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

• ClinicalTrials.gov Identifier: NCT03117309
• Recruitment Status: Active, not recruiting
• First Posted: April 17, 2017
• Last Update Posted: October 26, 2022
• Sponsor: Michael B. Atkins, MD
• Collaborators: Bristol-Myers Squibb; Hoosier Cancer Research Network
• Information provided by (Responsible Party): Michael B. Atkins, MD, Hoosier Cancer Research Network

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Advanced Renal Cell Carcinoma	Drug: Nivolumab 240 mg; Drug: Ipilimumab 1mg/kg; Drug: Nivolumab 3mg/kg; Drug: Nivolumab 360mg	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 164 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Masking Description: Open Label
• Primary Purpose: Treatment
• Official Title: Phase II Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma. HCRN: GU16-260
• Actual Study Start Date: April 24, 2017
• Actual Primary Completion Date: March 25, 2022
• Estimated Study Completion Date: September 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: PART A: Nivolumab; Nivolumab 240mg; Nivolumab 360mg	Drug: Nivolumab 240 mg; PART A Nivolumab 240 mg IV every 2 weeks x 6 then initial disease assessment; Other Name: OPDIVO; Drug: Nivolumab 360mg; Continue Nivolumab 360 mg IV every 3 weeks; Other Name: OPDIVO
Experimental: PART B: Nivolumab + Ipilimumab; Nivolumab 3mg/kg and Ipilimumab 1mg/kg; Nivolumab 360mg	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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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
2. Objective Response Rate (CR/PR) [ Time Frame: 1 year ]
   Determine the objective response rate (CR/PR) for nivolumab in patients with treatment naïve ccRCC
3. Response Rate [ Time Frame: 1 year ]
   Determine the response rate of combined nivolumab and ipilimumab therapy at the time of nivolumab failure
4. 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
5. Progression Free Survival (PFS) at one year [ Time Frame: 1 year ]
   Evaluate patients on nivolumab for progressive disease or death
6. 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)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.
• 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.
• Age ≥ 18 years.
• 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
• 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 5 months after the last dose of study drug. NOTE: Contraception is not required for male participants.
• 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. 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 must not be breastfeeding.
• 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

Contacts and Locations

Locations

United States, Connecticut

Yale University, Yale Cancer Center

New Haven, Connecticut, United States, 06520

United States, District of Columbia

Georgetown University

Washington, District of Columbia, United States, 20057

United States, Georgia

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

Northwestern University Feinberg Schooll Of Medicine

Chicago, Illinois, United States, 60611

University of Illinois Cancer Center

Chicago, Illinois, United States, 60612

United States, Massachusetts

Beth Isreal Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, New Jersey

Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

United States, New York

Columbia University

New York, New York, United States, 10032

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44915

United States, Pennsylvania

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States, 19111

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Sponsors and Collaborators

Michael B. Atkins, MD

Bristol-Myers Squibb

Hoosier Cancer Research Network

Investigators

• Study Chair: Michael B. Atkins, MD; Hoosier Cancer Research Network

More Information

Additional Information:

Hoosier Cancer Research Network Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Atkins MB, Jegede OA, Haas NB, McDermott DF, Bilen MA, Stein M, Sosman JA, Alter R, Plimack ER, Ornstein M, Hurwitz M, Peace DJ, Signoretti S, Denize T, Cimadamore A, Wu CJ, Braun D, Einstein D, Catalano PJ, Hammers H. Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A). J Clin Oncol. 2022 Sep 1;40(25):2913-2923. doi: 10.1200/JCO.21.02938. Epub 2022 Apr 20.

• Responsible Party: Michael B. Atkins, MD, Sponsor-Investigator, Hoosier Cancer Research Network
• ClinicalTrials.gov Identifier: NCT03117309
• Other Study ID Numbers: HCRN GU16-260
• First Posted: April 17, 2017
• Last Update Posted: October 26, 2022
• Last Verified: October 2022

• 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

Keywords provided by Michael B. Atkins, MD, Hoosier Cancer Research Network:

Nivolumab; Ipilimumab; OPDIVO; IgG1 kappa immunoglobulin

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Nivolumab; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action