tumor recurrence, or death, assessed up to 4 years
Safety Issue:
Description:DFS will be estimated with the Kaplan-Meier method. The DFS of each patient group at specific time points such as 6 months, 1 year, 3 years, etc. and will be also estimated alone with 95% CI.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

Last Updated

May 18, 2020