Clinical Trials /

Nivolumab in Treating Patients With High-Risk Kidney Cancer Before Surgery

NCT02595918

Description:

This pilot phase I trial studies the side effects of nivolumab and how well it works in treating patients with high-risk kidney cancer before surgery. 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.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab in Treating Patients With High-Risk Kidney Cancer Before Surgery
  • Official Title: A Pilot Study of Preoperative Nivolumab in High-Risk Non-Metastatic and Metastatic Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01913
  • SECONDARY ID: NCI-2015-01913
  • SECONDARY ID: 16-195 A(1)
  • SECONDARY ID: 16-195
  • SECONDARY ID: 9913
  • SECONDARY ID: 9913
  • SECONDARY ID: P30CA008748
  • NCT ID: NCT02595918

Conditions

  • Clear Cell Renal Cell Carcinoma
  • Metastatic Renal Cell Carcinoma
  • Stage I Renal Cell Cancer AJCC v6 and v7
  • Stage II Renal Cell Cancer AJCC v7
  • Stage III Renal Cell Cancer AJCC v7
  • Stage IV Renal Cell Cancer AJCC v7

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab)

Purpose

This pilot phase I trial studies the side effects of nivolumab and how well it works in treating patients with high-risk kidney cancer before surgery. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To study the safety and feasibility of preoperative nivolumab administration in subjects
      with resectable, high-risk, non-metastatic and metastatic renal cell carcinoma undergoing
      planned cytoreductive nephrectomy or metastasectomy.

      SECONDARY OBJECTIVES:

      I. To assess overall response rate in patients receiving preoperative nivolumab.

      II. To assess recurrence free survival at 2 years in patients receiving preoperative
      nivolumab in patients with high-risk, non-metastatic disease.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the association between baseline tumor mutational burden and both immune
      infiltration and radiographic tumor response to nivolumab.

      II. To explore predicted and expressed tumor neoantigens and their correlation with
      radiographic tumor response to nivolumab.

      III. To explore the association between the predicted immune signature (via ribonucleic acid
      sequencing [RNAseq]) in the tumor microenvironment with radiographic tumor response to
      nivolumab.

      IV. To determine whether changes in the tumor microenvironment before, during, and after
      therapy are associated with response.

      V. To assess the potential association between PD-L1 expression (by immunohistochemistry
      [IHC]) and radiographic tumor response to nivolumab.

      OUTLINE:

      Patients receive nivolumab intravenously (IV) over 60 minutes on days -56, -42, -28, and -14
      in the absence of disease progression or unacceptable toxicity. Patients then undergo
      nephrectomy or metastasectomy on day 0.

      After completion of study treatment, patients are followed up at 14-28 days, at 90 days, and
      then at 24-28 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab)ExperimentalPatients receive nivolumab IV over 60 minutes on days -56, -42, -28, and -14 in the absence of disease progression or unacceptable toxicity. Patients then undergo nephrectomy or metastasectomy on day 0.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed clear cell renal cell
             carcinoma (RCC)

          -  For non-metastatic patients, the preoperative Memorial Sloan-Kettering (MSK) nomogram
             estimates the patient's likelihood of freedom from metastatic recurrence within the
             first 12 years following radical or partial nephrectomy to be =< 80%

          -  Measurable disease, defined as at least one lesion that can be accurately measured in
             at least one dimension (longest diameter to be recorded for non-nodal lesions and
             short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as
             >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance
             imaging (MRI), or calipers by clinical exam

          -  Non-metastatic disease will be defined by no evidence of metastases other than
             regional lymphadenopathy as assessed by imaging of the chest, abdomen and pelvis with
             CT of the chest and CT or MRI of the abdomen; regional lymph nodes, per 7th edition
             American Joint Committee on Cancer (AJCC) staging manual (2010) for kidney cancer,
             include the following positions: renal hilar, precaval, paracaval, retrocaval,
             interaortocaval, paraaortic, preaortic, and retroaortic

          -  Scheduled to undergo nephrectomy or metastasectomy as part of treatment plan, per
             assessment through an MSK urologic surgeon or medical oncologist listed as
             investigator on this trial

          -  Availability of a frozen biopsy core prior to cycle 1, day 1

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >=
             80%)

          -  Leukocytes >= 2,500/mcL

          -  Absolute neutrophil count >= 1,500/mcL (without granulocyte colony-stimulating factor
             support within 2 weeks prior to cycle 1, day 1)

          -  Platelets >= 100,000/mcL (without transfusion within 2 weeks prior to cycle 1, day 1)

          -  Hemoglobin >= 9.0 g/dL (patients may be transfused to meet this criterion)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
             with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x ULN

          -  Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the
             Cockcroft-Gault formula)

          -  The effects of nivolumab on the developing human fetus are unknown; for this reason,
             women of child-bearing potential (WOCBP) and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry and for the duration of study participation; WOCBP should use an adequate method
             to avoid pregnancy for 23 weeks after the last dose of investigational drug; women of
             childbearing potential must have a negative serum or urine pregnancy test (minimum
             sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within
             14 days prior to the start of nivolumab; women must not be breastfeeding; men who are
             sexually active with WOCBP must use any contraceptive method with a failure rate of
             less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP
             will be instructed to adhere to contraception for a period of 31 weeks after the last
             dose of investigational product; women who are not of childbearing potential (i.e.,
             who are postmenopausal or surgically sterile as well as azoospermic men) do not
             require contraception

          -  Women of childbearing potential (WOCBP) is defined as any female who has experienced
             menarche and who has not undergone surgical sterilization (hysterectomy or bilateral
             oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12
             months of amenorrhea in a woman over 45 in the absence of other biological or
             physiological causes; in addition, women under the age of 55 must have a documented
             serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL

          -  WOCBP receiving nivolumab will be instructed to adhere to contraception for a period
             of 23 weeks after the last dose of investigational product; men receiving nivolumab
             and who are sexually active with WOCBP will be instructed to adhere to contraception
             for a period of 31 weeks after the last dose of investigational product; these
             durations have been calculated using the upper limit of the half-life for nivolumab
             (25 days) and are based on the protocol requirement that WOCBP use contraception for 5
             half-lives plus 30 days and men who are sexually active with WOCBP use contraception
             for 5 half-lives plus 90 days

          -  Should a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she (or the participating partner) should inform the
             treating physician immediately

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Prior receipt of systemic checkpoint inhibitor therapy for renal cell carcinoma

          -  Inability to safely delay surgery by 8 weeks as per surgeon's discretion

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to nivolumab

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because nivolumab has a potential for
             teratogenic or abortifacient effects; because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with
             nivolumab, breastfeeding should be discontinued if the mother is treated with
             nivolumab

          -  Patients should be excluded if they have known history of testing positive for human
             immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

          -  Patients should be excluded if they have a positive test for hepatitis B virus surface
             antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or
             chronic infection

          -  Patients with active autoimmune disease or history of autoimmune disease that might
             recur, which may affect vital organ function or require immune suppressive treatment
             including systemic corticosteroids, should be excluded; these include but are not
             limited to patients with a history of immune related neurologic disease, multiple
             sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
             gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
             connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
             ulcerative colitis, hepatitis; and patients with a history of toxic epidermal
             necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
             excluded because of the risk of recurrence or exacerbation of disease; patients with
             rheumatoid arthritis and other arthropathies, Sjogren's syndrome, psoriasis controlled
             with topical medication, and patients with positive serology, such as antinuclear
             antibodies (ANA) or anti-thyroid antibodies, should be evaluated for the presence of
             target organ involvement and potential need for systemic treatment but should
             otherwise be eligible

          -  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
             residual hypothyroidism due to autoimmune condition only requiring hormone
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to
             recur in the absence of an external trigger (precipitating event)

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids or other immunosuppressive medications within 14 days of study
             drug administration; patients are permitted to use topical, ocular, intra-articular,
             intranasal, and inhalational corticosteroids (with minimal systemic absorption); a
             brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
             treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
             caused by contact allergen) is permitted

          -  Diagnosis of any second malignancy within the last 5 years prior to cycle 1, day 1,
             with the exception of those with a negligible risk of metastasis or death, per
             investigator's discretion (such as adequately treated carcinoma in situ of the cervix,
             basal or squamous cell skin cancer, localized prostate cancer treated surgically with
             curative intent, ductal carcinoma in situ treated surgically with curative intent)

          -  Use of live vaccines against infectious disease (e.g. varicella) within 28 days of
             initiation of study therapy; killed vaccinations (e.g. influenza) are allowed at any
             appropriate time before and during the study

          -  Life expectancy < 3 months, per consenting investigator's opinion
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Feasibility of a patient to receive at least 3 doses of nivolumab and complete surgery without significant delay attributable to nivolumab therapy
Time Frame:Up to 8 weeks
Safety Issue:
Description:Significant delay is defined as delay of > 112 days after the first dose of nivolumab, which would constitute a doubling of the 'planned delay' that our design requires for administration of preoperative therapy (56 days).

Secondary Outcome Measures

Measure:Incidence of toxicity
Time Frame:Up to 90 days
Safety Issue:
Description:Will be defined per Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018). All patients who receive any amount of the study drug will be evaluable for toxicity. Toxicity will be summarized according to grade as a number and percentage of participants. Each adverse event will be summarized as the highest grade experienced for an individual patient. Descriptive statistics will be used for summaries of the reported toxicity.
Measure:Surgical complications
Time Frame:Up to 90 days
Safety Issue:
Description:Defined per Clavien-Dindo Complications score.
Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description:WIll be measured by radiographic response assessment for each cross sectional scan obtained using Response Evaluation Criteria in Solid Tumors 1.1. All patients will be categorized per their best radiographic response (complete response/partial response/stable disease/progressive disease), and the frequency of each category will be determined. The overall response rate will be calculated by dividing the sum of all patients achieving a complete response or confirmed partial response by the number of all evaluable patients.
Measure:Recurrence free survival
Time Frame:Time from the start of the treatment to recurrence or death, assessed up to 2 years
Safety Issue:
Description:Recurrence free survival will be estimated using the Kaplan-Meier method. Two-year recurrence free survival will be provided along with 95% confidence interval. Patients who are unable to undergo nephrectomy or metastasectomy for any reason will not be included in the analysis.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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