A Phase 1 and 2 First-in-human, Open-label, Multicenter Study to Assess the Safety, Tolerability and Preliminary Efficacy of VMD-102 in Participants With Hepatocellular Carcinoma and Other Advanced Solid Tumors
This study is to evaluate the safety and tolerability to determine (i) the recommended Phase 2 dose (RP2D) of VMD-102 (Phase 1), and (ii) preliminary anti-tumor efficacy (Phase 2), in participants with advanced HCC, metastatic uveal melanoma (MUM), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). The pharmacokinetics (PK), preliminary anti-tumor activity, and potential biomarkers of VMD-102 will also be assessed. VMD-102 will be the first selective PKC epsilon (PKCε or PKCe) kinase inhibitor to enter human clinical testing. Preclinical VMD-102 anti-tumor activities in mouse liver/HCC tumor models and preclinical toxicology and pharmacology studies support this study.
• Histological or cytological or radiological diagnosis of advanced (unresectable and/or metastatic) HCC, MUM, RCC, NSCLC and CRC that is not responsive to standard of care (SOC), had progressed following SOC, is intolerant to SOC, or for whom the SOC is not considered appropriate by the investigator.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, or 1.
• Has at least one measurable target lesion according to RECIST v1.1 \[Response Evaluation Criteria In Solid Tumors\], or mRECIST \[modified RECIST\] for unresectable HCC participants, and either (a). has not been previously treated with local therapy (e.g., radiation therapy, hepatic arterial embolization, radiofrequency ablation, and percutaneous interventional therapy), or (b). if the target lesion was within the field of local therapy, the lesion has shown an increase in size of 25% or greater following local therapy.
• Adequate organ function evidenced by:
∙ Hematology
• Hemoglobin ≥ 9 g/dL (SI Units: 90 g/L) (post-transfusion if transfusion-dependent)
• Platelet count ≥ 60000/mm3 (60 x109/L) without support(transfusion) within 7 days of testing
• Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5x109/L) Chemistry
• Total bilirubin (TBIL) ≤ 2.0 x upper limit of normal (ULN). (For participants with Gilbert's syndrome, TBIL ≤3.0 x ULN provided that direct bilirubin DBIL) is \<30% of the TBIL)
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 1 ≤ 5 x U LN (participants with advanced HCC or liver metastases)
• AST and/or ALT 1 ≤ 3 x ULN (participants without known liver disease or liver metastases)
• Calculated creatinine clearance or 24h urine creatinine clearance ≥50 mL/min using Cockroft-Gault formula.
• Serum creatinine ≤ 1.5x ULN
∙ Coagulation (unless taking an anti-coagulant):
• Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (except for participants receiving therapeutic anticoagulants)
• International normalized ratio (INR) ≤ 1.5 unless the participant is receiving anticoagulant therapy as long as the participant is within therapeutic range of intended use of anticoagulants
• Albumin ≥2.8g/d/L.
‣ For HCC participants: the diagnosis must be made based on American Association for the Study of Liver Diseases (AASLD) Guidelines with confirmed advanced (unresectable) HCC staged by Barcelona Clinic Liver cancer criteria (BCLC). Cirrhosis will be staged by Child-Pugh score, and such a score ≤ 6 will be eligible for Phase 1 and ≤7 for Phase 2.
⁃ Participants must either have available archival tumor tissue samples, or consent to fresh tumor tissue sampling prior to the first dose unless the biopsy is not safe or not feasible per investigator assessment and with medical monitor approval.
⁃ Women of childbearing potential (WOCBP) must have a negative pregnancy test prior to enrolment and agree to use a highly effective and acceptable method of contraception from the time of informed consent (or screening) until 6 months after the last dose of investigational agent.
⁃ Male participants who are sexually active with a female partner of childbearing potential must agree to use a condom with spermicide from first dose of investigational agent until 6 months after the last dose, and refrain from sperm donation during that period. Abstinence from heterosexual intercourse is an acceptable method only if the participant's usual lifestyle already includes abstinence.
⁃ Participant has a life expectancy of ≥3 months.
⁃ No history of liver transplantation.
⁃ Ability to swallow and absorb an orally self-administered medication in tablet form.
⁃ Have completed any prior chemotherapy, monoclonal antibody or immunotherapy (e.g., tumor vaccine, cytokine, or growth factor given to control the cancer) at least 4 weeks or 5 half-lives (whichever is shorter) before study drug administration. Exceptions to these prior therapy timeframes are possible, on a case by case basis, following discussion and mutual agreement between Investigator and Sponsor.
⁃ Adverse effects related to prior anticancer therapies must have either returned to baseline or resolved to Grade 0 or 1. Some toxicities with higher grades such as alopecia, immunotherapy-induced hypothyroidism or adrenal insufficiency or panhypopituitarism requiring stable doses of hormone replacement therapy or rash from prior therapy may be permitted with medical monitor approval.