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.
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.
After completion of study treatment, patients are followed up every 6 months for up to 5
years from study registration.
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 2 metastatic bone lesions 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
>= 14 days prior to registration, as long as they still have at least 2
metastatic bone lesions that were not treated with radiation. Patients with
visceral metastases are allowed, as long as they have at least two untreated bone
metastases
- No more than 2 prior lines of systemic therapy including but not limited to
anti-angiogenic therapy, checkpoint inhibitors, mammalian target of rapamycin (mTOR)
inhibitors, clinical trial compounds or cytokine-based therapy. Prior radiation
therapy does not count as a prior systemic therapy
- No prior treatment with cabozantinb
- 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)
- Karnofsky performance status >= 60%
- Symptomatic bone pain defined as either regular use of analgesic medication for cancer
related bone pain (>= level 1; World Health Organization [WHO] ladder for cancer pain)
or prior SSE defined as bone pain requiring radiation, bone pain secondary to a
pathologic fracture related to a bone metastasis, symptomatic spinal cord compression
related to a bone metastasis, surgery to bone secondary to symptomatic bone metastasis
or radiographic progression of bone metastases as defined by the presence of bone
metastases on radiographic imaging
- 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; screening Fridericia's correction
formula (QTcF) =< 500 msec
- 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 >= 10 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 =< 1 mg/mg OR 24-hr urine protein < 1g
