Phase 2 Study to Evaluate the Efficacy and Safety of Rivoceranib in Subjects With Recurrent or Metastatic ACC

Open to people ages 18 years and up

• 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:
3. At least a 20% increase in radiologically or clinically measurable lesions
4. Appearance of any new lesions
5. Presence of at least one measurable target lesion which is evaluable by RECIST v1.1 criteria
6. Subjects with history of central nervous system (CNS) metastases are eligible if CNS disease has been stable, in the opinion of the investigator, for at least 4 weeks prior to study enrollment. Stable doses of corticosteroids (not to exceed 20 mg of prednisone) for symptomatic management are allowed Note: Only subjects with a known history or indication of CNS disease are required to have CNS imaging prior to study entry Laboratory
7. Adequate organ and marrow function within 14 days prior to the first dose of rivoceranib administration, defined as:
8. Absolute neutrophil count ≥1500/μL
9. Platelet count ≥100,000/μL
10. Serum bilirubin ≤1.5× upper limit of normal (ULN)
11. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0×ULN (≤5.0×ULN, if with liver metastasis)
12. Estimated Creatinine Clearance >50 mL/min (Cockcroft-Gault)
13. Partial thromboplastin time (PTT) and international normalized ratio (INR) ≤1.5×ULN
14. Hemoglobin ≥9.0 g/dL
15. 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
16. Men and women ≥18 years of age (or age of majority, if higher per local regulations)
17. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Ethical/Other
18. The ability to understand and the willingness to sign a written informed consent
19. . Female subjects who are of non-reproductive potential (i.e. post-menopausal by history
20. 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
21. . 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
22. . QTc interval > 480 milliseconds (ms) (CTCAE grade 2) using Fredericia's QT correction formula

• 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:
5. Carcinoma of the skin without melanomatous features
6. Curatively treated cervical carcinoma in situ
7. Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in situ (Tis)
8. Thyroid papillary cancer with prior treatment
9. Prostate cancer which has been surgically or medically treated
10. 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
11. Prior tyrosine kinase inhibitor therapy targeting vascular endothelial growth factor receptors (VEGFR), within 5 half-lives prior to rivoceranib administration
12. Subjects who have not recovered to ≤ Grade 1 from prior tyrosine kinase inhibitor-related adverse events
13. History of uncontrolled hypertension (blood pressure ≥140/90 mmHg and/or change in antihypertensive medication within 7 days prior to rivoceranib administration)
14. 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
15. . 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
16. . History of bleeding diathesis or clinically significant bleeding within 14 days prior to treatment with rivoceranib
17. . 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
18. . 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
19. . Gastrointestinal malabsorption, or any other condition that in the opinion of the investigator might affect the absorption of rivoceranib
20. . History of clinically significant glomerulonephritis, biopsy-proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies
21. . An uncontrolled intercurrent illness including, but not limited to any of the following:
22. Ongoing or active infection (including minor localized infections) requiring oral or intravenous treatment
23. 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
24. Unstable angina pectoris
25. Cardiac arrhythmia
26. 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
27. . A female subject who is pregnant or breast-feeding
28. . Psychiatric illness/social situations that would limit compliance with study requirements
29. . History of drug or alcohol abuse within the past 5 years
30. . Known seropositive requiring anti-viral therapy for human immunodeficiency virus (HIV) infection
31. . 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
32. . 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

1. . Participation in another clinical study with any investigational medication or product administered within ≤28 days prior to first dose of rivoceranib
2. . Subjects unable or unwilling to discontinue excluded medications for at least 2 weeks prior to first dose of rivoceranib