Nivolumab with or without Ipilimumab as Front Line Therapy in Treating Patients with Advanced Kidney Cancer
This phase II trial studies how well nivolumab with or without ipilimumab as front line therapy work in treating patients with kidney cancer that has spread to other places in the body. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread.
- INCLUSION CRITERIA - PART A
- 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
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Have signed the current approved informed consent form
- Within 14 days prior to study entry: White blood cell (WBC) >= 2000/uL
- Within 14 days prior to study entry: Absolute neutrophil count (ANC) >= 1500/uL
- Within 14 days prior to study entry: Platelets (Plt) >= 100 x 10^3/L
- Within 14 days prior to study entry: Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion)
- Within 14 days prior to study entry: Serum creatinine =< 1.5 x ULN
- Within 14 days prior to study entry: Calculated creatinine clearance >= 40 mL/min using Cockcroft-Gault formula
- Within 14 days prior to study entry: Bilirubin =< 1.5 x upper limit of normal (ULN); except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL
- Within 14 days prior to study entry: Aspartate aminotransferase (AST) =< 3 x ULN
- Within 14 days prior to study entry: Alanine aminotransferase (ALT) =< 3 x 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 requested; 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 (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of study 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 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
- NOTE: “Women of childbearing potential” 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 less than 40 mIU/ml
- Women of childbearing potential (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
- 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 a new tumor biopsy for acquisition of resistant tumor tissue; subjects unable to undergo a new tumor biopsy are not eligible for Part B
- Must not have had a grade >= 3 immune related adverse event (irAE) on nivolumab monotherapy (excluding endocrine toxicity managed with replacement therapy)
- 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 (see protocol for exceptions)
- 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)
- 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 stereotactic radiosurgery (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, carcinoma in situ (CIS) or localized prostate cancer that has been treated or is being observed)
Locations & Contacts
District of Columbia
Contact: Gayle Cramer
Contact: Mehmet Asim Bilen
Contact: Maureen Sadim
Contact: Frank George Riley
Contact: Sabina Signoretti
Contact: Renee Lomelino
Contact: Karen Bradley
Contact: Brian I. Rini
Contact: Marla Jones
Contact: Jennifer L. King
Contact: Doreen Simonsen
Trial Objectives and Outline
I. Determine the progression-free survival (PFS) rate at 1 year of nivolumab in patients with treatment naive clear cell renal cell cancer (ccRCC) based on tumor PD-L1 expression.
I. Determine the PFS rate at 1 year- by both Response Evaluation Criteria in Solid Tumors (RECIST) and immune related (ir)RECIST of nivolumab in patients with treatment naive ccRCC based on the PD1- blockade durable response predictive (PRP) biomarker model developed in the Dana–Farber/Harvard Cancer Center (DFHCC) Kidney Cancer Specialized Program in Research Excellence (SPORE).
II. Determine the objective response rate (complete response [CR]/partial response [PR]=objective response rate [ORR]), the ORR based on PDL1 expression and the PRP model, and duration of response for nivolumab in patients with treatment naive ccRCC.
III. Determine the response rate of combined nivolumab and ipilimumab therapy at the time of nivolumab failure (or lack of response at 1 year).
IV. Determine the clinical activity (CR, PR and stable disease [SD]) and PFS at 1 year of nivolumab in patients with treatment naive non-clear cell (ncc)RCC.
V. Assess the toxicity of nivolumab monotherapy in patients with treatment naive cc or nccRCC.
I. Explore novel potential predictive biomarkers for patients with treatment naive ccRCC and nccRCC.
II. Explore the mechanisms of innate and acquired resistance to nivolumab therapy in treatment naive patients with ccRCC.
III. Identify biomarkers associated with response to nivolumab + ipilimumab in patients whose disease has not responded or progressed on nivolumab monotherapy.
OUTLINE: Patients are assigned to 1 of 2 parts.
PART A: Patients receive nivolumab intravenously (IV) over 60 minutes on days 1, 15, and 29. Treatment repeats every 42 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on days 1 and 22. Courses repeat every 42 days for up to 96 weeks in the absence of disease progression or unacceptable toxicity. Patients with persistent progressive disease may be enrolled to Part B.
PART B: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 42 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on days 1 and 22. Courses repeat every 42 days for up to 48 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 3 years and then every 6 months for 2 years.
Trial Phase & Type
MedStar Georgetown University Hospital
Michael B. Atkins
Secondary IDs NCI-2017-02166, GU16-260, CA209-669
Clinicaltrials.gov ID NCT03117309