Inclusion
1. Male and female subjects aged more than or equal to 18 years on the day of consent, with a documented histological or cytological diagnosis of advanced or metastatic renal cell carcinoma.
2. Subjects with evaluable or measurable disease per RECIST 1.1.
3. Systemic therapy-naïve subjects diagnosed with advanced or metastatic renal cell carcinoma and eligible to receive cabozantinib monotherapy (e.g., intermediate or poor IMDC risk score).
OR
Subjects diagnosed with advanced or metastatic renal cell carcinoma that are eligible to receive cabozantinib monotherapy, irrespective of the line of treatment (e.g., 1st, 2nd, 3rd, 4th, etc.) it may constitute, as per treating investigator’s clinical judgement and standard of care. Eligible subjects must have radiographically documented progression of disease, as per RECIST 1.1, on or after treatment. Prior therapies may include:
a. Vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitor (TKI) (i.e., sorafenib, sunitinib, axitinib, pazopanib lenvatinib, or tivozanib) as monotherapy or as a combination regimen (e.g., axitinib with pembrolizumab or avelumab, lenvatinib with everolimus or pembrolizumab),
b. Cytokines (i.e., interleukin-2, interferon-alfa)
c. Monoclonal antibodies as monotherapy (i.e., bevacizumab, anti-PD-1) or in combination (e.g., bevacizumab with everolimus or erlotinib, anti-PD-1 with anti-CTLA-4)
d. Cytotoxic chemotherapy (e.g., platinum based, gemcitabine with carboplatin or cisplatin, paclitaxel with carboplatin).
Please see Exclusion Criterion #2 and #3.
4. For subjects who have received VEGFR-targeting TKI, the following criteria must apply:
a. Must have radiographically documented progression either during treatment or been treated for at least 4 weeks and progressed within 6 months after the last dose. Radiographic progression is defined as per RECIST 1.1.
b. The last dose must have been within 6 months before the date of randomization.
5. Subjects who have achieved recovery to baseline or more than or equal to Grade 1 CTCAE version 5.0 from toxicities related to any prior treatments, unless adverse events are not clinically significant and/or stable on supportive therapy.
Note: For diarrhea only grade 0 (no diarrhea) is acceptable, per CTCAE version 5.0
6. Subjects with Karnofsky Performance Status (KPS) score of more than or equal to 70%..
7. Subjects with adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 7 days before randomization:
a. Absolute neutrophil count (ANC): more than or equal to 1500/mm3.
b. Platelets: more than or equal to 100,000/mm3.
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): less than or equal to 3.0 × upper limit of normal (ULN); [For subjects with liver metastases: less than or equal to 5 x ULN].
d. Total bilirubin: less than or equal to 1.5 X ULN; [For subjects with Gilbert’s disease or liver metastases, less than or equal to 3 mg/dL (less than or equal to 51.3 µmol/L).]
e. HbA1c: equal to 8%.
f. Calculated creatinine clearance: more than or equal to 30 mL/min (more than or equal to 0.5 mL/sec) using the Cockroft-Gault equation.
g. Electrolyte levels: serum calcium more than or equal to 8.5 mg/dL; magnesium more than or equal to 1.7 mg/dL; phosphorus more than or equal to 2.5 mg/dL
h. Within normal limits or clinically non-significant laboratory evaluation results for the coagulation parameters: PT, aPTT and INR
8. If a subject is female, she shall be: a) of non-childbearing potential or b) of childbearing potential practicing at-least two acceptable methods of contraception during the study and should use an effective form of birth control during study and for at least 4 months after the last dose of study treatment.
Acceptable contraceptive measures are:
a. Oral, parenteral, patch, or implant hormonal contraception
b. Intrauterine device (IUD) or intrauterine system (IUS)
c. Double barrier method of contraception (condom and occlusive cap or condom and spermicidal agent)
d. Male partner sterilization (at least 6 months prior to screening, should be the sole male partner for that subject)
e. Female sterilization (surgical bilateral oophorectomy) or tubal ligation at least 6 weeks prior to study participation
f. Total abstinence from heterosexual intercourse as part of routine lifestyle; partial abstinence is not acceptable
Note: Female subjects of childbearing potential (FOCBP) are defined as premenopausal females capable of becoming pregnant (i.e., 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.
9. Female subject will be considered of ‘non-childbearing’ potential if one of the following is reported and documented on the medical history:
a. Postmenopausal with spontaneous amenorrhea for at least one year, or spontaneous amenorrhea for less than one (less than 1) year with serum FSH levels more than 40mIU/ml, or
b. Bilateral oophorectomy with or without a hysterectomy and an absence of bleeding for at least 6 months before randomization, or
c. Total hysterectomy and an absence of bleeding for at least 3 months before randomization.
10. Female subjects of childbearing potential with negative serum pregnancy test at screening and negative urine pregnancy test at Day 1.
11. Male subjects whose partner is a FOCBP, should use effective birth control (e.g., condom, vasectomy with confirmed absence of sperm, sexual abstinence defined as refraining from heterosexual intercourse) during study and for at least 4 months after the last dose.
12. Subjects who are able to understand, and are willing to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments and will complete the subject diary.
13. Subjects with no history of addiction to any recreational drug or drug dependence or alcohol addiction.
14. Subject with left ventricular ejection fraction (LVEF) more than or equal to 50% by an echocardiogram during screening.
Exclusion
1. Subjects with known hypersensitivity to cabozantinib or to any of the excipients of the formulation.
2. Subjects who have received prior treatment with cabozantinib (including as an investigational product from participation in a previous clinical trial).
3. Subjects who have received any type of small molecule kinase inhibitor (including an investigational kinase inhibitor) or cytokine or chemotherapy or anticancer antibody (including an investigational antibody) within 28 days prior to randomization.
4. Subjects who have received radiation therapy for bone metastasis within 2 weeks prior to randomization, or any other external radiation therapy within 4 weeks before randomization. Subjects with clinically relevant ongoing complications from radiation therapy are also not eligible for enrolment in the study.
5. Subjects with active brain metastases, or carcinomatous meningitis or cranial epidural disease unless adequately treated (e.g., radiotherapy and/or surgery, etc.) and neurologically stable for at least 2 weeks prior to randomization without the use of corticosteroids or are on a stable or decreasing dose of less than or equal to 10 mg daily prednisone (or equivalent).
6. Subjects diagnosed with another malignancy within 2 years before randomization, except for superficial skin cancers, or localized low grade tumors deemed cured and not treated with systemic therapy.
7. Subjects with serious non-healing wounds, ulcers, or bone fractures, requiring intervention within 28 days prior to randomization.
8. Subjects with prior history of diarrhea more than Grade 3 or colitis more than or equal to Grade 3.
9. Subjects with arterial thrombotic events within 6 months prior to screening 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 screening, or myocardial infarction (MI).
10. Subjects with clinically significant peripheral artery disease (i.e., claudication on less than one block) or significant vascular disease (i.e., aortic aneurysm, history of aortic dissection).
11. Subjects with a history of pulmonary embolism or untreated deep venous thrombosis (DVT) within 6 months prior to screening. Note: Subjects with recent DVT who have been treated with therapeutic anticoagulation with low molecular weight heparin for at least 6 weeks are eligible at the discretion of the PI and Sponsor.
12. Subjects who are receiving therapeutic warfarin (more than 2 mg/day). Note: Subjects on warfarin may be switched to low molecular weight heparin at the discretion of the PI.
13. Subjects with ongoing need for a strong CYP3A4 inhibitors/inducer medication that cannot be switched to alternative treatment or that are not candidates to receive Cabozantinib at the study starting dose (e.g., 60 mg CABOMETYX® (cabozantinib) tablets or 39 mg Azurity Cabozantinib tablets) prior to study entry.
14. Subjects with uncontrolled hypertension (i.e., sustained systolic blood pressure more than or equal to 150 mmHg and/or diastolic blood pressure more than or equal to 90 mmHg despite optimal antihypertensive treatment).
15. Subjects with congestive heart failure based on New York Heart Association class 3 or 4.
16. Subjects with unstable cardiac arrhythmia within 6 months prior to screening.
17. During screening, subjects with corrected QT interval calculated by the Fridericia formula (QTcF) more than 480 msec.
18. Subjects with GI disorders including those associated with a high risk of perforation or fistula formation and/or sepsis:
a. Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, toxic megacolon, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction, or presence of an intestinal ostomy.
b. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months of screening. Complete healing of intra-abdominal abscess must be confirmed before randomization.
19. Subjects with positive serology for Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV).
Note: Subjects with Hepatitis B core antibody (HBcAb) positive result can be enrolled if a confirmatory negative test is obtained suggestive of no active infection currently
20. Subjects with uncompensated/symptomatic hypothyroidism.
21. Subjects with moderate to severe hepatic impairment (i.e., Child-Pugh B or C).
22. Subjects with known malabsorption syndrome.
23. Subjects requiring hemodialysis or peritoneal dialysis.
24. Subjects with a history of solid organ transplantation.
25. Subjects who had major surgery (i.e., GI surgery, removal or biopsy of brain metastasis) within 2 months of screening. Complete wound healing from major surgery must have occurred at least 1 month prior to randomization and from minor surgery (i.e., simple excision, tooth extraction) by at least 2 weeks before randomization.
26. Pregnant or lactating women, or female subjects unwilling to use any form of contraception during the study.
27. Subjects participating in any other clinical study within 30 days prior to enrolment into the study or have participated in a drug trial within 4 to 5 half-lives of the drug being tested, whichever was longer, prior to enrolment into the study.
28. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical condition or history, including laboratory results, which in the Investigator’s opinion, would be likely to interfere with the subject’s capacity to provide informed consent, with the subject’s participation in the study, or with the interpretation of the results.