Inclusion Criteria:
- Subjects are eligible to be included in the study only if all the following criteria
apply:
Disease Related
1. Histologically or cytologically confirmed metastatic/recurrent ACC not amenable to
potentially curative surgery or radiotherapy
2. Evidence of disease progression Note: Disease progression is defined as one of the
following occurring within the 6 months prior to study entry:
1. At least a 20% increase in radiologically or clinically measurable lesions
2. Appearance of any new lesions
3. Presence of at least one measurable target lesion which is evaluable by RECIST v1.1
criteria
4. Patients are eligible if CNS metastases have been treated and patients are
neurologically returned to baseline or neurologically stable in the opinion of
Investigator (except for residual signs or symptoms related to the CNS treatment) for
at least 4 weeks prior to first dose of study drug administration. In addition,
patients must be either off corticosteroids, or on a stable dose or decreasing dose of
<20 mg daily prednisone or prednisone equivalent.
Note: Only subjects with a known history or indication of CNS disease are required to
have CNS imaging prior to study entry
5. Adequate organ and marrow function within 14 days prior to the first dose of
rivoceranib administration, defined as:
1. Absolute neutrophil count ≥1500/μL
2. Platelet count ≥100,000/μL
3. Serum bilirubin ≤1.5× upper limit of normal (ULN)
4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×ULN
(≤5.0×ULN, if with liver metastasis)
5. Estimated Creatinine Clearance >50 mL/min (Cockcroft-Gault)
6. Partial thromboplastin time (PTT), prothrombin time (PT) and international
normalized ratio (INR) ≤1.5×ULN
7. Hemoglobin ≥9.0 g/dL
6. Urinary protein <2+ on dipstick or routine urinalysis. If urine dipstick or routine
analysis indicates proteinuria ≥2+, a 24-hour urine or urine protein/creatinine ratio
must be collected and must demonstrate <2 g of protein in 24 hours Demographic
7. Men and women ≥18 years of age (or age of majority, if higher per local regulations)
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Ethical/Other
9. The ability to understand and the willingness to sign a written informed consent
10. Female subjects who are of non-reproductive potential (i.e. post-menopausal by history
- no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal
ligation; OR history of bilateral oophorectomy). Female subjects of childbearing
potential must have a negative serum pregnancy test within 72 hours prior to the first
dose of rivoceranib
11. Male and female subjects of reproductive potential who agree to use both a highly
effective method of birth control (e.g. implants, injectables, combined oral
contraceptives, some intrauterine devices, complete abstinence, or sterilized partner)
and a barrier method (e.g. condoms, cervical ring, sponge, etc.) during the period of
therapy and for 30 days after the final dose of rivoceranib. Female subjects should
also refrain from breastfeeding and egg donation and males should refrain from sperm
donation throughout this period
12. QTc interval <480 milliseconds (ms) (CTCAE Grade 1) using Fredericia's QT correction
formula
Exclusion Criteria:
- Subjects will be excluded from the study if any of the following criteria apply:
Disease Related
1. Previous treatment with rivoceranib
2. Known hypersensitivity to rivoceranib or components of the formulation
3. Packed red blood cell transfusion or erythropoietin therapy within 14 days prior to
the first dose of rivoceranib administration
4. History of another malignancy within 3 years prior to enrollment. A subject with the
following malignancies is eligible for this study if, surgically and medically treated
and in the opinion of the investigator, they do not pose a significant risk to life
expectancy or not likely to recur within 3 years:
1. Carcinoma of the skin without melanomatous features
2. Curatively treated cervical carcinoma in situ
3. Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in
situ (Tis)
4. Thyroid papillary cancer with prior treatment
5. Prostate cancer which has been surgically or medically treated
5. Prior chemotherapy, radiation therapy or major surgery within 4 weeks prior to
rivoceranib administration or presence of any nonhealing wound (procedures such as
catheter placement are not considered to be major surgery). Prior immunotherapy within
12 weeks prior to first dose of study drug. Palliative radiotherapy to non-target
lesions within 2 weeks prior to rivoceranib administration or biopsy any time prior to
rivoceranib administration is permitted
6. Prior tyrosine kinase inhibitor therapy targeting vascular endothelial growth factor
receptors (VEGFR), within 5 half-lives prior to rivoceranib administration
7. Subjects who have not recovered to ≤ Grade 1 from prior tyrosine kinase
inhibitor-related adverse events
8. History of uncontrolled hypertension based on Investigator's clinical judgement
(consistent blood pressure readings ≥140/90 mmHg and/or change in antihypertensive
medication within 7 days prior to rivoceranib administration)
9. History of severe adverse events including uncontrolled hypertension or other common
anti-angiogenesis class drug effects (e.g. ramucirumab) that may indicate a higher
risk to the safety of the subject if provided further anti-angiogenesis treatment, in
the investigator's opinion
10. History of vascular disease including arterial or venous embolic events (pulmonary
embolism), other than hypertension, within the last 3 months prior to treatment with
rivoceranib (e.g. hypertensive crisis, hypertensive encephalopathy, stroke or
transient ischemic attack [TIA], or significant peripheral vascular diseases) that, in
the investigator's opinion, may pose a risk to the subject on vascular endothelial
growth factor (VEGF) inhibitor therapy
11. History of bleeding diathesis or clinically significant bleeding within 14 days prior
to treatment with rivoceranib
12. History of clinically significant thrombosis within 3 months prior to treatment with
rivoceranib that, in the investigator's opinion, may place the subject at risk of side
effects from anti-angiogenesis products
13. Therapy with systemic anticoagulant or antithrombotic agents within 7 days prior to
treatment with rivoceranib that in the investigator's opinion could interfere with
clotting. The maximum allowable daily dose of aspirin is 325 mg
14. Gastrointestinal malabsorption, or any other condition that in the opinion of the
investigator might affect the absorption of rivoceranib
15. History of clinically significant glomerulonephritis, biopsy-proven tubulointerstitial
nephritis, crystal nephropathy, or other renal insufficiencies
16. An uncontrolled intercurrent illness including, but not limited to any of the
following:
1. Ongoing or active infection (including minor localized infections) requiring oral
or intravenous treatment
2. Symptomatic class 3 or 4 congestive heart failure, defined as a clinical syndrome
resulting from any structural or functional cardiac disorder that impairs the
ability of the ventricle to fill with or eject blood
3. Unstable angina pectoris
4. Cardiac arrhythmia
5. Any other illness or condition that the treating investigator feels would
interfere with study compliance or would compromise the subject's safety or study
endpoints Ethical/Other
17. A female subject who is pregnant or breast-feeding
18. Psychiatric illness/social situations that would limit compliance with study
requirements
19. History of drug or alcohol abuse within the past 5 years
20. Known seropositive requiring anti-viral therapy for human immunodeficiency virus (HIV)
infection
21. Known seropositive requiring antiviral therapy for hepatitis B virus (HBV) infection
OR evidence of active hepatitis B infection by detectable viral load if the antibody
tests are positive NOTE: A positive hepatitis B core antibody (HBcAb) subject with an
undetectable surface antigen and negative hepatitis B DNA test (e.g., polymerase chain
reaction [PCR] test) can be enrolled
22. Known seropositive requiring antiviral therapy for hepatitis C virus (HCV) infection
OR subjects with positive hepatitis C virus antibody NOTE: A positive Anti-HCV subject
with an undetectable/negative hepatitis C RNA test can be enrolled
23. Participation in another clinical study with any investigational medication or product
administered within ≤28 days prior to first dose of rivoceranib
24. Subjects unable or unwilling to discontinue excluded medications for at least 5
half-lives prior to first dose of study drug