First-in-human Study of CA102N Monotherapy and CA102N Combined With Trifluridine/Tipiracil (LONSURF) in Subjects With Advanced Solid Tumors

Study HS-CA102N-101 is a phase 1, two part (dose escalation, dose expansion), multicenter, non-randomized, open-label, multiple dose, first-in-human study of CA102N monotherapy and of CA102N combined with trifluridine/tipiracil (LONSURF) in subjects with advanced solid tumors.

Part 1 (dose escalation) will determine the safety and tolerability of three dose levels of CA102N as monotherapy and the safety, tolerability and preliminary recommended phase 2 dose (RP2D) of CA102N in combination with trifluridine/tipiracil (LONSURF) in patients with locally advanced or metastatic solid tumors.

Part 2 (dose expansion) will further investigate the safety and tolerability of the combination of CA102N and trifluridine/tipiracil (LONSURF) at the preliminary RP2D in patients with locally advanced or metastatic colorectal cancer that has relapsed after or is refractory to oxaliplatin and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and if RAS wild-type metastatic colorectal cancer, an anti-epidermal growth factor receptor (EGFR) therapy..

Preliminary efficacy will be evaluated in Parts 1 and 2 of the study as an exploratory endpoint.

Inclusion criteria

• Subjects enrolled in Part 1 must have histologically documented locally advanced or metastatic solid tumor for which there is no effective therapy available.
• Subjects enrolled in Part 2 must have histologically documented locally advanced or metastatic colorectal cancer that has relapsed after or is refractory to oxaliplatin and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
• Age ≥18 years (US) or ≥20 years (Taiwan).
• ECOG performance status 0-1.
• Measurable or non-measurable disease based on RECIST version 1.1. Subjects enrolled in Part 2 must have at least one measurable lesion.
• Adequate organ function within 14 days before 1st dose of study drug, defined as:

• Platelet count ≥ 100,000/mm3.
• Hemoglobin ≥ 9.0 g/dL.
• Absolute neutrophil count ≥ 1500/mm3 (without hematopoietic growth factor support).
• Creatinine ≤ 1.5 x ULN, or creatinine clearance ≥ 50 mL/min as calculated using the modified Cockcroft-Gault equation.
• Aspartate aminotransferase: (i) ≤3 x ULN in subjects without liver metastasis or ≤5 x ULN in subjects with liver metastasis in CA102N monotherapy treatment group; (ii) ≤3 x ULN in subjects who will be treated with CA102N combined with trifluridine/tipiracil (LONSURF).
• Alanine aminotransferase: (i) ≤3 x ULN in subjects without liver metastasis or ≤5 x ULN in subjects with liver metastasis in CA102N monotherapy treatment group; (ii) ≤3 x ULN in subjects who will be treated with CA102N combined with trifluridine/tipiracil (LONSURF).
• Total bilirubin ≤1.5 x ULN (unless documented Gilbert's Syndrome).
• Has had an adequate treatment washout period prior to 1st dose of study drug defined as:

• No major surgery within the past 4 weeks.
• No extended field radiation therapy within the prior 4 weeks.
• No anticancer therapy or bevacizumab within the prior 3 weeks.
• No investigational agent received within prior 4 weeks (or 5 times the half-life of the investigational agent, whichever is shorter).
• No aspirin or NSAIDs for at least 72 hours before 1st dose of study drug.
• No herbal supplements taken as anticancer agents within the prior 7 days.
• Able to provide written informed consent.
• Life expectancy of ≥ 3 months.
• Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective means of contraception from study entry through at least 6 months after the last dose of CA102N. Women of childbearing potential are those women who have not been permanently sterilized or are not postmenopausal.

Exclusion criteria

• For Part 2, active malignancies other than colorectal cancer.
• History of hypersensitivity or hepatotoxic reaction to nimesulide or to any excipient.
• Requiring therapeutic doses of anticoagulants.
• History or presence of a bleeding tendency or disorder.
• History of gastrointestinal bleed or perforation related to previous NSAID therapy.
• Presence or history of recurrent peptic ulcer or hemorrhage.
• History of cerebrovascular or other active bleeding.
• Myocardial infarction within the last 12 months, severe or unstable angina, symptomatic congestive heart failure New York Heart Association (NYHA) Class III or IV.
• History of a serious cardiac arrhythmia requiring treatment.
• Corrected QT prolongation using Fridericia formula (QTcF), of > 450 msec for males or > 470 msec for females based on a triplicate 12-lead ECG.
• Clinically significant lung disease (eg, interstitial pneumonia, interstitial lung disease, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) requiring continuous systemic corticosteroid treatment for 6 months before registration or who are suspected to have such diseases by imaging at Screening.
• Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks.
• Active autoimmune disease that has required systemic treatment in past 2 years.
• History of allogeneic transplantation requiring immunosuppressive therapy.
• Known positive test for hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus (HIV).
• Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.
• Pregnant or breast feeding.
• Unresolved toxicity of greater than or equal to NCI-CTCAE (version 5.0) Grade 2 attributed to any prior therapies (excluding anemia, alopecia, skin pigmentation, and platinum-induced neurotoxicity).
• Concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator.