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Nivolumab vs Nivolumab + Bevacizumab vs Nivolumab + Ipilimumab in Metastatic Renal Cell Carcinoma (mRCC)

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ClinicalTrials.gov Identifier: NCT02210117
Recruitment Status : Recruiting
First Posted : August 6, 2014
Last Update Posted : January 8, 2018
Information provided by (Responsible Party):

Study Description
Brief Summary:

This is an investigational study. Nivolumab is FDA approved to treat metastatic melanoma or non-small cell lung cancer after the disease has gotten worse while receiving platinum-based chemotherapy. Ipilimumab is FDA approved to treat metastatic melanoma. The use of nivolumab and ipilimumab in this study is investigational.

Bevacizumab is approved for certain types of kidney cancer and several other types of cancer, including breast, colon, and lung cancer. It is not FDA approved for the treatment of metastatic kidney cancer. The use of bevacizumab in this study is investigational. The study doctor can explain how the study drug(s) are designed to work.

Up to 105 participants will take part in this study. All will be enrolled at MD Anderson.

Condition or disease Intervention/treatment Phase
Kidney Cancer Drug: Nivolumab Drug: Bevacizumab Drug: Ipilimumab Early Phase 1

  Show Detailed Description

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Pilot Randomized Tissue-Based Study Evaluating Anti-PD1 Antibody or Anti-PD1 + Bevacizumab or Anti-PD1 + Anti-CTLA-4 in Patients With Metastatic Renal Cell Carcinoma Who Are Eligible for Cytoreductive Nephrectomy, Metastasectomy or Post-Treatment Biopsy
Actual Study Start Date : November 2014
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Cancer
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Arm A - Nivolumab
Participants receive Nivolumab 3 mg/kg by vein every 2 weeks for a total of 6 weeks followed by cytoreductive nephrectomy. Nephrectomy will occur about 4 weeks after the last cycle of Nivolumab.
Drug: Nivolumab

Arms A + B: 3 mg/kg by vein every 2 weeks for 6 weeks.

Arm C: 3 mg/kg by vein every 3 weeks for 6 weeks.

Other Name: BMS-936558
Experimental: Arm B - Nivolumab + Bevacizumab
Participants receive Nivolumab at 3 mg/kg by vein every 2 weeks plus Bevacizumab 10 mg/kg by vein every 2 weeks for 6 weeks followed by cytoreductive surgery. Nephrectomy will occur about 4 weeks after the last cycle of Nivolumab.
Drug: Nivolumab

Arms A + B: 3 mg/kg by vein every 2 weeks for 6 weeks.

Arm C: 3 mg/kg by vein every 3 weeks for 6 weeks.

Other Name: BMS-936558
Drug: Bevacizumab
Arm B: 10 mg/kg by vein every 2 weeks for 6 weeks.
Other Names:
  • Avastin
  • Anti-VEGF monoclonal antibody
  • rhuMab-VEGF
Experimental: Arm C - Nivolumab + Ipilimumab
Participants receive Nivolumab at 3 mg/kg by vein every 3 weeks plus Ipilimumab 1 mg/kg by vein every 3 weeks for 6 weeks followed by cytoreductive surgery. Nephrectomy will occur about 4 weeks after the last cycle of Nivolumab.
Drug: Nivolumab

Arms A + B: 3 mg/kg by vein every 2 weeks for 6 weeks.

Arm C: 3 mg/kg by vein every 3 weeks for 6 weeks.

Other Name: BMS-936558
Drug: Ipilimumab
Arm C: 1 mg/kg by vein every 3 weeks for 6 weeks.
Other Names:
  • Yervoy
  • BMS-734016
  • MDX010

Outcome Measures

Primary Outcome Measures :
  1. Overall Toxicity to Assess Safety and Tolerability of Nivolumab vs. Nivolumab + Bevacizumab vs. Nivolumab + Ipilimumab [ Time Frame: 6 weeks ]
    Safety recorded through incidence of adverse events, serious adverse events and specific laboratory abnormalities (worst grade) in each treatment arm. Toxicities graded using the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.0. Extreme toxicities (TOX) defined as any grade 3 or higher adverse event that is possibly, probably, or definitely related to therapy, and occur within first 6 weeks of therapy with one exception. Any grade 3 or higher adverse event that is potentially treatable with steroids will only count as an extreme toxicity if it does not improve to grade 1 or better within 2 weeks.

Secondary Outcome Measures :
  1. Immunological Changes in Tumor Tissues [ Time Frame: 10 weeks ]
    Immunological variables measured based on peripheral blood (pb) samples and tumor tissue samples.

Other Outcome Measures:
  1. Objective Response Rate (ORR) [ Time Frame: 12 weeks ]
    Objective response rate (ORR) defined as number of subjects with a best response of complete response (CR) or partial response (PR) after 12 weeks of therapy by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria divided by the number of randomized subjects.

Eligibility Criteria

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

Inclusion Criteria:

  1. Patients must give written informed consent prior to initiation of therapy, in keeping with the policies of the institution. Patients with a history of major psychiatric illness must be judged able to fully understand the investigational nature of the study and the risks associated with the therapy.
  2. Patients with histologically or cytologically confirmed metastatic clear cell RCC who are eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy. Diagnosis must be confirmed by pathologist review of screening biopsy. The determination of resectability will ultimately lie in the clinical judgment of the urologist and medical oncologist involved in the care of the patient.
  3. Patient must have measurable disease and is defined as a lesion that can be accurately measured on the long axis with a minimum size of 10 mm or a lymph node that can be accurately measured along the short axis of a minimum size of 15 mm (CT scan slice thickness can be no greater than 5 mm).
  4. Patients can have had prior treatment for RCC including prior surgery, radiation therapy, immunotherapy with IL-2 or interferon (but not anti-PD1 or anti-CTLA-4), target therapy with RTK inhibitors/mTOR inhibitors, such as Sunitinib, Sorafenib, Pazopanib, Axitinib, Everolimus, and Temsirolimus (but not Bevacizumab) or chemotherapy.
  5. ECOG performance status </= 2.
  6. Within 14 days of the first dose of study drug, patients must have adequate organ and marrow function as defined below: Absolute neutrophil count >/= 1,500/uL, Platelets >/= 100,000/uL, Hgb > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen®] to maintain or exceed this level), Total bilirubin </= 1.5 mg/dl, Serum creatinine </= 1.5 times the upper limit of normal or estimated CrCl >40mL/min, AST (SGOT) and/or ALT (SGPT) </= 2.5 X institutional upper limit of normal for patients without evidence of liver metastases, AST (SGOT) and/or ALT (SGPT) </= 5 X institutional upper limit of normal for patients with documented liver metastases.
  7. Mild autoimmune conditions (such as localized psoriasis) requiring minimal treatment or systemic autoimmune conditions well controlled by target agents such as an anti-IL-17 that do not affect overall immune system.
  8. Patients with a history of Hashimoto's thyroiditis only requiring hormone replacement, Type I diabetes, or conditions not expected to recur in the absence of an external trigger are allowed to participate.
  9. Men and women >/= 18 years of age
  10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
  11. Women must not be breastfeeding
  12. WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment completion.
  13. Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days duration of sperm turnover) for a total of 31 weeks post-treatment completion.
  14. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However WOCBP must still undergo pregnancy testing as described in these sections. Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% per year when used consistently and correctly. At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below: HIGHLY EFFECTIVE METHODS OF CONTRACEPTION: a) Male condoms with spermicide;
  15. (Continued from #12) b) Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject's WOCBP partner.; c) Nonhormonal IUDs, such as ParaGard; d) Tubal ligation; e) Vasectomy; f) Complete Abstinence* *Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Abstinence is only acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, profession of abstinence for entry into a clinical trial, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  16. (Continued from #12) Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence. LESS EFFECTIVE METHODS OF CONTRACEPTION: a) Diaphragm with spermicide; b) Cervical cap with spermicide; c) Vaginal sponge; d) Male Condom without spermicide*; e) Progestin only pills by WOCBP subject or male subject's WOCBP partner; f) Female Condom* *A male and female condom must not be used together

Exclusion Criteria:

  1. Any other malignancy from which the patient has been disease-free for less than 2 years, except for non-melanoma skin cancer, in situ carcinoma of any site.
  2. Patients who have organ allografts.
  3. Patients who have had a major surgical procedure, open biopsy, or significant traumatic injury with poorly healed wound within 6 weeks prior to first dose of study drug; or anticipation of need for major surgical procedure during the course of the study (other than defined by protocol); or fine needle aspirations or core biopsies within 7 days prior to first dose of study drug.
  4. 4. Known or suspected autoimmune disease. Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are excluded from this study. Any condition requiring systemic treatment with corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroids doses >10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  5. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection.
  6. Any underlying medical condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
  7. Patients who have had a history of acute diverticulitis, abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis which are known risks factors for bowel perforation, should be excluded from the study.
  8. Patients who have a primary brain tumor (excluding meningiomas and other benign lesions), any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, history of stroke within the past year.
  9. History of serious systemic disease, including myocardial infarction or unstable angina within the last 12 months, history of hypertensive crisis or hypertensive encephalopathy, uncontrolled hypertension (blood pressure of >140/90 mmHg) at the time of enrollment, New York Heart Association (NYHA) Grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), significant vascular disease or symptomatic peripheral vascular disease.
  10. Patients who have history of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications.
  11. Patients who have proteinuria at baseline. Patients who are unexpectedly discovered to have >/= grade 2 proteinuria at baseline routine urinalysis should undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate </=1 g of protein/24 hr to allow participation in the study.
  12. Patients who have uncontrolled hypertension (systolic > 140 mmHg and/or diastolic > 90 mmHg). It is permissible to start treatment for hypertension prior to randomization.
  13. Patients who are on high dose steroid (e.g. > 10mg prednisone daily or equivalent) or other more potent immune suppression medications(e.g. infliximab).
  14. Patients who have had flu, hepatitis, or other vaccines within a month prior to initiation of study drugs.
  15. Patients who have clinical history of coagulopathy, bleeding diathesis or thrombosis within the past year.
  16. Patients who have serious, non-healing wound, ulcer, or bone fracture.
  17. Pregnancy (positive pregnancy test) or lactation.
  18. Patients must not have received prior anticancer therapy with bevacizumab, anti-CLTA-4, or anti-PD1 for renal cell carcinoma. Patients receiving any concomitant systemic therapy for renal cell cancer are excluded.
  19. Patients must not be scheduled to receive another experimental drug while on this study.
  20. Patients who require ongoing anticoagulation will be excluded. Only aspirin will be permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted.
  21. Patients must not require total parenteral nutrition with lipids.
  22. Any patients who cannot be compliant with the appointments required in this protocol must not be enrolled in this study.
Contacts and Locations

Information from the National Library of Medicine

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): NCT02210117

Contact: Padmanee Sharma, MD, PHD 713-792-2830

United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: MD Anderson Health Information Specialist    877-632-6789      
Sponsors and Collaborators
M.D. Anderson Cancer Center
Bristol-Myers Squibb
High Impact Clinical Research Support Program
Principal Investigator: Padmanee Sharma, MD, PHD M.D. Anderson Cancer Center
More Information

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02210117     History of Changes
Other Study ID Numbers: 2013-0715
NCI-2014-01857 ( Registry Identifier: NCI CTRP )
First Posted: August 6, 2014    Key Record Dates
Last Update Posted: January 8, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Kidney Cancer
Metastatic Renal Cell Carcinoma
Cytoreductive Nephrectomy
Presurgical therapy
Anti-VEGF monoclonal antibody

Additional relevant MeSH terms:
Carcinoma, Renal Cell
Kidney Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors