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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04071223
Other study ID # NCI-2019-05619
Secondary ID NCI-2019-05619A0
Status Recruiting
Phase Phase 2
First received
Last updated
Start date July 29, 2020
Est. completion date October 1, 2024

Study information

Verified date June 2024
Source National Cancer Institute (NCI)
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This phase II trial studies whether adding radium-223 dichloride to the usual treatment, cabozantinib, improves outcomes in patients with renal cell cancer that has spread to the bone. Radioactive drugs such as radium-223 dichloride may directly target radiation to cancer cells and minimize harm to normal cells. Cabozantinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving radium-223 dichloride and cabozantinib may help lessen the pain and symptoms from renal cell cancer that has spread to the bone, compared to cabozantinib alone.


Description:

PRIMARY OBJECTIVE: I. To assess the symptomatic skeletal event (SSE)-free survival of metastatic renal cell cancer (mRCC) patients with bone metastases treated with cabozantinib S-malate (cabozantinib) + radium Ra 223 dichloride (radium-223 dichloride) compared to cabozantinib alone. SECONDARY OBJECTIVES: I. To investigate the safety, toxicity and tolerability as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 in patients treated with cabozantinib + radium-223 dichloride compared to cabozantinib alone. II. To assess SSE-free survival of each treatment arm in predefined sub-groups. III. To assess progression-free survival (PFS) in each treatment arm. IV. To assess overall survival (OS) in each treatment arm. V. To assess time to first SSE (defined as first use of radiation therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or non-vertebral bone fractures, spinal cord compression, or symptomatic tumor-related orthopaedic surgical intervention) in each treatment arm. VI. To assess the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. VII. To assess time to subsequent anti-cancer systemic therapy and type of systemic therapy. EXPLORATORY QUALITY OF LIFE OBJECTIVES: I. To compare patient-reported pain as assessed by the Brief Pain Inventory questionnaire (BPI) between patients randomized to cabozantinib versus cabozantinib + radium-223 dichloride at 6 months. II. To compare patient-reported pain as assessed by the BPI between patients randomized to cabozantinib versus cabozantinib + radium-223 dichloride at other timepoints. III. To compare overall health-related quality of life as assessed by the Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health 10 between patients randomized to cabozantinib versus cabozantinib + radium-223 dichloride. IV. To compare quality-adjusted survival (overall survival x utility score assessed by European Quality of Life Five Dimension Five Level Scale [EQ5D-5L]) between patients randomized to cabozantinib + radium-223 dichloride. CORRELATIVE OBJECTIVES: I. To evaluate changes in the following bone turnover markers between arms: Ia. Marker of bone formation: P1NP, BSAP. Ib. Marker of bone resorption: CTX, NTX. II. To correlate changes in bone turnover markers with SSE-free survival. III. To assess the immunomodulatory properties of cabozantinib with or without radium-223 dichloride at baseline, during treatment, and at progression. IV. To identify prognostic and predictive genomic biomarkers of response to cabozantinib and radium-223 dichloride via assessment of tissue, circulating tumor cells (CTCs) and circulating tumor deoxyribonucleic acid (DNA) (cfDNA). V. To assess the association between bone response according to MD Anderson response criteria and SSE-free survival (FS). VI. To correlate change in level of total alkaline phosphatase and bone-specific alkaline phosphatase to overall response to cabozantinib + radium-223 dichloride compared to cabozantinib alone. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive radium Ra 223 dichloride intravenously (IV) over 1 minute on day 1 of cycles 1-6 and cabozantinib S-malate orally (PO) once daily (QD) on days 1-28 of every cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. All patients undergo blood sample collection, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI), and may undergo fludeoxyglucose (FDG)-positron emission tomography (PET) or sodium fluoride (NaF)-PET throughout the study. After completion of study treatment, patients are followed up every 6 months for up to 5 years from study registration.


Recruitment information / eligibility

Status Recruiting
Enrollment 134
Est. completion date October 1, 2024
Est. primary completion date October 1, 2024
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Documented histologic or cytologic diagnosis of renal cell cancer (RCC). All subtypes of RCC are eligible including but not limited to clear cell, papillary, chromophobe, translocation, collecting duct carcinoma, medullary carcinoma, and unclassified categories. Enrollment of non-clear cell patients will be limited to 20% of the total sample size (~ 42 patients). Once this goal is met, accrual of non-clear cell patients will be discontinued (a notice will be sent out 2 weeks in advance). Sarcomatoid and rhabdoid differentiation are allowed - Presence of at least 1 metastatic bone lesion not treated with prior radiation is required. - The presence of bone metastases can be detected by computed tomography (CT), magnetic resonance imaging (MRI), Tc-99m bone scan or positron emission tomography (PET) (fludeoxyglucose F-18 [FDG] or sodium fluoride [NaF]) imaging. Patients with non-measurable bone-only disease are allowed. Patients may have received prior radiation therapy for bone metastases or other external radiation >= 7 days prior to registration, as long as they still have at least 1 metastatic bone lesion not treated with radiation. Patients with visceral metastases are allowed, as long as they have at least one untreated bone metastases - No prior treatment with cabozantinib - No treatment with any type of small molecular kinase inhibitor (including investigational kinase inhibitors) within 2 weeks or 5 half-lives (whichever is shorter) of registration or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of registration - No prior hemibody external radiotherapy - No prior therapy with radium-223 dichloride or systemic radiotherapy (such as samarium, strontium) - No major surgery within 6 weeks of randomization. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Moh's or other topical skin surgery, Lasik eye surgery are not considered major surgery. Patients who have had a nephrectomy may be registered >= 3 weeks after surgery, providing there are no wound-healing complications. Subjects with clinically relevant ongoing complications from prior surgery are not eligible - Recovery to baseline or =< grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically nonsignificant and/or stable on supportive therapy - The use of osteoclast targeted therapy including either bisphosphonates or denosumab is mandated on this study except in patients with contraindications as determined by the treating investigator, including: - Hypocalcemia - Hypophosphatemia - Renal impairment including those with a glomerular filtration rate (GFR) < 35 mL/min using the Cockcroft-Gault equation or acute renal impairment - Hypersensitivity to drug formulation - Dental condition or need for dental intervention that per the investigator would increase the risk of osteonecrosis of jaw (ONJ). - Use of osteoclast targeted therapy or reason against use needs to be recorded in the electronic case report form (eCRF). Additionally, reason for discontinuation of osteoclast targeted therapy need to be appropriately documented in the eCRF - Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. - Therefore, for women of childbearing potential only, a negative urine pregnancy test done =< 28 days prior to registration is required. A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) - Age >= 18 years - Karnofsky performance status >= 60% - No brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator - No imminent or established spinal cord compression based on clinical symptoms and/or imaging. In patients with untreated imminent or established spinal cord compression, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration - No imminent or impending pathologic fracture based on clinical symptoms and/or imaging. In patients with untreated imminent or impending pathologic fracture, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration - No significant, uncontrolled intercurrent or recent illness, including but not limited to the following conditions: - Cardiovascular disorders: Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia; uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment; stroke (including transient ischemic attack), myocardial infarction, or other ischemic event, within 6 months before randomization; thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization - Gastrointestinal disorders: Disorders associated with a high risk of perforation or fistula formation: active inflammatory bowel disease, active diverticulitis, active cholecystitis, active symptomatic cholangitis or active appendicitis, active acute pancreatitis or active acute obstruction of the pancreatic or biliary duct, or active gastric outlet obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 3 months before randomization. Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization - No clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization - No lesions invading major pulmonary blood vessels - No other clinically significant disorders: - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]) with undetectable viral load within 6 months are eligible for this trial - For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]), if indicated - Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load (with no medications prohibited by this protocol [e.g. drug-drug interactions]) - No serious non-healing wound or ulcer - No malabsorption syndrome - No uncompensated/symptomatic hypothyroidism - No moderate to severe hepatic impairment (Child-Pugh B or C) - No requirements for hemodialysis or peritoneal dialysis - No history of solid organ transplantation - No chronic concomitant treatment with strong CYP3A4 inducers or inhibitors. Because the list of these agents is constantly changing, it is important to regularly consult a frequently updated medical reference. Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7 days prior to registration - No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants include: - Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). - Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor. - Absolute neutrophil count (ANC) >= 1,500/mm^3 - Platelet count >= 100,000/mm^3 - Hemoglobin >= 9 g/dl (transfusions allowed) - Calculated (calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation - Total bilirubin =< 1.5 x upper limit of normal (ULN), for patients with Gilberts disease =< 3.0 x ULN - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN - Urine protein to creatinine (UPC) ratio =< 2 mg/mg OR 24-hr urine protein < 2 g

Study Design


Related Conditions & MeSH terms


Intervention

Procedure:
Biospecimen Collection
Undergo blood sample collection
Bone Scan
Undergo bone scan
Drug:
Cabozantinib S-malate
Given PO
Procedure:
Computed Tomography
Undergo CT
Magnetic Resonance Imaging
Undergo MRI
Positron Emission Tomography
Undergo FDG-PET or NaF-PET
Other:
Quality-of-Life Assessment
Ancillary studies
Questionnaire Administration
Ancillary studies
Radiation:
Radium Ra 223 Dichloride
Given IV

Locations

Country Name City State
United States Mission Cancer and Blood - Ankeny Ankeny Iowa
United States Trinity Health Saint Joseph Mercy Hospital Ann Arbor Ann Arbor Michigan
United States University of Alabama at Birmingham Cancer Center Birmingham Alabama
United States Dana-Farber Cancer Institute Boston Massachusetts
United States UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina
United States Rush University Medical Center Chicago Illinois
United States University of Chicago Comprehensive Cancer Center Chicago Illinois
United States Ohio State University Comprehensive Cancer Center Columbus Ohio
United States Siteman Cancer Center at West County Hospital Creve Coeur Missouri
United States UT Southwestern Simmons Cancer Center - RedBird Dallas Texas
United States UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas
United States Cancer Care Specialists of Illinois - Decatur Decatur Illinois
United States Iowa Methodist Medical Center Des Moines Iowa
United States Mission Cancer and Blood - Des Moines Des Moines Iowa
United States Henry Ford Hospital Detroit Michigan
United States Duke University Medical Center Durham North Carolina
United States UT Southwestern/Simmons Cancer Center-Fort Worth Fort Worth Texas
United States University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa
United States University of Kansas Cancer Center Kansas City Kansas
United States University of Kansas Cancer Center - North Kansas City Missouri
United States UC San Diego Moores Cancer Center La Jolla California
United States University of Kansas Cancer Center - Lee's Summit Lee's Summit Missouri
United States Trinity Health Saint Mary Mercy Livonia Hospital Livonia Michigan
United States Minnesota Oncology Hematology PA-Maplewood Maplewood Minnesota
United States Loyola University Medical Center Maywood Illinois
United States East Jefferson General Hospital Metairie Louisiana
United States LSU Healthcare Network / Metairie Multi-Specialty Clinic Metairie Louisiana
United States Medical College of Wisconsin Milwaukee Wisconsin
United States UC Comprehensive Cancer Center at Silver Cross New Lenox Illinois
United States Tulane University School of Medicine New Orleans Louisiana
United States NYP/Weill Cornell Medical Center New York New York
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States University of Chicago Medicine-Orland Park Orland Park Illinois
United States University of Kansas Cancer Center-Overland Park Overland Park Kansas
United States University of Pittsburgh Cancer Institute (UPCI) Pittsburgh Pennsylvania
United States UPMC-Shadyside Hospital Pittsburgh Pennsylvania
United States UT Southwestern Clinical Center at Richardson/Plano Richardson Texas
United States University of California Davis Comprehensive Cancer Center Sacramento California
United States Missouri Baptist Medical Center Saint Louis Missouri
United States Siteman Cancer Center-South County Saint Louis Missouri
United States Washington University School of Medicine Saint Louis Missouri
United States Siteman Cancer Center at Saint Peters Hospital Saint Peters Missouri
United States Huntsman Cancer Institute/University of Utah Salt Lake City Utah
United States University of Kansas Hospital-Westwood Cancer Center Westwood Kansas
United States UMass Memorial Medical Center - University Campus Worcester Massachusetts

Sponsors (1)

Lead Sponsor Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Symptomatic skeletal event (SSE)-free survival (FS) SSE-FS distribution will be estimated using the method of Kaplan-Meier by treatment arm. Comparison between the two arms will be performed using a one-sided log-rank test and one-sided p-value less than 0.025 will indicate that the experimental arm is superior to the control arm. SSE-FS will be censored at the date of last SSE assessment for those alive and SSE free. Hazard ratio (experimental over control arm) as well as two-sided 90% confidence interval (CI) for treatment will be estimated using the stratified Cox proportional hazard model with a single treatment covariate. From the date of randomization to the date of the earliest occurrence of SSE or death from any cause, assessed up to 5 years
Secondary Incidence of adverse events Will be determined using Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized and compared between arms using chi-square or fisher exact tests as appropriate. Up to 5 years
Secondary SSE-FS Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test. From randomization to the date of SSE or death due to any cause, whichever comes first, assessed up to 5 years
Secondary Progression-free survival Radiographic progression will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test. From randomization to time of radiographic progression or death due to any cause, whichever occurs first, assessed up to 5 years
Secondary Overall survival Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test. Patients who are alive will be censored at last follow up date. From randomization to the date of death due to any cause, assessed up to 5 years
Secondary Time to first SSE Will be determined in each treatment. The median estimate to first SSE-FS will be calculated. From randomization to the date of first SSE or death due to any cause, assessed up to 5 years
Secondary Overall response rate (ORR) Will be defined by RECIST version 1.1. Number and proportion of patients achieving ORR (by RECIST) will be summarized with two-sided 90% CI by treatment arm; comparison between arms will be conducted using chi-square or Fisher's exact test as appropriate. Up to 5 years
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