CYTO Reductive Surgery in Kidney Cancer Plus Immunotherapy and Targeted Kinase Inhibition (Cyto-KIK)

Cyto-KIK; TRIAL (CYTO Reductive Surgery in Kidney Cancer Plus Immunotherapy (Nivolumab) and Targeted Kinase Inhibition (Cabozantinib)

The purpose of this study is to determine if the use of immunotherapy nivolumab and the targeted therapy cabozantinib prior to removal of the kidney, will increase the number subjects who are without any visible kidney cancer in their body at some point during the course of treatment.

Study Overview

• Status: Recruiting
• Conditions: Kidney Cancer; Renal Cell Carcinoma
• Intervention / Treatment: Drug: Cabozantinib; Drug: Nivolumab; Procedure: Cytoreductive nephrectomy

Detailed Description

People with metastatic kidney cancer are usually treated with medications to slow the growth of the cancer. In addition, people who still have the kidney where the cancer started may have the kidney removed during the course of treatment. This surgery is done in order to decrease the amount of tumor in the body. This surgery is referred to as a cytoreductive nephrectomy. In the current study, nivolumab, an immune checkpoint inhibitor, is being administered in combination with cabozantinib, a targeted therapy. The combination of nivolumab and cabozantinib is FDA approved for the treatment of metastatic kidney cancer. In this study, treatment consists of cabozantinib and nivolumab plus a cytoreductive nephrectomy. Eligible subjects, who have not received prior therapy for metastatic clear cell renal cell carcinoma, are treated with cabozantinib and nivolumab for approximately 3 months prior to undergoing cytoreductive nephrectomy. After nephrectomy, patients who are benefiting from treatment may resume cabozantinib and nivolumab. This study will help investigators to understand the immune effects of cabozantinib and nivoluamb in the kidney tumor and will provide information on the potential clinical benefit associated with cytoreductive nephrectomy in combination with cabozanitnib and nivolumab.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Research Nurse Navigator; Phone Number: 212-342-5162; Email: cancerclinicaltrials@cumc.columbia.edu

Study Locations

• United States
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Recruiting
      • The Rutgers Cancer Institute of New Jersey
      • Contact: Biren Saraiya, MD; Phone Number: 732-235-2465
      • Principal Investigator: Biren Saraiya, MD
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Principal Investigator: Mark N Stein, MD
      • Contact: Research Nurse Navigator; Phone Number: 212-342-5162; Email: cancerclinicaltrials@cumc.columbia.edu
  • Ohio
    • Cleveland, Ohio, United States, 44012
      • Recruiting
      • Cleveland Clinic
      • Contact: Moshe Ornstein, MD,MA; Phone Number: 917-587-3359; Email: ornstem@ccf.org
    • Columbus, Ohio, United States, 43221
      • Recruiting
      • Ohio State University Wexner Medical Center
      • Contact: Eric Singer, MD, MS; Email: eric.singer@osumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information.
2. Age ≥ 18years at the time of consent.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 28 days prior to registration.
4. Radiographically consistent with metastatic renal cell carcinoma (with subsequent pathologic confirmation of renal cell carcinoma with a clear cell component) OR histological/ cytological evidence of metastatic renal cell carcinoma with a clear cell component
5. Measurable tumor in the kidney according to RECIST 1.1
6. No prior therapy for metastatic renal cell carcinoma
7. Demonstrate adequate organ function as defined in the protocol; all screening labs to be obtained within 14 days prior to registration.
8. Females of childbearing potential must have a negative serum pregnancy test during screening, within 14 days of Cycle 1 Day 1. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
9. Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 6 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.
10. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria:

1. Patients who had previously undergone nephrectomy for renal cancer are excluded
2. Uncontrolled bleeding, hypertension, or cardiovascular disease.
3. Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4 inhibitors
4. The subject has active brain metastases or epidural disease
5. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment.
6. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test ≥1.3 x the laboratory upper limit of normal (ULN)
7. The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, thrombin or Factor Xa inhibitors. Aspirin (up to 325 mg/day), low-dose warfarin (≤1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted
8. Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
9. Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
10. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation.
11. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
12. Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment
13. Patients are 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 start

14. Cardiovascular disorders including:

    • Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
    • Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment within 14 days of the first dose of study treatment.
    • The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before registration.
15. Severe active infection requiring systemic treatment within 28 days before the first dose of study treatment
16. Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
17. Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
18. History of organ transplant
19. Concurrent uncompensated hypothyroidism
20. Unable to swallow tablets
21. Active infection requiring systemic therapy
22. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
23. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least 2 years.
24. Active central nervous system (CNS) metastases
25. Treatment with any investigational drug within 28 days prior to registration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment with cabozantinib and nivolumab with nephrectomy; All study participants will receive the same study medications, cabozantinib and nivolumab. The study drug, nivolumab, will be administered through an IV infusion every 4 weeks and cabozantinib will be administered orally daily. Initially participants will receive study treatment for 12 weeks. The cabozantinib will then be stopped prior to the nephrectomy. Initially patients enrolled on the study will be assigned to cohort 1. Patients who are assigned to cohort 1 will be treated with cabozantinib until 21 days prior to surgery. A patient in cohort 1 will be evaluable for assessment of the cabozantinib washout interval ("evaluable patients") if they; complete at least 10 of the 14 scheduled cabozantinib doses in the two week period prior to stopping cabozantinib AND; have surgical resection of the primary tumor. In cohort 2, subjects will receive cabozantinib until 14 days prior to nephrectomy.

Drug: Cabozantinib; 2 x 20 mg capsules taken orally daily; Other Names: XL184; Drug: Nivolumab; 480mg IV on first day of each 28-day cycle; Other Names: BMS-936558; Procedure: Cytoreductive nephrectomy; Surgery removing as much tumor tissue as possible, possibly including surrounding tissues.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with a Complete Response	The percentage of participants with a complete response following treatment. Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.	Up to 5 years after completion of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Size Reduction of the Primary Tumor	Median size reduction of the primary tumor after treatment for 12 weeks prior to nephrectomy will be determined using RECIST 1.1 criteria applied to the primary tumor.	12 weeks
Progression Free Survival (PFS)	PFS is defined as the time from the time of first treatment on study until disease's progression or death as a result of any cause.	Up to 5 years after completion of treatment
Response Rate	Response rate will include confirmed complete response (CR) + confirmed partial response (PR) and will be determined as per RECIST1.1.	Up to 5 years after completion of treatment
Overall Survival	Overall survival will be measured from the time of first treatment on study until death or last follow-up.	Up to 5 years after completion of treatment
Surgical Outcomes	Surgical outcomes will be assessed by the Clavien-Dindo classification system, which ranks the severity of surgical complications. The scale consists of several grades (Grade I, II, IIIa, IIIb, IVa, IVb and V) from Grade I being of low severity outcome to Grade V being highest and worst outcome.	Up to 5 years after completion of treatment

Collaborators and Investigators

• Sponsor: Mark Stein
• Collaborators: Bristol-Myers Squibb; Exelixis
• Investigators: Principal Investigator: Mark N Stein, MD, Associate Professor of Medicine Division of Hematology/Oncology

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2020
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: February 10, 2020
• First Submitted That Met QC Criteria: March 25, 2020
• First Posted (Actual): March 26, 2020

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Neoplasms; Carcinoma, Renal Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: AAAS6927

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No