Phase 1b/2 Study of Rivoceranib and Trifluridine/Tipiracil for Metastatic Colorectal Cancer

• Status: Recruiting
• Trial end date: 2020-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Comparing the efficacy of rivoceranib and trifluridine/tipiracil administered individually as monotherapies, as well as a rivocernib plus trifluridine/tipiracil combination therapy in the treatment of mCRC that is unresponsive to traditional chemotherapies.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Elevar Therapeutics; LSK BioPartners Inc.
• Treatments: Apatinib; Trifluridine

Criteria

Inclusion Criteria:

• Subjects are eligible to be included in the study only if all the following criteria apply:

Disease related

1. Histological or cytological confirmation of the diagnosis of mCRC

2. Failure to respond or be intolerant of at least 2 prior regimens of standard anti-cancer treatments (study treatment must be 3rd-line or greater for mCRC).

Failed prior treatments may include:

• Fluoropyrimidines-based chemotherapy

• Irinotecan-based chemotherapy

• Oxaliplatin-based chemotherapy

• Anti-Vascular Endothelial Growth Factor (VEGF) biological therapy

• Anti-Epidermal Growth Factor Receptor (EGFR) therapy, if RAS wild-type

• Immunotherapy (e.g., nivolumab, pembrolizumab and ipilimumab), in patients with Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/dMMR) Subjects who had received adjuvant chemotherapy and had recurrence during or within 6 months of completion of the adjuvant chemotherapy would be considered as 1 prior line of therapy

3. Have progressed based on imaging during or within 3 months of the last administration of most recent standard therapy

4. Have measurable disease, as defined by RECIST v1.1

Laboratory

5. Adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days prior to study treatment

• Absolute neutrophil count (ANC) ≥1,500/mm3

• Platelets ≥75,000/mm3

• Hemoglobin ≥9.0 g/dL

• Creatinine clearance (according to Cockcroft-Gault Equation or by 24 hr urine collection) > 50 mL/min and serum creatinine <1.0× ULN

• AST and ALT ≤3.0x ULN (≤5.0 × ULN for subjects with liver involvement of their cancer)

• Bilirubin ≤1.5 × ULN

• Alkaline phosphatase ≤2.5 × ULN (≤5 × ULN with liver involvement of their cancer)

• INR/PTT ≤1.5 × ULN (Subjects currently under treatment with anti-thrombotic agents such as warfarin or heparin with no abnormal coagulation values can participate in this study)

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 to allow participation in the study.

Demographic

7. Men and women at least 18 years of age at the time of study entry (or age of majority, if higher per local regulations)

8. Have an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 Ethical/Other

9. Able to understand and willing to provide written informed consent prior to enrollment in the study

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 upon study entry.

11. Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices, complete abstinence, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc.) during the period of therapy and for 3 months after the final dose of study drugs for male subjects and 6 months after the final dose of study drugs for female subjects. Female subjects should also refrain from breastfeeding and egg donation and males should refrain from sperm donation throughout this period.

12. In the assessment of the Investigator, subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

• Subjects will be excluded from the study if any of the following criteria apply:

Disease-related

1. Prior treatment with rivoceranib or trifluridine/tipiracil

2. Prior treatment with other VEGFR small molecule inhibitors (eg, regorafenib)

3. Packed red blood cell transfusion or erythropoietin therapy within 14 days prior to first dose of study drug

4. History of another malignancy within 3 years prior to Cycle 1 Day 1. A subject with the following malignancies is eligible for this study if, in the opinion of the Investigator, they do not pose a significant risk to life expectancy:

• Carcinoma of the skin without melanomatous features

• Curatively treated cervical carcinoma in situ

• Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in situ (Tis)

• Thyroid papillary cancer with prior treatment

• Prostate cancer which has been surgically or medically treated and not likely to recur within 3 years

5. Prior chemotherapy, radiation therapy or major surgery within 4 weeks prior to first dose of study drug or presence of any non-healing wound (a procedure such as catheter placement is 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 first dose of study drug or biopsy within 1 week prior to first dose of study drug is permitted

6. Active renal dysfunction that requires dialysis treatments

7. Active cardiac disease including any of the following:

• Congestive heart failure New York Heart Association (NYHA) ≥Class 2

• Myocardial infarction less than 6 months before the start of Cycle 1 Day 1 of treatment

8. Cardiac arrhythmias requiring antiarrhythmic therapy (beta-blockers or digoxin are permitted)

9. History of uncontrolled hypertension (blood pressure ≥140/90 mmHg and/or change in antihypertensive medication within 7 days prior to first dose of study drug)

10. History of antiangiogenic drug class-related severe adverse reactions, including uncontrolled hypertension or others related to prior therapy discontinuation and/or those that may indicate a higher risk to a subject's safety, in the Investigator's opinion, if provided further antiangiogenic treatment.

11. History of vascular disease including arterial or venous embolic events (pulmonary embolism), other than hypertension, within 6 months prior to Cycle 1 Day 1 (eg, 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 VEGF inhibitor therapy.

12. History of clinically significant thrombosis within 3 months prior to first dose of study drug that, in the Investigator's opinion, may place the subject at risk of side effects from antiangiogenics medications

13. History of bleeding diathesis or clinically significant bleeding within 14 days prior to first dose of study drug

14. Therapy with systemic anticoagulant or antithrombotic agents within 7 days prior to first dose of study drug that in the Investigator's opinion could interfere with clotting. The maximum allowable daily dose of aspirin is 325 mg

15. Subjects with unstable seizure disorder requiring medication changes within 3 months of Cycle 1 Day 1 treatment

16. Untreated or active central nervous system (CNS) or leptomeningeal metastases. Subjects are eligible if metastases have been treated and subjects are neurologically returned to baseline or neurologically stable (expect for residual signs and symptoms related to the CNS treatment) for at least 4 weeks prior to first dose of study drug. In addition, subjects must be either off corticosteroids, or on a stable dose or decreasing dose of ≤ 20 mg daily prednisone or prednisone-equivalent. A baseline radiological assessment of the brain will be performed on subjects who have prior history of metastases with CNS involvement

17. History of clinically significant glomerulonephritis, biopsy-proven nephritis, crystal nephropathy or other renal insufficiencies

18. Unresolved adverse reactions >Grade 1 excluding peripheral neuropathy or treatment related myelosuppression

19. Known hypersensitivity to any of the study drugs, study drug classes, or any components of study drug formulations

20. Inability to swallow oral medications

21. An active malabsorption condition, or any other condition that in the opinion of the Investigator might affect the absorption of study drug Ethical/Other

22. Psychiatric illness/social situations that would limit compliance with study requirements

23. History of drug or alcohol abuse within past 5 years

24. Known seropositive requiring antiviral therapy for human immunodeficiency virus (HIV) infection

25. 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-HBcAb subject with an undetectable surface antigen and negative hepatitis B DNA test (eg, polymerase chain reaction [PCR] test) can be enrolled

26. Known seropositive requiring anti-viral therapy for hepatitis C virus (HCV) infection OR subjects with positive hepatitis C virus antibody (Ab).

NOTE: A positive Anti-HCV subject with an undetectable/negative hepatitis C RNA test can be enrolled

27. Participation in another clinical study with any investigational medication or product administered within 28 days prior to first dose of study drug

28. Female subjects who are pregnant or breast-feeding

29. Subjects unable or unwilling to discontinue excluded medications for at least 2 weeks prior to first dose of study drug

30. Other serious conditions, in the Investigator's opinion