Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy
|
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: NCT03055013 |
|
Recruitment Status :
Recruiting
First Posted : February 16, 2017
Last Update Posted : December 10, 2018
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Sarcomatoid Renal Cell Carcinoma Stage II Renal Cell Cancer AJCC v7 Stage III Renal Cell Cancer AJCC v7 Unclassified Renal Cell Carcinoma | Procedure: Conventional Surgery Other: Laboratory Biomarker Analysis Biological: Nivolumab Other: Patient Observation Other: Pharmacological Study Other: Quality-of-Life Assessment | Phase 3 |
PRIMARY OBJECTIVES:
I. To compare recurrence-free survival (RFS) between patients with locally advanced renal cell carcinoma randomly assigned to perioperative nivolumab in conjunction with radical or partial nephrectomy with patients randomized to surgery alone.
SECONDARY OBJECTIVES:
I. To evaluate for differences in recurrence-free survival associated with perioperative nivolumab compared to surgery alone among the subset of patients with clear cell histology.
II. To compare the overall survival between patients randomized to perioperative nivolumab in addition to resection to patients randomized to primary tumor resection alone.
III. To describe the safety and tolerability of perioperative nivolumab.
TERTIARY OBJECTIVES:
I. To correlate the primary tumor's expression of programmed cell death 1 ligand 1 (PD-L1) with outcome.
II. To correlate the expression of PD-L1 on tumor tissue at recurrence with outcome.
III. To archive images for central confirmation of recurrence and for future correlative work with American College of Radiology Imaging Network (ACRIN), including markers predicting outcome or response.
IV. To prospectively collect tumor and biologic specimens (e.g., serum, peripheral blood mononuclear cells [PBMCs]) for future correlative studies.
V. To characterize the pharmacokinetics of nivolumab and explore exposure response relationships with respect to safety and efficacy.
VI. To characterize the immunogenicity of nivolumab. VII. To evaluate differences in change from baseline in patient-reported symptoms and toxicities among patients randomized to treatment with nivolumab compared to surgery alone.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for 2 courses. Patients then undergo partial or radical nephrectomy. Patient then receive nivolumab IV on day 1. Treatment repeats every 14 days for 6 courses, and then every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
ARM II: Patients undergo partial or radical nephrectomy followed by observation.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and every 12 months for 5 years.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 766 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Single (Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 3 Randomized Study Comparing Perioperative Nivolumab vs. Observation in Patients With Localized Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC) |
| Actual Study Start Date : | February 2, 2017 |
| Estimated Primary Completion Date : | November 30, 2023 |
| Estimated Study Completion Date : | November 30, 2023 |
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Arm I (nivolumab, nephrectomy)
Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 2 courses. Patients then undergo partial or radical nephrectomy. Patient then receive nivolumab IV on day 1. Treatment repeats every 14 days for 6 courses, and then every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
|
Procedure: Conventional Surgery
Undergo nephrectomy Other: Laboratory Biomarker Analysis Correlative studies Biological: Nivolumab Given IV
Other Names:
Other: Pharmacological Study Correlative studies Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment |
|
Active Comparator: Arm II (nephrectomy)
Patients undergo partial or radical nephrectomy followed by observation.
|
Procedure: Conventional Surgery
Undergo nephrectomy Other: Laboratory Biomarker Analysis Correlative studies Other: Patient Observation Undergo observation
Other Names:
Other: Pharmacological Study Correlative studies Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment |
- Recurrence-free survival (RFS) [ Time Frame: Time from randomization to disease recurrence or death from any cause, assessed up to 10 years ]Will be assessed among all randomized patients using a stratified log rank test, with nominal one-sided type I error of 2.5%. The type I error will be adjusted for interim analyses.
- Overall survival [ Time Frame: Time from randomization to death from any cause, assessed up to 10 years ]
- RFS among patients with clear cell cancer [ Time Frame: Up to 10 years ]The stratified logrank test will be used.
- Incidence of toxicity using Common Criteria for Adverse Events version 4.0 [ Time Frame: Up to 10 years ]Adverse events will be described separately for patients treated on each arm to evaluate safety and tolerability.
- Primary tumor's expression of PD-L1 [ Time Frame: Baseline to up to 10 years ]The percentage of cells exhibiting cell-surface staining for PD-L1 will be scored. PD-L1 positivity will be defined per specimen by a 5% expression threshold. Additional analyses will assess the 1% and 10% threshold levels. Information with respect to the relative abundance and location (peritumoral/intratumoral) of immune cell (macrophage and lymphocyte) PD-L1 staining will be captured. The expression-by-treatment interaction will be tested using a proportional hazards model. McNemar's Test will be used to explore categorical changes within each treatment group.
- Expression of PD-L1 on tumor tissue at recurrence [ Time Frame: Up to 10 years ]
- Pharmacokinetic analysis of nivolumab [ Time Frame: Up to 10 years ]Serum concentration analyses for nivolumab will be performed by validated bio-analytical methods for nivolumab.
- Change in patient-reported symptoms and toxicities [ Time Frame: Baseline to up to 10 years ]Using the NCCN/FACT Kidney Symptom Index-19 (NFKSI-19), and a carefully selected subset of 5 questions from the PRO-CTCAE pool of items measuring patient-reported toxicity. Descriptive statistics will be used to summarize outcomes at each time point. The impact of nivolumab on symptoms can be assessed by considering the differences between arms in QOL at 18 and 36 weeks. To consider the overall impact of treatment, an area under the curve analysis comparing the entire period from randomization to one year will be used, based on the NFKSI-19 total score. Scoring of the NFKSI-19 will be done using published procedures (Rothrock et al 2013).
- Absolute T cell clonotype abundance [ Time Frame: Up to 10 years ]Will be determined by assessing the number of unique clonotypes identified. The data will be summarized descriptively and graphically.
- Change in T cell repertoire [ Time Frame: From diagnosis to on therapy or to time of recurrence, assessed up to 10 years ]Morisita's distance will be used as utilized by Cha and colleagues. Morisita's distance ranges from 0-1. Zero indicates minimal change in T cell repertoire (TCR) repertoire size (number of unique clonotypes) and 1 indicates maximal change after treatment.
- T cell receptor (TCR) diversity using change in repertoire size per patient [ Time Frame: Baseline to up to 10 years ]The top 25% of unique clonotypes will be identified by sorting for clone frequency. Fold change after recurrence will be measured and plotted on a logarithmic scale.
- Change in cytokine levels in patients randomized to the nivolumab arm [ Time Frame: Baseline to up to 10 years ]Differences in RFS between patients with and without robust CD8 infiltration will be explored. A Cox proportional hazards model will be used to test the interaction between treatment and cytokine changes.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- ELIGIBILITY CRITERIA FOR PREREGISTRATION (STEP 0):
-
Preoperative biopsy for confirmation of renal cell carcinoma (RCC) must be performed within four (4) months prior to randomization
- If biopsy was performed as part of patients standard care, and will not be performed during step 0 proceed directly to randomization
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1):
- Patients with newly diagnosed higher risk RCC of any histology including sarcomatoid or (if preoperative biopsy was uninformative) - "unknown" histology; RCC must have been confirmed by biopsy within 4 months prior to randomization; if the biopsy clearly demonstrated a benign condition or a different type of cancer, the patient is not eligible to be randomized
- Clinical stage >= T2NxM0 or TanyN+ disease for which radical or partial nephrectomy is planned
- Patients must have no clinical or radiological evidence of distant metastases (M0)
-
No concurrent or prior systemic or local anti-cancer therapy for RCC is permitted; examples of these prohibited therapies include:
- Radical or partial nephrectomy for prior RCC
- Metastectomy for RCC
- Radiation therapy to the renal bed or any distant metastatic sites
- Antineoplastic systemic therapies for RCC: i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or investigational agents for treatment of RCC
- Prior treatment with an anti-programmed cell death 1 (PD-1), anti-programmed cell death-ligand 1 (PD-L1), anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
- Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
-
Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy, or
- Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- Women of childbearing potential and sexually active males must be strongly advised to use accepted and effective methods of contraception, as described in the informed consent form (ICF), or to abstain from sexual intercourse for the duration of their participation in the study; women of childbearing potential should use adequate methods to avoid pregnancy for 23 weeks after the last dose of nivolumab; sexually active males should use adequate methods to avoid pregnancy for 31 weeks after the last dose of nivolumab
- Patient must have no prior history of RCC that was resected with curative intent within the past 5 years
-
Patients must not have other current malignancies:
- Adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 3 years prior to the time of registration and they are not receiving any current treatment
-
Prior or current prostate cancer is excluded
- A history of superficial Ta urothelial cancer is permitted (not being currently treated) but T1 or greater disease is excluded
- No active known or suspected autoimmune disease; the following are permitted: patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune or non-autoimmune condition requiring hormone replacement, asymptomatic hypothyroidism not requiring treatment, psoriasis not requiring systemic treatment, or conditions not expected to recur
- No ongoing condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications; no treatment with other immunosuppressive agents within 14 days prior to the first dose of study drug; topical, ocular, intra-articular, intranasal, inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.; a brief (less than 3 weeks) course of corticosteroids (any amount) for prophylaxis (for example: contrast dye allergy) or for treatment of non-autoimmune conditions (for example: delayed-type hypersensitivity reaction caused by a contact allergen) is permitted if > 14 days since last dose
- No uncontrolled adrenal insufficiency
- No known chronic active liver disease or evidence of acute or chronic hepatitis B virus (HBV) or hepatitis C (HCV)
- Patients must not have a serious intercurrent illness, including ongoing or active infection requiring parental antibiotics
- No known evidence of human immunodeficiency virus (HIV) infection
- No known medical condition (e.g. a condition associated with uncontrolled diarrhea such as ulcerative colitis or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or interfere with the interpretation of safety results
- No major surgery within 28 days prior to randomization
- Patients currently enrolled in other clinical trials testing a therapeutic intervention
- White blood cells >= 2000/uL, within 4 weeks of randomization
- Absolute granulocyte count (AGC) >= 1,500/mm^3, within 4 weeks of randomization
- Platelet count >= 100,000/mm^3, within 4 weeks of randomization
- Hemoglobin >= 9.0 g/dL, within 4 weeks of randomization
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) >= 40 mL/min, within 4 weeks of randomization
- Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 x ULN), within 4 weeks of randomization
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN, within 4 weeks of randomization
- No history of severe hypersensitivity to a monoclonal antibody
- Signed, dated informed consent
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03055013
Show 254 Study Locations
| Principal Investigator: | Lauren Harshman | ECOG-ACRIN Cancer Research Group |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT03055013 History of Changes |
| Other Study ID Numbers: |
NCI-2016-00326 NCI-2016-00326 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) EA8143 EA8143 ( Other Identifier: ECOG-ACRIN Cancer Research Group ) EA8143 ( Other Identifier: CTEP ) U10CA180820 ( U.S. NIH Grant/Contract ) |
| First Posted: | February 16, 2017 Key Record Dates |
| Last Update Posted: | December 10, 2018 |
| Last Verified: | July 2018 |
| Studies a U.S. FDA-regulated Drug Product: | Yes | |
| Studies a U.S. FDA-regulated Device Product: | No | |
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 Antibodies, Monoclonal Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs |