Clinical Trials /

A Study to Compare Treatments for a Type of Kidney Cancer Called TFE/Translocation Renal Cell Carcinoma (tRCC)

NCT03595124

Description:

This phase II trial studies how well axitinib and nivolumab work in treating patients with TFE/translocation renal cell carcinoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). 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:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Compare Treatments for a Type of Kidney Cancer Called TFE/Translocation Renal Cell Carcinoma (tRCC)
  • Official Title: A Randomized Phase 2 Trial of Axitinib/Nivolumab Combination Therapy vs. Single Agent 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
  • Unresectable Renal Cell Carcinoma

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 work in treating patients with TFE/translocation renal cell carcinoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). 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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To establish the clinical activity, assessed primarily by progression-free survival, of
      nivolumab therapy with or without axitinib for advanced transcription factor E3/translocation
      morphology renal cell carcinoma (TFE/tRCC).

      SECONDARY OBJECTIVE:

      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: Patients are now randomized to 1 of 2 arms - Arm A or Arm C.

      ARM A: Patients receive axitinib orally (PO) twice daily (BID) on days 1-28 and nivolumab
      intravenously (IV) over 30 minutes, or per institutional guidelines, on days 1 and 15 (if <
      18 years old) or on day 1 (if >= 18 years old). Treatment repeats every 28 days for up to 26
      cycles (2 years) in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive axitinib PO BID on days 1-28. Treatment repeats every 28 days for up
      to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity.
      (CLOSED TO ACCRUAL AS OF 1/23/2020 - PROSPECTIVE PATIENTS ARE RANDOMLY ASSIGNED TO ARMS A OR
      C)

      ARM C: Patients receive nivolumab IV over 30 minutes, or per institutional guidelines, on
      days 1 and 15 (if < 18 years old) or on day 1 (if >= 18 years old). Treatment repeats every
      28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year,
      every 4 months for 1 year, and 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)ExperimentalPatients receive axitinib PO BID on days 1-28 and nivolumab intravenously (IV) over 30 minutes, or per institutional guidelines, on days 1 and 15 (if < 18 years old) or on day 1 (if >= 18 years old). Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity.
  • Axitinib
  • Nivolumab
Arm B (axitinib)ExperimentalPatients receive axitinib PO BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. (CLOSED TO ACCRUAL AS OF 1/23/2020 - PROSPECTIVE PATIENTS ARE RANDOMLY ASSIGNED TO ARMS A OR C)
  • Axitinib
Arm C (nivolumab)ExperimentalPatients receive nivolumab IV over 30 minutes, or per institutional guidelines, on days 1 and 15 (if < 18 years old) or on day 1 (if >= 18 years old). Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity.
  • Nivolumab

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 Dr. Elizabeth
                  Perlman, 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

          -  Peripheral absolute neutrophil count (ANC) >= 1000/uL (performed within 7 days prior
             to enrollment)

          -  Platelet count >= 75,000/uL (transfusion independent) (performed within 7 days prior
             to enrollment)

          -  Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performed
             within 7 days prior to enrollment)

          -  Urine protein: =< 30 mg/dL in urinalysis or =< 1+ on dipstick, unless quantitative
             protein is < 1000 mg in a 24 hours (h) urine sample (performed within 7 days prior to
             enrollment)

          -  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 (performed
             within 7 days prior to enrollment):

               -  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)

               -  Creatinine clearance should be calculated per institutional standard

          -  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 (performed within 7 days prior to
             enrollment)

               -  Creatinine clearance should be calculated per institutional standard

          -  Serum total bilirubin =< 1.5 x ULN for age, or direct bilirubin =< ULN for patients
             with total bilirubin levels > 1.5 X ULN (performed within 7 days prior to enrollment)

          -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
             serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x
             ULN for age (performed within 7 days prior to enrollment)

          -  Albumin > 2.5 mg/dL (performed within 7 days prior to enrollment)

          -  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, nivolumab, or other
                  PD1/PD-L1 targeted therapies

               -  Patients who have received prior therapy with more than one anti VEGF based agent
                  (antibody or tyrosine kinase inhibitor)

               -  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 are planning cytoreductive surgery within the first 12 weeks
                       following therapy 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 with the exception of
                  patients on an effective anti-retroviral therapy with an undetectable viral load
                  within 6 months prior to enrollment

               -  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 of reproductive potential 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 randomization to the earliest of disease progression (according to Response Evaluation Criteria in Solid Tumors adapted for immunotherapy) or death due to any cause, assessed up to 4 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From randomization to death due to any cause, assessed up to 4 years
Safety Issue:
Description:A stratified, one-sided log-rank test (using the stratification factors at randomization, age and prior therapy) will be performed to compare treatment arms with alpha = 0.05. Cox proportional hazards models will also be fit to evaluate the final hazard ratio between the treatment arms, with exploratory modeling taking into account the potential influence of other factors (e.g., baseline disease burden, upfront versus delayed nephrectomy). From these models, the hazard ratio for treatment assignment will be reported with a 90% confidence interval (to align with the overall alpha level of the primary log-rank test).
Measure:Overall response rate (ORR)
Time Frame:Up to 4 years
Safety Issue:
Description:Will be defined as the rate of complete or partial responses (assessed by imaging) among patients who initiated protocol therapy and completed at least one subsequent imaging assessment. A logistic regression model for overall response, stratified by the stratification factors used at randomization (age and prior therapy) will be fit, including treatment arm as a key covariate. From this model, the odds ratio for treatment arm will be reported with a 90% confidence interval. The ORR observed within each treatment arm will also be reported.
Measure:Incidence of adverse events (AEs)
Time Frame:Within 30 days of treatment discontinuation
Safety Issue:
Description:All grade 3 non-hematologic toxicities and all grade 4-5 or higher adverse events occurring during protocol therapy or within 30 days of treatment discontinuation will be analyzed. The rates of these events will be reported separately by treatment arm with 95% exact confidence intervals, both by individual AE and class of AE (e.g., hematologic). Given that some AEs may be rare, Fisher Exact tests will be used to test for statistical significance among any apparent differences by treatment arm.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 8, 2021