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A Study of Nivolumab In Combination With Cabozantinib in Patients With Non-Clear Cell Renal Cell Carcinoma

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ClinicalTrials.gov Identifier: NCT03635892
Recruitment Status : Recruiting
First Posted : August 17, 2018
Last Update Posted : October 11, 2018
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The purpose of this study is to compare any good and bad effects of using a combination of nivolumab (Opdivo®) and cabozantinib (Cabometyx®) in people with metastatic kidney cancer.

Condition or disease Intervention/treatment Phase
Advanced or Metastatic Non-clear Cell Renal Cell Carcinoma Drug: cabozantinib Drug: nivolumab Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single institution open-label phase II trial of cabozantinib and nivolumab in patients with advanced or metastatic non-clear cell Renal Cell Carcinoma (nccRCC), who have not received prior PD-1/PD-L1 directed therapy.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Open-Label Study of Nivolumab Combined With Cabozantinib in Subjects With Advanced or Metastatic Non-Clear Cell Renal Cell Carcinoma (CA209-9KU)
Actual Study Start Date : August 13, 2018
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: cabozantinib in combination with nivolumab
Cycle length will be defined as 28 days. Treatment will include cabozantinib 40mg, self administered orally once daily on a continuous schedule (days 1-28), and nivolumab 3mg/kg, administered intravenously on days 1 and 15 of each cycle ± 3 days. Treatment will be continued until confirmed disease progression, major toxicity, or withdrawal from the study for any reason.
Drug: cabozantinib
cabozantinib 40mg, self administered orally once daily on a continuous schedule (days 1-28)
Other Name: CABOMETYX®

Drug: nivolumab
nivolumab 3mg/kg, administered intravenously on days 1 and 15 of each cycle ± 3 days
Other Name: Opdivo




Primary Outcome Measures :
  1. objective response rate [ Time Frame: 2 years ]
    per RECIST v1.1



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

Inclusion Criteria:

  • Signed and dated IRB-approved Informed Consent Form
  • Pathologic or histologically confirmed unresectable advanced or metastatic nccRCC
  • 0 or 1 prior systemic therapies, including treatment in the adjuvant setting
  • Availability of a representative formalin fixed, paraffin embedded tumor specimen or fresh frozen tissue specimen that enables the definitive diagnosis of RCC, accompanied by an associated pathology report. Specimens can be collected by surgical resection or biopsy of the primary tumor or biopsy or resection of a metastatic lesion.
  • Measurable disease, as defined by RECIST 1.1
  • Age ≥18 years
  • KPS ≥ 70
  • Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless adverse events (AE(s)) are clinically nonsignificant and/or stable on supportive therapy.
  • Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:

    • ANC ≥ 1500 cells/μL (without granulocyte colony stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
    • WBC counts ≥ 2500/μL and ≤ 15,000/μL without G-CSF
    • Lymphocyte count ≥ 500/μL
    • Platelet count ≥100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
    • Hemoglobin ≥9.0 g/dL
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN with documented bone metastases.
  • Serum bilirubin ≤ 1.5 x ULN
  • Serum albumin ≥ 2.8 g/dl
  • Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
  • INR and aPTT ≤ 1.5 x ULN • This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
  • Creatinine ≤ 2.0 x ULN or Calculated Creatinine clearance ≥ 30mL/min
  • For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use two adequate methods of contraception, including at least one method with a failure rate of ≥ 1% per year
  • Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
  • Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 5 months after the last dose of study treatment for females and 7 months for males.
  • Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy).

However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.

  • Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.

Exclusion Criteria:

  • Prior treatment with an immunotherapy agent including high dose IL-2, anti-CTLA-4, anti-PD1, and anti-PD-L1 agents
  • Prior treatment with cabozantinib for non-clear cell RCC
  • Receipt of any type of small molecule kinase inhibitor within 2 weeks of treatment.
  • Receipt of any type of anti-cancer antibody, cytotoxic anticancer therapy, or any other investigational agents within 4 weeks of treatment start
  • Known malignancies of the brain or spinal cord or leptomeningeal disease
  • Patients requiring pain medication must be on a stable regimen at study entry
  • Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroids > 10 mg daily prednisone equivalents are allowed in the absence of autoimmune disease
  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
  • Uncontrolled hypercalcemia (≥ 1.5 mmol/L ionized calcium or Ca ≥ 12 mg/dL or corrected serum calcium ≥ ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
  • Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy
  • Pregnant and lactating women History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • History of HIV infection
  • Patients with active or chronic hepatitis B or hepatitis C infection
  • Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 6 months, unstable arrhythmias, unstable angina, or EF < 50%
  • Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
  • Patients with known coronary artery disease, congestive heart failure not meeting the above criteria must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
  • Major surgery (eg, 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 (eg, simple excision, biopsy, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
  • History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1
  • Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
  • Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
  • Patients with a history of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to study enrollment
  • Other clinically significant disorders that would preclude safe study participation

    • Serious non-healing wound/ulcer/bone fracture
    • Uncompensated/symptomatic hypothyroidism
    • Moderate to severe hepatic impairment (Child-Pugh B or C)
  • Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility
  • Inability to swallow tablets or capsules
  • Previously identified allergy or hypersensitivity to components of the study treatment formulations
  • Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
  • The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 14 days of first dose of study treatment
  • Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).

Allowed anticoagulants are the following:

  • Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted
  • Low-dose low molecular weight heparins (LMWH) are permitted
  • Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor

    • Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose
    • Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
    • The subject has tumor invading or encasing any major blood vessels
    • 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
    • Uncontrolled hypertension (>150 mmHg systolic or > 100 mmHg diastolic despite optimal antihypertensive treatment)
    • Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible. Radiation for palliation is allowable on study.

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): NCT03635892


Contacts
Contact: Chung-Han Lee, MD, PhD 646-888-5418 leec4@mskcc.org
Contact: Robert Motzer, MD 646-888-4722

Locations
United States, New Jersey
Memoral Sloan Kettering Basking Ridge Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Chung-Han Lee, MD, PhD    646-888-5418      
Memoral Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: Chung-Han Lee, MD, PhD    646-888-5418      
Memorial Sloan Kettering Bergen Recruiting
Montvale, New Jersey, United States, 07645
Contact: Chung-Han Lee, MD, PhD    646-888-5418      
United States, New York
Memorial Sloan Kettering Commack Recruiting
Commack, New York, United States, 11725
Contact: Chung-Han Lee, MD,PhD    646-888-5418      
Memoral Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Chung-Han Lee, MD, PhD    646-888-5418      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Chung-Han Lee, MD, PhD    646-888-5418      
Contact: Robert Motzer, MD    646-888-4722      
Memorial Sloan Kettering Rockville Centre Recruiting
Rockville Centre, New York, United States, 11570
Contact: Chung-Han Lee, MD, PhD    646-888-5418      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Investigators
Principal Investigator: Chung-Han Lee, MD, PhD Memorial Sloan Kettering Cancer Center

Additional Information:
Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03635892     History of Changes
Other Study ID Numbers: 18-254
First Posted: August 17, 2018    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: October 2018

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

Keywords provided by Memorial Sloan Kettering Cancer Center:
Nivolumab
Cabozantinib
18-254

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