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Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03117309
Recruitment Status : Recruiting
First Posted : April 17, 2017
Last Update Posted : April 17, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
Hoosier Cancer Research Network
Information provided by (Responsible Party):
Michael B. Atkins, MD, Hoosier Cancer Research Network

Tracking Information
First Submitted Date  ICMJE April 10, 2017
First Posted Date  ICMJE April 17, 2017
Last Update Posted Date April 17, 2020
Actual Study Start Date  ICMJE April 24, 2017
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 14, 2017)
Progression Free Survival (PFS) rate [ Time Frame: 1 year ]
Determine the PFS rate at 1 year of nivolumab in patients with treatment naïve ccRCC based on tumor PD-L1 expression
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2017)
  • Progression Free Survival (PFS) rate [ Time Frame: 1 year ]
    Determine the PFS at 1 year of nivolumab in patients with treatment naïve ccRCC based on the PD1- Blockade Durable Response Predictive (PRP) biomarker model developed in the DFHCC Kidney Cancer SPORE
  • Objective Response Rate (CR/PR) [ Time Frame: 1 year ]
    Determine the objective response rate (CR/PR) for nivolumab in patients with treatment naïve ccRCC
  • Response Rate [ Time Frame: 1 year ]
    Determine the response rate of combined nivolumab and ipilimumab therapy at the time of nivolumab failure
  • Clinical Activity (Complete Response (CR), Partial Response (PR) and Stable Disease (SD) [ Time Frame: 1 year ]
    Determine the clinical activity (CR, PR and SD) at 1 year of nivolumab in patients with treatment naive nccRCC
  • Progression Free Survival (PFS) at one year [ Time Frame: 1 year ]
    Evaluate patients on nivolumab for progressive disease or death
  • Toxicity by calculating the frequency and percentage of adverse event terms (CTCAE v4) [ Time Frame: 1 year ]
    Assess the toxicity of nivolumab monotherapy in patients with treatment naïve cc or nccRCC by calculating the frequency and percentage of adverse event terms (CTCAE v4)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma
Official Title  ICMJE Phase II Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma. HCRN: GU16-260
Brief Summary Phase II trial of nivolumab in 120 treatment naïve patients with ccRCC.
Detailed Description

Eligible patients with biopsiable (biopsied) disease will receive nivolumab 240 mg IV every 2 weeks x 6 doses then 360 mg every 3 weeks for up to 84 weeks. Tumor response will be assessed at weeks 12, 18 and 24 and then every 12 weeks. For patients who experience RECIST 1.1 defined PD, but remain clinically stable (and asymptomatic), a confirmatory scan after 6 weeks (± 1 week) of additional therapy is suggested. Patients with persistent PD at confirmatory scan will be evaluated for enrollment on Part B of this study. Symptomatic patients may be evaluated for Part B immediately. Patients without confirmed PD can continue on nivolumab therapy.

Patients who experience symptomatic or confirmed PD (or have best response of SD at 12 months) on nivolumab monotherapy will be eligible for consideration for Part B. Part B involves the addition of ipilimumab for up to 4 doses while maintaining nivolumab therapy. Dose of ipilimumab will be 1 mg/kg every 3 weeks together with nivolumab changed to 3 mg/kg every 3 weeks for up to 4 doses. Nivolumab will revert to 360 mg every 3 weeks after the completion of treatment with ipilimumab (beginning week 13-19 of Part B) for up to 48 weeks. Patients will be followed with serial imaging assessments weeks 12, 18 and 24 and then every 12 weeks after the initiation of ipilimumab. The tumor measurements at the time of ipilimumab institution will be the new baseline. If unequivocal symptomatic or confirmed new PD (as defined above) develops, treatment will be discontinued.

Patients for Part B must still meet the eligibility criteria for initial study enrollment. Patients with Grade 3 toxicity on nivolumab monotherapy, serious symptomatic disease that in the opinion of the site investigator requires immediate use of an alternative treatment approach or continued PR/CR will be excluded from enrolling in Part B. It is estimated that roughly half of the patients accrued to the first-line treatment will go on to enroll in Part B.

An additional biopsy will be performed of a metastatic lesion at time of confirmed PD in all patients enrolling in Part B. Confirmation of tumor in the biopsy specimen must occur prior to initiation of treatment on Part B. FFPE and frozen tissue will be stored from this sample and used for correlative studies described below.

An additional cohort of 40 non-ccRCC patients will be enrolled and analyzed separately for evidence of anti-tumor activity (CR, PR and SD and PFS at 1 year of nivolumab). These patients will also be eligible for participation in Part B. We anticipate that the accrual of these 40 patients will be able to be completed within the 1.5 years needed for accrual of the ccRCC patients.

Part A: Nivolumab Administration. Nivolumab will be given every 2 weeks x 6 at a dose of 240 mg Intravenously (IV) and then every 3 weeks at a dose of 360 mg IV until toxicity, complete response, disease progression, SD at 12 months or a maximum of 96 total weeks (12 weeks induction, 84 weeks maintenance) Patients with disease progression (at any time) or SD at 12 months will be eligible to be considered for participation in Part B of the study.

Part B: Nivolumab + Ipilimumab. Patients with Grade 3 toxicity on nivolumab monotherapy, (excluding endocrine toxicity), serious symptomatic disease that in the opinion of the site investigator requires immediate use of an alternative treatment approach or continued PR/CR will be excluded from enrolling in Part B. It is estimated that roughly half of the patients accrued to the first line treatment will go on to enroll in Part B.

Ipilimumab will be given 1 mg/kg every 3 weeks together with nivolumab 240 mg every 3 weeks for up to 4 doses. Nivolumab will revert to 3 mg/kg every 3 weeks after the completion of combination treatment with ipilimumab .

Following the first 4 doses of the combination of nivolumab and ipilimumab, nivolumab monotherapy will again be given every 3 weeks at a dose of 360 mg for a maximum of 48 weeks. Patients may be dosed no less than 18 days from the previous dose of drug; and dosed up to 3 days after the scheduled date, if necessary.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Masking Description:
Open Label
Primary Purpose: Treatment
Condition  ICMJE Advanced Renal Cell Carcinoma
Intervention  ICMJE
  • Drug: Nivolumab 240 mg
    PART A Nivolumab 240 mg IV every 2 weeks x 6 then initial disease assessment
    Other Name: OPDIVO
  • Drug: Ipilimumab 1mg/kg
    Ipilimumab 1 mg/kg every 3 weeks x 4
    Other Name: Yervoy
  • Drug: Nivolumab 3mg/kg
    In combination with Ipilimumab
    Other Name: OPDIVO
  • Drug: Nivolumab 360mg
    Continue Nivolumab 360 mg IV every 3 weeks
    Other Name: OPDIVO
Study Arms  ICMJE
  • Experimental: PART A: Nivolumab
    Nivolumab 240mg; Nivolumab 360mg
    Interventions:
    • Drug: Nivolumab 240 mg
    • Drug: Nivolumab 360mg
  • Experimental: PART B: Nivolumab + Ipilimumab
    Nivolumab 3mg/kg and Ipilimumab 1mg/kg; Nivolumab 360mg
    Interventions:
    • Drug: Ipilimumab 1mg/kg
    • Drug: Nivolumab 3mg/kg
    • Drug: Nivolumab 360mg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 14, 2017)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria-Part A:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

  • Patients must have histologically confirmed advanced RCC (any histology). Collecting duct tumors and tumors originating from the renal pelvis or upper urinary tract are considered of urothelial origin and are excluded from this protocol.
  • Patients must have at least one measurable site of disease, per RECIST 1.1, that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.
  • ECOG performance status 0-2
  • Have signed the current approved informed consent form

Patients must have adequate organ function within 14 days prior to study entry as evidenced by screening laboratory values that must meet the following criteria:

Hematological:

  • White blood cell (WBC) ≥ 2000/µL
  • Absolute Neutrophil Count (ANC) ≥ 1500/μL
  • Platelets (Plt) ≥ 100 x103/μL
  • Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion)

Renal:

  • Serum Creatinine ≤ 1.5 x ULN; if creatinine > 1.5, subject must demonstrate CrCl as outlined below.
  • Calculated creatinine clearance ≥ 40 mL/min using Cockcroft-Gault formula

Hepatic:

  • Bilirubin ≤ 1.5× upper limit of normal (ULN); Except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL
  • Aspartate aminotransferase (AST) ≤ 3 × ULN
  • Alanine aminotransferase (ALT) ≤ 3 × ULN
  • Archival tissue is mandatory (a tumor biopsy- core or excisional) of a metastatic lesion obtained within 1 year prior to study registration (within 4 weeks preferred). Tumor tissue from nephrectomy and site of metastasis will be required. If archival tissue of a metastatic lesion obtained within the preceding year is not available, patients must have at least one site of disease (not including bone metastases) accessible for core needle or excisional biopsy. If archival tissue of a metastatic lesion is not available and biopsy of a new lesion is not feasible, the subject is not eligible for the study.
  • Patients should not have received prior systemic therapy for metastatic RCC. Prior radiotherapy must have been completed at least 2 weeks prior to the administration of study drug. Patients must be 2 weeks from prior major surgery and 1 week from pre-treatment biopsy. Prior systemic adjuvant therapy (excluding with PD1 or CTLA4 pathway blockers) is allowed if treatment completed > 12 months previously.
  • Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks
  • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) during screening for registration purposes. This pregnancy test should be repeated within 24 hours 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 (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
  • Be willing and able to comply with this protocol.

Exclusion Criteria:

  • Patients are excluded if they have active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2 weeks of more after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
  • Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected without recurrence or treated with SRS without progression x 4 weeks.
  • Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects 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.
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen
  • Active infection requiring systemic therapy
  • Has any other medical or personal condition that, in the opinion of the site investigator, may potentially compromise the safety or compliance of the patient, or may preclude the patient's successful completion of the clinical trial
  • Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
  • Allergies and Adverse Drug Reaction

    • History of allergy to study drug components
    • History of severe hypersensitivity reaction to any monoclonal antibody
  • Known additional malignancies within the past 3 years (excluding basal of squamous cell skin cancers, CIS or localized prostate cancer that has been treated or is being observed)

Inclusion/Exclusion Criteria- Part B

  • Must meet eligibility criteria for initiation of Part A with the exception of being allowed to have prior nivolumab in Part A of this protocol
  • Must have evidence of either RECIST 1.1 defined Disease Progression or Stable Disease 1 year after initiating nivolumab therapy
  • Must undergo repeat tumor biopsy for acquisition of resistant tumor tissue
  • Must not have had a Grade ≥ 3 irAE on nivolumab monotherapy
  • Must not have untreated brain metastases
  • Must not have had major surgery or radiation therapy within 14 days of starting study treatment
  • Must not have active autoimmune disease
  • Must not have a concurrent medical condition requiring use of systemic corticosteroids with prednisone >10 mg per day
  • Must not have had prior systemic therapy for Stage IV RCC (except for nivolumab as part of part A of this protocol)
  • Prior solid organ or stem cell transplant
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michael Nunley 317.634.5842 ext 17 mnunley@hoosiercancer.org
Contact: Michael B. Atkins, MD 202.687.2795 mba41@Georgetown.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03117309
Other Study ID Numbers  ICMJE HCRN GU16-260
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Michael B. Atkins, MD, Hoosier Cancer Research Network
Study Sponsor  ICMJE Michael B. Atkins, MD
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Hoosier Cancer Research Network
Investigators  ICMJE
Study Chair: Michael B. Atkins, MD Hoosier Cancer Research Network
PRS Account Hoosier Cancer Research Network
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP