Clinical Trials /

Pembrolizumab With or Without Axitinib for Treatment of Locally Advanced or Metastatic Clear Cell Kidney Cancer in Patients Undergoing Surgery

NCT04370509

Description:

This phase II trial studies how well pembrolizumab with or without standard of care axitinib works in treating patients with clear cell kidney cancer that has spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic) who are undergoing surgery. Pembrolizumab is an antibody that is designed to bind to and block the activity of PD-1, a molecule in the body that may be responsible for inhibiting the body's immune response against cancer cells. Axitinib is a type of drug known as a tyrosine kinase inhibitor. Tyrosine kinase inhibitors work by blocking enzymes called tyrosine kinases. These enzymes may be too active or found at high levels in some types of cancer cells and blocking them may help keep cancer cells from growing. Giving pembrolizumab with or without axitinib may work better in controlling the cancer and decrease the likelihood of it coming back following surgery in patients with kidney cancer compared to usual treatment (surgery followed by chemotherapy and/or radiation therapy).

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab With or Without Axitinib for Treatment of Locally Advanced or Metastatic Clear Cell Kidney Cancer in Patients Undergoing Surgery
  • Official Title: A Phase II Study of Perioperative Pembrolizumab-Based Therapy in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Prior to Cytoreductive Nephrectomy or Metastasectomy

Clinical Trial IDs

  • ORG STUDY ID: 197017
  • SECONDARY ID: NCI-2020-02128
  • NCT ID: NCT04370509

Conditions

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

Interventions

DrugSynonymsArms
AxitinibAG-013736, AG013736, InlytaCohort B (pembrolizumab, axitinib, CN, MET)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Cohort A (pembrolizumab, cytoreductive nephrectomy (CN), MET)

Purpose

This phase II trial studies how well pembrolizumab with or without standard of care axitinib works in treating patients with clear cell kidney cancer that has spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic) who are undergoing surgery. Pembrolizumab is an antibody that is designed to bind to and block the activity of PD-1, a molecule in the body that may be responsible for inhibiting the body's immune response against cancer cells. Axitinib is a type of drug known as a tyrosine kinase inhibitor. Tyrosine kinase inhibitors work by blocking enzymes called tyrosine kinases. These enzymes may be too active or found at high levels in some types of cancer cells and blocking them may help keep cancer cells from growing. Giving pembrolizumab with or without axitinib may work better in controlling the cancer and decrease the likelihood of it coming back following surgery in patients with kidney cancer compared to usual treatment (surgery followed by chemotherapy and/or radiation therapy).

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the impact of pembrolizumab-based therapy on the composition, phenotype, and
      function of tumor-infiltrating immune cells (TIICs) in subjects with advanced renal cell
      carcinoma (RCC) undergoing cytoreductive nephrectomy (CN)/metastasectomy (MET).

      SECONDARY OBJECTIVES:

      I. To determine the clinical efficacy of preoperative pembrolizumab-based therapy in subjects
      with advanced RCC undergoing CN/MET.

      II. To explore the clinical efficacy of continued pembrolizumab-based therapy following
      CN/MET in subjects with advanced RCC.

      III. To determine the safety and tolerability of pembrolizumab-based therapy in subjects with
      advanced RCC undergoing CN/MET.

      EXPLORATORY OBJECTIVES:

      I. To explore the clinical efficacy of preoperative pembrolizumab-based therapy in subjects
      with advanced RCC, by pathologic response. (Clinical) II. To explore the relationship between
      changes in TIICs and clinical efficacy in subjects with advanced RCC treated with
      pembrolizumab-based therapy. (Scientific) III. To characterize changes in the frequency and
      number of circulating T cells induced by pembrolizumab-based therapy in subjects with
      advanced RCC. (Scientific) IV. To determine the impact of pembrolizumab-based therapy on the
      composition and phenotype of the tumor microenvironment (including tumor and stromal cells)
      in subjects with advanced RCC. (Scientific) V. To determine whether locally advanced versus
      metastatic RCC exhibit differences in immune composition or phenotype at baseline and in
      response to pembrolizumab-based therapy. (Scientific) VI. To determine the change in T cell
      repertoire within the tumor and blood induced by pembrolizumab-based therapy in subjects with
      advanced RCC. (Scientific) VII. To explore molecular profiles to identify potentially
      predictive biomarkers for subjects with advanced RCC treated with immunotherapy (Scientific)

      OUTLINE: Patients are sequentially assigned to 1 of 2 cohorts.

      COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
      Treatment repeats every 21 days for 3 cycles in the absence of disease progression or
      unacceptable toxicity. Within 14-21 days following the end of treatment, patients undergo
      standard of care CN or MET. Patients with progressive disease (PD) may undergo CN or MET per
      physician discretion. Within 21-42 days after surgery, patients with no disease (R0
      resection) or microscopic disease (R1 resection) receive pembrolizumab IV every 21 days for
      up to 18 cycles (1 year) and patients with macroscopic disease (R2 resection) receive
      pembrolizumab IV every 21 days for up to 36 cycles (2 years) in the absence of disease
      progression or unacceptable toxicity.

      COHORT B: Patients receive pembrolizumab IV over 30 minutes on day 1 and standard of care
      axitinib orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for 3
      cycles in the absence of disease progression or unacceptable toxicity. Within 14-21 days
      following the end of treatment, patients undergo standard of care CN or MET. Patients with PD
      may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients
      with an R0 or R1 resection receive pembrolizumab IV and axitinib PO BID every 21 days for up
      to 18 cycles (1 year), and patients with an R2 resection receive pembrolizumab IV and
      axitinib PO BID every 21 days for up to 36 cycles (2 years) in the absence of disease
      progression or unacceptable toxicity.

      Follow-up will occur at treatment discontinuation, 30 days post-discontinuation, and then
      every 12 weeks for up to 1 year post-discontinuation.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A (pembrolizumab, cytoreductive nephrectomy (CN), MET)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 14-21 days following the end of treatment, patients undergo standard of care CN or MET. Patients with PD may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients with R0 resection or R1 resection receive pembrolizumab IV every 21 days for up to 18 cycles (1 year) and patients with R2 resection receive pembrolizumab IV every 21 days for up to 36 cycles (2 years) in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
Cohort B (pembrolizumab, axitinib, CN, MET)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and standard of care axitinib PO BID on days 1-21. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 14-21 days following the end of treatment, patients undergo standard of care CN or MET. Patients with PD may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients with an R0 or R1 resection receive pembrolizumab IV and axitinib PO BID every 21 days for up to 18 cycles (1 year), and patients with an R2 resection receive pembrolizumab IV and axitinib PO BID every 21 days for up to 36 cycles (2 years) in the absence of disease progression or unacceptable toxicity.
  • Axitinib
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed renal cell carcinoma (RCC) with a clear cell component

          -  Locally advanced or metastatic disease (primary intact or status post nephrectomy with
             recurrent disease)

          -  Planned CN and/or MET

          -  Availability of pre-treatment tumor specimen:

               -  Archival, diagnostic tissue specimen is permissible, if:

                    -  Obtained within 120 days of study enrollment

                    -  Assessed by the principal investigator (PI) to be adequate for planned
                       analyses

                    -  Core biopsy, nephrectomy, or MET specimen; fine needle aspirate (FNA)
                       specimens are not acceptable

               -  Fresh tumor specimen acquisition: participants who do not have archival tissue
                  adequate for planned analyses must consent to fresh tumor specimen acquisition

                    -  Core biopsy, nephrectomy, or MET specimen

                         -  Participants who undergo nephrectomy or MET prior to study enrollment
                            are still eligible for the study, as long as they still have measurable
                            disease (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1)
                            that is amenable to CN or MET

                    -  FNA specimens are not acceptable

          -  Measurable disease per RECIST 1.1 as assessed by the investigator. Lesions situated in
             a previously irradiated area are considered measurable if progression has been
             demonstrated in such lesions

          -  Subject (or legally acceptable representative if applicable) must provide written
             informed consent for the trial

          -  Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Absolute neutrophil count (ANC) >= 1,500/microliter (uL) (within 10 days of treatment
             initiation)

          -  Platelets >= 100,000/uL (within 10 days of treatment initiation)

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment)

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
             creatinine clearance (CrCl) (glomerular filtration rate (GFR) can also be used in
             place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 x
             institutional ULN (within 10 days of treatment initiation)

               -  Creatinine clearance should be calculated per institutional standard

          -  Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with
             total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 2.5 x
             ULN (within 10 days of treatment initiation)

          -  Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             subject is receiving anticoagulant therapy as long as PT or activated partial
             thromboplastin time (aPTT) is within therapeutic range of intended use of
             anticoagulants (within 10 days of treatment initiation)

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
             anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended
             use of anticoagulants (within 10 days of treatment initiation)

          -  Negative urine or serum pregnancy test within 72 hours prior to receiving the first
             dose of study medication (day 1) (female participants of childbearing potential). If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required

          -  Male and female participants of childbearing potential must be willing to use an
             adequate method of contraception* for the course of the study through 120 days after
             the last dose of study medication

               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the subject

        Exclusion Criteria:

          -  RCC WITHOUT a clear cell component

          -  Prior systemic therapy for the treatment of RCC

          -  No measurable disease (e.g. only bone metastases)

          -  Not a candidate for CN and/or MET

          -  Currently participating in or has participated in a study of an investigational agent
             or has used an investigational device within 4 weeks prior to the first dose of study
             treatment

               -  Note: Participants who have entered the follow-up phase of an investigational
                  study may participate as long as it has been 4 weeks since the last dose of the
                  previous investigational agent

          -  Diagnosis of immunodeficiency or 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 trial treatment

          -  Known history of active Bacillus tuberculosis (TB)

          -  Severe hypersensitivity (>= grade 3) to pembrolizumab/axitinib or any of their
             excipients

          -  Prior systemic anti-cancer monoclonal antibody (mAb), targeted small molecule therapy,
             or radiation therapy within 2 weeks prior to the first dose of study treatment (day 1)

               -  Note: Participants must have recovered from all adverse events (AEs) due to
                  previous therapies to =< grade 1 or baseline. Participants with =< grade 2
                  neuropathy may be eligible

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting study
                  treatment

               -  Participants must have recovered from all radiation-related toxicities, not
                  require corticosteroids, and not have had radiation pneumonitis. A 1-week washout
                  is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central
                  nervous system (CNS) disease

          -  Known additional malignancy that is progressing or has required active treatment
             within the past 2 years

               -  Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
                  of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in
                  situ) that have undergone potentially curative therapy are not excluded

          -  Known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment. This exception does not include carcinomatous
             meningitis, which is excluded regardless of clinical stability

          -  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 and is allowed

          -  History of (non-infectious) pneumonitis that required treatment with steroids or has
             current pneumonitis

          -  Active infection requiring systemic therapy

          -  Any arterial thromboembolic events, including but not limited to myocardial
             infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
             within 6 months prior to randomization

          -  Uncontrolled or poorly controlled hypertension despite standard medical therapy

          -  Serious or nonhealing wound, ulcer, or bone fracture within 28 days of study
             enrollment

          -  History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the trial, interfere with the subject's participation
             for the full duration of the trial, or is not in the best interest of the subject to
             participate, in the opinion of the treating investigator

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial

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

          -  Any prior therapy with an anti-PD-1, anti-PD-L1,or anti-PD-L2 agent or with an agent
             directed to another stimulatory or co-inhibitory T cell receptor (e.g., cytotoxic
             T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)

          -  Known history of human immunodeficiency virus (HIV) infection. No HIV testing is
             required unless mandated by local health authority

          -  Known history of hepatitis B (defined as hepatitis B surface antigen reactive) or
             known active hepatitis C virus (defined as hepatitis C virus (HCV) ribonucleic acid
             (RNA) [qualitative] is detected) infection. No testing for hepatitis B and hepatitis C
             is required unless mandated by local health authority

          -  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

          -  History of grade 3-4 gastrointestinal (GI) bleeding within 12 weeks prior to study
             enrollment

          -  Solid organ or hematologic transplant

          -  Encephalopathy in the last 6 months. Those participants on rifaximin or lactulose to
             control their encephalopathy are not allowed

          -  Evident ascites on physical examination

               -  Note: Medically controlled ascites and ascites detectable on imaging studies only
                  is allowed

          -  Female of childbearing potential who has a positive urine pregnancy test within 72
             hours prior to allocation. If the urine test is positive or cannot be confirmed as
             negative, a serum pregnancy test will be required

          -  Has had an allogenic tissue/solid organ transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of subjects with >= 2-fold increase in the number of tumor-infiltrating immune cells (TIICs)
Time Frame:Baseline to cytoreductive nephrectomy (CN)/metastasectomy (MET), up to 1 year
Safety Issue:
Description:TIICs will be analyzed by immunohistochemistry (IHC) in pre- and post-pembrolizumab-based treatment tumor specimens. The proportion of subjects with a >=2-fold increase (from pre- to post-treatment) in the number of TIICs will be calculated.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Up to 1 year
Safety Issue:
Description:Will be defined as complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors 1.1 and described with descriptive statistics.
Measure:Disease-Free Survival Rate (DFS)
Time Frame:Up to 2 years
Safety Issue:
Description:In participants who achieve CR, PR or stable disease (SD) followed by R0 resection, proportion of participants who remain disease-free at the end of the 1 year continued treatment period (1-year DFS rate), and at 1 year following the end of the continued treatment period (2-year DFS rate)
Measure:Median DFS
Time Frame:Up to 2 years
Safety Issue:
Description:In participants who achieve CR, PR or stable disease (SD) followed by R0 resection, median time participants remain disease-free will be reported using the Kaplan-Meier estimate.
Measure:Progression-free survival rate (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:In participants who achieve PR/SD with residual disease following CN/MET, proportion of subjects who remain progression-free at the end of the 1 year continued treatment period (1-year PFS rate) and at 1 year following the end of the continued treatment period (2-year PFS rate)
Measure:Median PFS
Time Frame:Up to 2 years
Safety Issue:
Description:In participants who achieve CR, PR or stable disease (SD) followed by R0 resection, median time participants remain progression-free will be reported using the Kaplan-Meier estimate.
Measure:Incidence of treatment-related adverse events
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Will be reported with descriptive statistics. Will be assessed and reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

April 28, 2020