Clinical Trials /

Axitinib and Nivolumab in Treating Patients With Unresectable or Metastatic TFE/Translocation Renal Cell Carcinoma

NCT03595124

Description:

This phase II trial studies how well axitinib and nivolumab works in treating patients with TFE/translocation renal cell carcinoma that cannot be removed by surgery or has spread to other places in the body. Axitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving axitinib and nivolumab may work better in treating patients with TFE/translocation renal cell carcinoma compared to standard treatment, including surgery, chemotherapy, or immunotherapy.

Related Conditions:
  • Renal Cell Carcinoma
  • Translocation-Associated Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Axitinib and Nivolumab in Treating Participants With Unresectable or Metastatic TFE/Translocation Renal Cell Carcinoma
  • Official Title: A Randomized Phase 2 Trial of Axitinib/Nivolumab Combination Therapy vs Single Agent Axitinib or Nivolumab for the Treatment of TFE/Translocation Renal Cell Carcinoma (tRCC) Across All Age Groups

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01489
  • SECONDARY ID: NCI-2018-01489
  • SECONDARY ID: AREN1721
  • SECONDARY ID: AREN1721
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03595124

Conditions

  • Metastatic Renal Cell Carcinoma
  • Renal Cell Carcinoma Associated With Xp11.2 Translocations/TFE3 Gene Fusions
  • Stage III Renal Cell Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v8
  • TFE3 Gene Translocation
  • TFEB Gene Translocation

Interventions

DrugSynonymsArms
AxitinibAG-013736, AG013736, InlytaArm A (axitinib, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (axitinib, nivolumab)

Purpose

This phase II trial studies how well axitinib and nivolumab works in treating participants with TFE/translocation renal cell carcinoma that cannot be removed by surgery or has spread to other places in the body. Axitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving axitinib and nivolumab may work better in treating participants with TFE/translocation renal cell carcinoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the clinical activity of axitinib and/or nivolumab therapy for advanced
      transcription factor E3/translocation morphology renal cell carcinoma (TFE/tRCC).

      SECONDARY OBJECTIVES:

      I. To further define the toxicities of the study arms in the treatment of translocation
      morphology RCC across all ages.

      EXPLORATORY OBJECTIVES:

      I. To characterize tRCC clinical behavior across all age groups. II. To evaluate type of
      antitumor immune response and stability of T cell activation before and after treatment with
      immunotherapy or antiangiogenic therapy.

      III. To develop a tumor bank of tRCC tumor samples treated on study for further biological
      investigations.

      OUTLINE: Participants are randomized to 1 of 3 arms.

      ARM A: Participants receive axitinib orally (PO) twice daily (BID) on days 1-28 and nivolumab
      intravenously (IV) over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for
      up to 26 courses (2 years) in the absence of disease progression or unacceptable toxicity.

      ARM B: Participants receive axitinib PO BID on days 1-28. Treatment repeats every 28 days for
      up to 26 courses (2 years) in the absence of disease progression or unacceptable toxicity.

      ARM C: Participants receive nivolumab IV over 30-60 minutes on days 1 and 15. Treatment
      repeats every 28 days for up to 26 courses (2 years) in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, participants are followed up every 3 months for 1 year,
      every 4 months for 1 year, every 6 months for 2 years. Follow-up at year 5 and beyond is at
      the discretion of the treating physician.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (axitinib, nivolumab)ExperimentalParticipants receive axitinib PO BID on days 1-28 and nivolumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 26 courses (2 years) in the absence of disease progression or unacceptable toxicity.
  • Axitinib
Arm B (axitinib)ExperimentalParticipants receive axitinib PO BID on days 1-28. Treatment repeats every 28 days for up to 26 courses (2 years) in the absence of disease progression or unacceptable toxicity.
  • Axitinib
Arm C (nivolumab)ExperimentalParticipants receive nivolumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 26 courses (2 years) in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients must have a body surface area (BSA) >= 0.53 m^2
    
              -  Histologically confirmed unresectable or metastatic translocation morphology renal
                 cell carcinoma diagnosed using World Health Organization (WHO)-defined criteria.
                 Patients may be newly diagnosed or have received prior cancer therapy
    
                   -  Patients must have had histologic verification of the malignancy
    
                   -  Patients must have measurable disease, documented by clinical, radiographic, or
                      histologic criteria as defined by Response Evaluation Criteria in Solid Tumors
                      (RECIST) version (v)1.1
    
                   -  Patients must have a tumor showing the appropriate morphologic appearance, and
                      either confirmed TFE3 nuclear protein expression by immunohistochemistry with
                      appropriate positive and negative controls performed at a Clinical Laboratory
                      Improvement Act (CLIA)-certified laboratory, or evidence of TFE3 or TFEb
                      translocation by either fluorescence in situ hybridization (FISH) or reverse
                      transcriptase- polymerase chain reaction (RT-PCR) performed at a CLIA-certified
                      laboratory. For TFE3 immunohistochemistry, any nuclear positivity in the presence
                      of appropriate positive and negative controls should be considered as evidence of
                      TFE3 immunohistochemical expression. NOTE: If the institution is unable to
                      perform these studies, unstained slides may be submitted to the study review
                      pathologists, who will perform TFE3 analysis at no charge. The slide will be
                      returned to the referring institution for local evaluation, to be included in
                      their institutional report
    
              -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
                 Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
                 Lansky for patients =< 16 years of age
    
              -  Patients must have a life expectancy of >= 8 weeks
    
              -  Patients must have fully recovered from the acute toxic effects of all prior
                 chemotherapy, immunotherapy, or radiotherapy prior to entering this study
    
                   -  Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry
                      onto this study (6 weeks if prior nitrosourea)
    
                   -  Immunotherapy: Must not have received within 4 weeks of entry onto this study
    
                   -  Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
                      with a biologic agent
    
                   -  Radiation therapy (RT): >= 2 weeks for local palliative RT (small port); >= 6
                      months must have elapsed if prior craniospinal RT or if >= 50% radiation of
                      pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM)
                      radiation
    
                   -  Prior therapy with tyrosine kinase inhibitors (TKIs) that have no known activity
                      against VEGFR1-3 are permitted
    
              -  Peripheral absolute neutrophil count (ANC) >= 1000/uL
    
              -  Platelet count >= 75,000/uL (transfusion independent)
    
              -  Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
    
              -  Urine protein: =< 30 mg/dL in urinalysis or =< 1+ on dipstick, unless quantitative
                 protein is < 1000 mg in a 24 hours (h) urine sample
    
              -  For patients < 18 years of age: Serum creatinine =< 1.5 X upper limit of normal (ULN),
                 or measured or calculated creatinine clearance or radioisotope glomerular filtration
                 rate (GFR) >= 60 mL/min/1.73 m^2 for patient with creatinine levels > 1.5 X
                 institutional ULN, or a serum creatinine based on age/gender as follows:
    
                   -  1 to < 2 years - 0.6 mg/dL (male, female)
    
                   -  2 to < 6 years - 0.8 mg/dL (male, female)
    
                   -  6 to < 10 years - 1 mg/dL (male, female)
    
                   -  10 to < 13 years - 1.2 mg/dL (male, female)
    
                   -  13 to < 16 years - 1.5 mg/dL (male), 1.4 mg/dL (female)
    
                   -  >= 16 years - 1.7 mg/dL (male), 1.4 mg/dL (female)
    
              -  For patients >= 18 years of age: Serum creatinine =< 2 X ULN, or measured or
                 calculated creatinine clearance or radioisotope GFR >= 40 mL/min/1.73 m^2 for patient
                 with creatinine levels > 2 X institutional ULN
    
              -  Serum total bilirubin =< 1.5 X ULN for age, or direct bilirubin =< ULN for patients
                 with total bilirubin levels > 1.5 X ULN
    
              -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
                 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 X
                 ULN for age
    
              -  Albumin > 2.5 mg/dL
    
              -  Shortening fraction of >= 27% by echocardiogram, or
    
              -  Ejection fraction of >= 50% by radionuclide angiogram
    
              -  No history of myocardial infarction, severe or unstable angina, or peripheral vascular
                 disease
    
              -  Corrected QT (QTc) =< 480 msec. Note: Patients with grade 1 prolonged QTc (450-480
                 msec) at the time of study enrollment should have correctable causes of prolonged QTc
                 addressed if possible (i.e., electrolytes, medications)
    
              -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN. However,
                 if patient is receiving anticoagulant therapy, PT or partial thromboplastin time (PTT)
                 should be within therapeutic range of intended use of anticoagulants
    
              -  Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless patient is receiving
                 anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
                 of anticoagulants
    
              -  A baseline blood pressure (BP) =< the 95th percentile for age, height, and gender for
                 patients < 18 years old, or =< 150 mmHg (systolic) and =< 90 mmHg (diastolic) for
                 patients >= 18 years old
    
                   -  Note: 2 serial blood pressures should be taken at least 1 hour apart and averaged
                      to determine baseline BP
    
              -  Patients are eligible if on stable doses (>= 7 days) of anti-hypertensive medications
                 with a baseline BP meeting the criteria above
    
            Exclusion Criteria:
    
              -  Patients unable to swallow whole tablets
    
              -  Patients who in the opinion of the investigator are not able to comply with the study
                 procedures are not eligible
    
              -  Prior Therapy
    
                   -  Patients who have received prior therapy with axitinib or nivolumab or other VEGF
                      or PD1/PD-L1 targeted therapies
    
                   -  Patients with hypersensitivity to axitinib, nivolumab, or any of its excipients
    
                   -  Patients who previously received an allogeneic stem cell transplant (SCT) or
                      solid organ transplant are not eligible
    
                   -  Patients may not be receiving any other investigational agents (within 4 weeks
                      prior to study enrollment)
    
                   -  Patients who have received prior anti-cancer monoclonal antibody (mAb) within 4
                      weeks prior to study enrollment or who have not recovered (i.e., =< grade 1 or at
                      baseline) from adverse events due to agents administered more than 4 weeks prior
                      to enrollment
    
                   -  Surgery: Patients who have had or who are planning to have the following invasive
                      procedures are not eligible:
    
                        -  Major surgical procedure, laparoscopic procedure, open biopsy, core biopsy,
                           fine needle aspirate, or significant traumatic injury within 7 days prior to
                           enrollment. NOTE: External central lines must be placed at least 3 days
                           prior to planned treatment initiation and subcutaneous ports must be placed
                           at least 7 days prior to planned treatment initiation
    
                        -  Patients who have a serious or non-healing wound or ulcer at the time of
                           study enrollment are not eligible
    
                        -  Patients who have a history of abdominal fistula, gastrointestinal
                           perforation, or intra-abdominal abscess within 28 days of study enrollment
                           are not eligible
    
                        -  Patients who have received prior targeted small molecule therapy within 2
                           weeks of enrollment or have not recovered (i.e., =< grade 1 or at baseline)
                           from adverse events due to agents administered more than 4 weeks prior to
                           enrollment. NOTE: Subjects with =< grade 2 neuropathy are an exception to
                           this criterion and may qualify for the study
    
              -  Pre-existing conditions, which may include:
    
                   -  Additional known malignancy that is progressing or requires active treatment.
                      Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma
                      of the skin that has undergone potentially curative therapy, or in situ cervical
                      cancer
    
                   -  Patients with underlying immune deficiency, chronic infections including
                      hepatitis, tuberculosis (TB), or autoimmune disease
    
                   -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
                      therapy with undetectable viral load within 6 months are eligible for this trial
    
                   -  Patients with underlying hematologic issues including congenital bleeding
                      diathesis, known previous gastrointestinal (GI) bleeding requiring intervention
                      within the past 6 months, history of hemoptysis within 42 days prior to study
                      enrollment, active pulmonary emboli, or deep vein thromboses (DVT) that are not
                      stable on anticoagulation regimen
    
                   -  Patients must not have had significant vascular disease (i.e. Moya-Moya, aortic
                      aneurysm requiring surgical repair)
    
                   -  A known history of, or any evidence of active, non-infectious pneumonitis
    
                   -  Patients with known active central nervous system (CNS) metastases and/or
                      carcinomatous meningitis or leptomeningeal disease. Patients with previously
                      treated brain metastases may participate provided they are stable (without
                      evidence of progression by imaging for at least 4 weeks prior to study enrollment
                      and any neurologic symptoms have returned to baseline), have no evidence of new
                      or enlarging brain metastases, and are not using steroids for at least 7 days
                      prior to study enrollment. This exception does not include carcinomatous
                      meningitis which is excluded regardless of clinical stability
    
                   -  Any uncontrolled, intercurrent illness including but not limited to ongoing or
                      active infection, symptomatic congestive heart failure, unstable angina pectoris,
                      cardiac arrhythmia
    
                   -  Any serious medical or psychiatric illness/condition including substance use
                      disorders likely in the judgment of the investigator(s) to interfere or limit
                      compliance with study requirements/treatment
    
                   -  Patients with 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
    
              -  Treatments and/or medications the patient is receiving or has received that would make
                 her/him ineligible, including:
    
                   -  Concomitant (or receipt of) treatment with medications that may affect the
                      metabolism of nivolumab and/or axitinib within 7 days prior to planned first dose
                      of protocol therapy
    
                   -  A live vaccine within 30 days of planned first dose of protocol therapy. NOTE:
                      Inactivated flu vaccines are allowed; however intranasal influenza vaccines
                      (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
    
              -  Pregnancy and breast feeding
    
                   -  Due to risks of fetal and teratogenic adverse events as seen in animal studies, a
                      negative pregnancy test must be obtained in females of childbearing potential,
                      defined as females who are post-menarchal. If the urine test is positive or
                      cannot be confirmed as negative, a serum pregnancy test will be required
    
                   -  Females of childbearing potential that are sexually active must agree to either
                      practice 2 medically accepted highly-effective methods of contraception at the
                      same time or abstain from heterosexual intercourse from the time of signing the
                      informed consent through 5 months after the last dose of study drug
    
                   -  Lactating females are not eligible unless they have agreed not to breastfeed
                      their infants starting with the first dose of study therapy through 5 months
                      after the last dose of study therapy
    
              -  Male patients must agree to use an adequate method of contraception starting with the
                 first dose of study therapy through 7 months after the last dose of study therapy.
                 Prior history of vasectomy does not replace requirement for contraceptive use
    
              -  Regulatory requirements
    
                   -  All patients and/or their parents or legal guardians must sign a written informed
                      consent
    
                   -  All institutional, Food and Drug Administration (FDA), and National Cancer
                      Institute (NCI) requirements for human studies must be met
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:12 Months
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression free survival
    Time Frame:From initiation of treatment assessed up to 4 years
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated