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Randomized Phase II Study Comparing Cabozantinib (NSC #761968 and IND #116059) With Commercially Supplied Sunitinib in Patients With Previously Untreated Locally Advanced or Metastatic Renal Cell Carcinoma

Phase 2
18 Years
Not Enrolling
Clear Cell Renal Cell Carcinoma, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer

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Trial Information

Randomized Phase II Study Comparing Cabozantinib (NSC #761968 and IND #116059) With Commercially Supplied Sunitinib in Patients With Previously Untreated Locally Advanced or Metastatic Renal Cell Carcinoma


I. To determine if patients with renal cancer treated with cabozantinib
(cabozantinib-s-malate) will have improved progression-free survival compared to patients
treated with sunitinib (sunitinib malate).


I. To determine whether the response rate of patients with renal cancer treated with
cabozantinib will be higher when compared with patients treated with sunitinib.

II. To determine whether patients with renal cancer treated with cabozantinib will have an
improved overall survival when compared with patients treated with sunitinib.


I. To determine whether renal cancer patients with high met proto-oncogene (MET) expression
by immunohistochemistry (IHC) have improvement in progression-free survival compared to
patients with low MET expression on both arms of this study.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cabozantinib-s-malate orally (PO) daily for 6 weeks. Courses repeat
every 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive sunitinib malate PO daily for 4 weeks. Courses repeat every 6 weeks
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Inclusion Criteria:

- Histologic documentation: renal cell carcinoma with some component of clear cell

- Stage: locally advanced (defined as disease not amenable to curative surgery or
radiation therapy) or metastatic renal cell carcinoma (RCC) (equivalent to stage IV
RCC, according to American Joint Committee on Cancer [AJCC] staging)

- Eligible patients must be intermediate/poor risk, per the International Metastatic
Renal Cell Carcinoma (mRCC) Database Consortium (Heng) criteria defined as one or
more of the following six factors:

- Time from diagnosis of RCC to systemic treatment < 1 year

- Hemoglobin < the lower limit of normal (LLN)

- Corrected calcium > the upper limit of normal (ULN)

- Karnofsky performance status < 80%

- Neutrophil count > ULN

- Platelet count > ULN

- No radiographic evidence of cavitating pulmonary lesion(s)

- No tumor in contact with, invading or encasing any major blood vessels; tumor
abutting the vessels is acceptable

- No evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach,
small or large bowel, rectum or anus), or any evidence of endotracheal or
endobronchial tumor within 28 days prior to registration

- No prior systemic treatment for RCC; supportive therapies such as bisphosphonates
(zoledronic acid) or denosumab are permitted

- Patients must not have had a major surgical procedure or significant traumatic injury
within 4 weeks prior to study registration, and must have fully recovered from any
such procedure; the following are not considered to be major procedures:
thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy,
endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional
biopsies, imaging-guided biopsy for diagnostic purposes, and routine dental

- Radiation

- to the brain, thoracic cavity, abdomen, or pelvis must be completed within 90
days before registration;

- to bone must be completed within 14 days before registration; and

- to any other sites must be completed within 28 days before registration

- No chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine,
rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort)

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria; lesions that can be accurately measured in at least one dimension
(longest diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1
cm with spiral computed tomography (CT) scan

- No active brain metastases; patients with treated, stable brain metastases for at
least three months are eligible as long as they meet the following criteria:

- Treated brain metastases are defined as having no ongoing requirement for
steroids and no evidence of progression or hemorrhage after treatment for at
least 3 months, as ascertained by clinical examination and brain imaging
(magnetic resonance imaging [MRI] or CT); (stable dose of anticonvulsants are
allowed); treatment for brain metastases may include whole brain radiotherapy
(WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or
equivalent) or a combination as deemed appropriate by the treating physician;
patients with central nervous system (CNS) metastases treated by neurosurgical
resection or brain biopsy performed within 3 months prior to registration are
not eligible

- Baseline brain imaging (MRI/CT) is required

- No serious non-healing wound, ulcer, or bone fracture

- No arterial thrombotic events within 6 months prior to registration, including
transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial
thrombus, unstable angina or angina requiring surgical or medical intervention in the
6 months prior to registration, or myocardial infarction (MI); patients with
clinically significant peripheral artery disease (i.e., claudication on less than one
block), significant vascular disease (i.e., aortic aneurysm, history of aortic
dissection), or any other arterial thrombotic event are ineligible

- No history of pulmonary embolism or untreated deep venous thrombosis (DVT) within 6
months prior to registration; note: patients with recent DVT who have been treated
with therapeutic anticoagulanting agents for at least 6 weeks are eligible; patients
receiving warfarin are not eligible, but could be switched to low molecular weight
heparin if acceptable to the treating physician

- No inadequately controlled hypertension (defined as a blood pressure of >= 150 mmHg
systolic and/or >= 90 mmHg diastolic), or any prior history of hypertensive crisis or
hypertensive encephalopathy

- No New York Heart Association (NYHA) class >= 2 congestive heart failure

- Ejection fraction on echocardiogram (Echo) or multi gated acquisition scan (MUGA) >

- No corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within
28 days before randomization; note: if initial QTcF is found to be > 500 ms, two
additional electrocardiograms (EKGs) separated by at least 3 minutes should be
performed; if the average of these three consecutive results for QTcF is =< 500 ms,
the subject meets eligibility in this regard

- No evidence of active bleeding or bleeding diathesis, or hemoptysis within 6 weeks
prior to registration

- No history of abdominal fistula, gastrointestinal perforation or intra-abdominal
abscess within 6 months prior to registration

- No active peptic ulcer disease, within 28 days before registration

- No inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis within 28 days
before registration

- No malabsorption syndrome within 28 days before registration

- No untreated hypothyroidism; patients with hypothyroidism on therapy are required to
have thyroid stimulating hormone (TSH) within normal limits

- No radiologic or clinical evidence of pancreatitis

- Patients who are pregnant or nursing are not eligible; women of child bearing
potential must have a negative serum or urine pregnancy test within 16 days prior to
registration; women of child-bearing potential include:

- Any female who has experienced menarche and who has not undergone surgical
sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy)
or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)

- Women on hormone replacement therapy (HRT) with documented serum follicle
stimulating hormone (FSH) level > 35m IU/mL

- Women who are using oral, implanted or injectable contraceptive hormones or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence
or where partner is sterile (e.g., vasectomy)

- Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2 or Karnofsky score
>= 60%

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelet count >= 100,000/uL

- Hemoglobin >= 9 g/dL; patients may not have had a transfusion within 7 days prior to
screening assessment

- Total bilirubin =< 1.5 x upper limits of normal

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN

- Serum creatinine =< 1.5 x ULN, OR calculated creatinine clearance >= 30 mL/minute
(modified Cockroft and Gault formula)

- Urine protein to creatinine (UPC) ratio < 1.0; if UPC >= 1, then a 24-hour urine
protein must be assessed; eligible patients must have a 24-hour urine protein value <
1 g

- Total serum calcium < 12 mg/dL

- International normalized ratio (INR) =< 1.2 x ULN; subjects receiving anticoagulant
therapy are eligible if their INR is stable and within the recommended range for the
desired level of anticoagulation

- TSH within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival (PFS)

Outcome Description:

The primary analysis will be based on the stratified log-rank statistic to compare the two treatment arms on PFS. The Kaplan-Meier product-limit estimator will be used to estimate PFS distributions.

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Toni Choueiri

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B


United States: Food and Drug Administration

Study ID:




Start Date:

November 2012

Completion Date:

Related Keywords:

  • Clear Cell Renal Cell Carcinoma
  • Stage III Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Carcinoma
  • Carcinoma, Renal Cell



Cancer and Leukemia Group B Chicago, Illinois  60606