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
Overview
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.
Phase 1:
The Phase 1 dose escalation will evaluate escalating dose levels of VMD-102 in approximately 25 evaluable participants. This phase will assess the safety, PKs and tolerability of VMD-102 during cycle 1 (of 21-day cycle). Dose escalation will be guided according to the Bayesian Optimal Interval (BOIN) design to determine the next dose level based on dose-limiting toxicity (DLT) occurrence with participants of advanced HCC, MUM, RCC, NSCLC, and CRC to determine the MTD and the RP2D. Retrospective biomarker studies for the preclinical identified biomarkers may be carried out from tumor tissue and blood samples collected from participants.
Phase 2:
The Phase 2 dose expansion will employ a Bayesian Optimal Phase II (BOP2) design to enroll participants to assess the anti-tumor activity and safety of VMD-102 in Cohort 1 (approximately 43) participants with HCC, and Cohort 2 (approximately 43) participants with MUM, RCC, NSCLC and CRC. A biomarker guided enrollment criterion may be added via amendment. For each of two cohorts, once RP2D is determined, the Phase 2 expansion may be opened in both cohorts parallelly.
Sex: ALL
Minimum Age: 18 Years
Maximum Age: 75 Years
Healthy Volunteers: No
Age Groups: ADULT, OLDER_ADULT
Inclusion Criteria:
* 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 (1.5×109/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 100 IU/mL. Participants on active HBV therapy with viral loads <100 IU/mL should stay on the same therapy throughout study intervention and at least 12 weeks after the study is over. Participants cannot be actively co-infected with hepatitis C virus (HCV; HCV RNA detectable) or hepatitis delta virus (HDV; HDV RNA detectable).
* Positive HBsAg, with or without detectable HBV DNA, if there is evidence in the medical history of an advanced stage of cirrhosis ( Child-Pugh B) or history of decompensated chronic liver disease
* HCV antibody (HCVAb) positive and HCV viral load (HCV RNA) detectable. Previous HCVAb positive with HCV RNA undetectable due to treatment (DAAs or interferon) is allowed but the treated participants must have completed their treatment at least 12 weeks prior to starting study intervention and HCV RNA must be documented at below the limit of quantification.
* History of allogeneic tissue/organ transplantation (including bone marrow, stem cell, liver, or kidney transplants), except those that do not require immunosuppressive therapy (e.g., corneal or hair transplants).
* Coronavirus disease 2019 (COVID-19) or any live attenuated vaccine within 4 weeks of study entry.
* Participants with active alcohol and/or substances abuse, Phosphatidylethanol (Peth) must be 90% such as but not limited to: basal cell and squamous skin cancer and completely resected carcinoma in situs.
* Participants have uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage. Exception may be possible, on a case by case basis, e.g. if no more than one paracentesis in a month and a drain is pre-placed for the participant to drain, following discussion and mutual agreement between Investigator and Sponsor
* Participants have long-term unhealed wounds or fractures.
* Participants receiving known potent P-glycoprotein (P-gp) efflux transporter inhibitors that cannot be discontinued 3 days prior to the start of study treatment and during the course of the Phase 1 study.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drug, or excipients.
* Known history of uncontrolled human immunodeficiency virus (HIV) infection.
* Any other condition that, in the opinion of the Investigator or the medical monitor, could increase the risk to the participant, interfere with study participation, or affect the proper interpretation of study results and objectives. Such conditions may include but are not limited to, active infections, uncontrolled diabetes, psychiatric illness, social situations, and concomitant therapies.