Clinical Trials /

Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Renal Medullary Carcinoma

NCT03274258

Description:

This phase II trial studies how well nivolumab and ipilimumab work in treating patients with kidney cancer. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, 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:
  • Kidney Medullary Carcinoma
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Renal Medullary Carcinoma
  • Official Title: Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Renal Medullary Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2017-0201
  • SECONDARY ID: NCI-2018-01066
  • SECONDARY ID: 2017-0201
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03274258

Conditions

  • Kidney Medullary Carcinoma
  • Loss of INI 1 Protein Expression
  • Stage III Renal Cell Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v8

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, ipilimumab)

Purpose

This phase II trial studies how well nivolumab and ipilimumab work in treating patients with kidney cancer. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, 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 determine the objective response rate (ORR) of patients with locally advanced or
      metastatic renal medullary carcinoma (RMC) treated with combination of nivolumab plus
      ipilimumab.

      SECONDARY OBJECTIVES:

      I. To determine the efficacy and safety of the combination of nivolumab plus ipilimumab in
      patients with RMC.

      II. To evaluate potential biomarkers for patient stratification and treatment response, as
      well as tumor antigen-specific immune responses, such as antibody and T cell responses, as
      surrogates for anti-tumor activity.

      OUTLINE:

      Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90
      minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of
      disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 60
      minutes on day 1. Courses repeat every 28 days for up to 2 years in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, ipilimumab)ExperimentalPatients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on day 1. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must give written informed consent prior to initiation of therapy, in keeping
             with the policies of the institution. Patients with a history of major psychiatric
             illness must be judged able to fully understand the investigational nature of the
             study and the risks associated with the therapy.

          -  Patients with locally advanced or metastatic RMC histologically confirmed by expert
             pathology review and loss of SMARCB1 staining by immunohistochemistry. Patients with
             advanced or metastatic unclassified renal cell carcinoma with medullary phenotype (a
             rare SMARCB1 negative RMC variant occurring in individuals without sickle
             hemoglobinopathies) are also eligible. The principal investigator (PI) is the final
             arbiter in questions related to eligibility.

          -  Patients will be eligible regardless of whether they have had prior nephrectomy or
             still have their primary tumor in-situ.

          -  Patients must have at least one measurable site of disease, defined as a lesion that
             can be accurately measured in at least one dimension (longest diameter to be recorded)
             and measures >= 15 mm with conventional techniques or >= 10 mm with more sensitive
             techniques such as magnetic resonance imaging (MRI) or spiral computerized tomography
             (CT) scan. If the patient has had previous radiation to the marker lesion(s), there
             must be evidence of progression since the radiation.

          -  Patients should be willing to provide a newly obtained fresh core biopsy of a tumor
             lesion. Not required if there is a recently obtained fresh specimen on an
             Institutional Review Board (IRB) approved correlated trial up to 6 weeks (42 days)
             prior to initiation of treatment on day 1.

          -  Patients can be either naive for any previous systemic treatment or have had any
             number of prior systemic therapies. However, patients must not have received prior
             anticancer therapy with anti-PD1, anti-PD-L1, or anti-CTLA-4 immune checkpoint
             inhibitors.

          -  There must be evidence of progression on or after last treatment regimen received.
             NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair,
             subject is considered to be ambulatory for the purpose of assessing their performance
             status.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

          -  Consent to MD Anderson companion laboratory protocol 2014-0938.

          -  Hemoglobin >= 9 g/dl (treatment allowed) (within 14 days of the first dose of the
             study drugs).

          -  Absolute neutrophil count >= 1000/mcL (within 14 days of the first dose of the study
             drugs).

          -  Platelets >= 75,000/L (within 14 days of the first dose of the study drugs).

          -  Total bilirubin =< 1.5 mg/dl (within 14 days of the first dose of the study drugs).

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
             institutional upper limit of normal (ULN), except in known hepatic metastasis, wherein
             may be =< 5 x ULN (within 14 days of the first dose of the study drugs).

          -  Serum creatinine =< 1.5 x ULN by gender (as long as patient does not require dialysis)
             (within 14 days of the first dose of the study drugs); May receive transfusion;
             Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days; If
             creatinine is not < 1.5 x ULN, then calculate by Cockcroft-Gault methods or local
             institutional standard and creatinine clearance (CrCl) must be > 30 mL/kg/1.73 m^2.

          -  International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x
             ULN prior to study entry. Therapeutic anticoagulation with warfarin is allowed if
             target INR =< 3 on a stable dose of warfarin or on a stable dose of low molecular
             weight (LMW) heparin for > 2 weeks (14 days) at the time of enrollment.

          -  Patients with controlled brain metastases are allowed on protocol if they had solitary
             brain metastases that was surgically resected or treated with radiosurgery or Gamma
             knife, without recurrence or edema for 1 month (4 weeks).

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG]) within 24 hours prior to the start of the study drug.

          -  Women must not be breastfeeding.

          -  WOCBP must agree to follow instructions for method(s) of contraception from the time
             of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of
             study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post
             treatment completion.

          -  Men who are sexually active with WOCBP must agree to follow instructions for method(s)
             of contraception for the duration of treatment with study drug (s) plus 5 half-lives
             of study drug (s) plus 90 days duration of sperm turnover for a total of 5 months
             post-treatment completion.

          -  Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
             from contraceptive requirements. However WOCBP must still undergo pregnancy testing as
             described in these sections.

        Exclusion Criteria:

          -  Patients must not have any other malignancies within the past 2 years except for in
             situ carcinoma of any site, or adequately treated (without recurrence post-resection
             or post-radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of
             the skin.

          -  Patients currently receiving anticancer therapies or who have received anticancer
             therapies (including chemotherapy and targeted therapy) within 2 weeks (14 days) prior
             to study day are excluded. Patients who have completed palliative radiation therapy
             more than 14 days prior to the first dose of the combination ipilimumab plus nivolumab
             are eligible.

          -  Patients, who have had a major surgery or significant traumatic injury (injury
             requiring > 4 weeks [28 days] to heal) within 4 weeks (28 days) of start of study
             drug, patients who have not recovered from the side effects of any major surgery
             (defined as requiring general anesthesia) or patients that are expected to require
             major surgery, other than cytoreductive nephrectomy +/- retroperitoneal lymph node
             dissection, during the course of the study.

          -  Patients who have organ allografts.

          -  Known or suspected autoimmune disease. Patients with a history of inflammatory bowel
             disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders
             such as rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic
             lupus erythematosus or autoimmune vasculitis (e.g., Wegener's granulomatosis) are
             excluded from this study. Patients with a history of Hashimoto's thyroiditis only
             requiring hormone replacement, type I diabetes, or psoriasis not requiring systemic
             treatment, or conditions not expected to recur in the absence of an external trigger
             are allowed to participate.

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS).

          -  Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or
             positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV
             antibody test indicating acute or chronic infection. If hepatitis C antibody test is
             positive then active infection has to be confirmed by hepatitis C RNA testing for the
             patient to be excluded.

          -  Any underlying medical condition, which in the opinion of the investigator, will make
             the administration of study drug hazardous or obscure the interpretation of adverse
             events, such as a condition associated with frequent diarrhea, uncontrolled nausea or
             vomiting.

          -  Patients must not have received prior anticancer therapy with anti-PD1, anti-PD-L1, or
             anti- CTLA-4 immune checkpoint inhibitors.

          -  Patients receiving any concomitant systemic therapy for renal cell cancer are
             excluded.

          -  Patients must not be scheduled to receive another experimental drug while on this
             study.

          -  Patients who are on high dose steroid (e.g., > 10 mg prednisone daily or equivalent)
             or other more potent immune suppression medications (e.g., infliximab). Topical,
             inhaled, intraarticular, ocular, or intranasal corticosteroids (with minimal systemic
             absorption) are allowed. A brief course (< 48 hours) of systemic corticosteroids for
             prophylaxis (e.g., from contrast dye allergy) is permitted. Physiological
             corticosteroid replacement therapy for adrenal insufficiency is also permitted.

          -  Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation in the study such as: a) Symptomatic
             congestive heart failure of New York heart Association class III or IV; b) Unstable
             angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6
             months of start of study drug, serious uncontrolled cardiac arrhythmia or any other
             clinically significant cardiac disease; c) Severely impaired lung function as defined
             as oxygen (O2) saturation that is 92% or less at rest on room air; d) Uncontrolled
             diabetes as defined by fasting serum glucose > 1.5 x ULN; e) Systemic fungal,
             bacterial, viral, or other infection that is not controlled (defined as exhibiting
             ongoing signs/symptoms related to the infection and without improvement) despite
             appropriate antibiotics or other treatment; f) Known active or symptomatic viral
             hepatitis or chronic liver disease. Uncontrolled adrenal insufficiency.

          -  Patients must not have history of other diseases, metabolic dysfunction, physical
             examination finding, or clinical laboratory finding giving reasonable suspicion of a
             disease or condition that contraindicates the use of ipilimumab or nivolumab or that
             might affect the interpretation of the results of the study or render the subject at
             high risk from treatment complications.

          -  Patients should not receive immunization with attenuated live vaccines within one week
             (7 days) of study entry or during study period; Note: Seasonal influenza vaccines for
             injection are generally inactivated flu vaccines and are allowed; however intranasal
             influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.

          -  Uncontrolled brain or leptomeningeal metastases, including patients who continue to
             require glucocorticoids for brain or leptomeningeal metastases.

          -  Female patients who are pregnant or breast feeding, or adults of reproductive
             potential who are not using effective birth control methods as defined above. If
             barrier contraceptives are being used, these must be continued throughout the trial by
             both sexes. Hormonal contraceptives are not acceptable as a sole method of
             contraception.

          -  Any patients who cannot be compliant with the appointments required in this protocol
             must not be enrolled in this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) defined as completion response or partial response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Time Frame:At 12 weeks
Safety Issue:
Description:Descriptive statistics will include tabulations of frequencies. The estimate of the posterior ORR and its 95% credible interval will be estimated using the same prior as utilized in the futility monitoring rules. The posterior distribution for ORR of this trial will be compared to the historical data. The Kaplan-Meier method will be utilized to display time to ORR. Association with ORR, clinical benefit rate (CBR), or toxicity (TOX) events will be explored with logistic regression.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Adverse effects that will be evaluated include, but are not limited to infections, renal toxicity, hepatic toxicity, and pulmonary toxicity. Methods of assessment will include monitoring blood counts, and performing laboratory tests as indicated by clinical signs and symptoms. Evidence of toxicity or adverse events will be recorded at all clinic visits. All observed adverse effects will be graded for all patients and the degree of association of each with therapy assessed.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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