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

  • STATUS
    Recruiting
  • End date
    Sep 28, 2022
  • participants needed
    134
  • sponsor
    Michael B. Atkins, MD
Updated on 28 January 2021

Summary

Phase II trial of nivolumab in 120 treatment nave patients with ccRCC.

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.

Details
Condition Advanced Renal Cell Carcinoma
Treatment Nivolumab 240 mg, Ipilimumab 1mg/kg, Nivolumab 3mg/kg, Nivolumab 360mg
Clinical Study IdentifierNCT03117309
SponsorMichael B. Atkins, MD
Last Modified on28 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Advanced Renal Cell Carcinoma?
Do you have any of these conditions: Do you have Advanced Renal Cell Carcinoma??
Do you have any of these conditions: Do you have Advanced Renal Cell Carcinoma??
Do you have any of these conditions: Do you have Advanced Renal Cell Carcinoma??
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
Archival tissue of a metastatic lesion obtained within 1 year prior to study registration (within 4 weeks preferred) and tumor tissue from nephrectomy is required if available. In addition to archival tissue of a metastatic lesion and nephrectomy, patients must have at least one site of disease (not including bone metastases) accessible for biopsy. If biopsy/resection of a new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq study (as specified in the CLM) is not feasible, the subject is not eligible for the study. All biopsies must be core needle or excisional. Fine needle aspirate is not acceptable. NOTE: The tissue collected from a surgical resection or multiple core biopsies of either a metastatic lesion or primary tumor for the slow freezing of fresh tissue after the patient has signed consent for the study could also be used for collecting the FFPE specimens
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/L
Absolute Neutrophil Count (ANC) 1500/L
Platelets (Plt) 100 x103/L
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
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
Tumor biopsy prior to combination treatment is mandatory. If a biopsy/resection of a new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq study (as specified in the CLM) is not feasible, the subject is not eligible for the study. All biopsies must be core needle or excisional. Fine needle aspirate is not acceptable
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
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