A Phase 1 and 2 Study of VMD-102 in Hepatocellular Carcinoma and Other Solid Tumors

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.

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 (1.5x109/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.

Exclusion criteria

• Received anticancer therapy with radiation, immunotherapy, a biologic, surgery and/or tumor embolization within the past 2 weeks or 5 half-lives (whichever is longer).
• Currently pregnant, nursing, or planning to become pregnant during the course of study.
• The Fridericia Corrected QT (QTcF) interval ≥ 480 msec.
• Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system (Section 14.8); or presence of clinically significant and uncontrolled cardiac disease, as assessed by the investigator. Such as but not limited to: symptomatic congestive heart failure, unstable angina, cardiac arrhythmia.
• Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would compromise the participant's safety or interfere with assessment of the drug.
• Psychological, familial, sociological, geographical or other concurrent conditions that would interfere with safety evaluation, limit the participant's ability to follow the procedures in the protocol or otherwise jeopardize compliance with the protocol. Participants with uncontrolled major depression, bipolar disorder, or severe anxiety disorder are excluded.
• Participants have multiple factors that affect their oral medication (such as inability to swallow and intestinal obstruction or resection).
• Participants have long-term unhealed wounds or fractures.
• Participants have uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage.
• Any current medical conditions, including impairment of GI function or GI disease, which would alter the absorption, distribution, metabolism or excretion of VMD-102 including but not limited to:

• Severe uncontrolled nausea or vomiting.
• Severe uncontrolled diarrhea or ongoing active diarrhea requires medications (e.g. bile acid sequestrant, loperamide).
• A history of short bowel syndrome; irritable bowel syndrome with diarrheal signs/symptoms or require medications.
• Clinically diagnosed malabsorption secondary to bowel resection.
• Active Ulcerative colitis or Crohn's disease requiring medication for control.
• Surgical procedures of the GI tract impacting the drug absorption such as but not limited to small bowel resection and gastric bypass.
• Unstable central nervous system (CNS) metastases. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least one cycle prior to the first dose and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are on stable doses of steroids for at least one cycle prior to the first dose.
• Known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC or HCC due to cirrhosis caused from autoimmune-associated hepatitis.
• Hepatitis B surface antigen (HBsAg) positive with detectable the hepatitis B virus load (HBV DNA) >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 <50 ng/mL).
• Concurrent secondary malignancy other than that being treated in this study. Exceptions to this exclusion include malignancies treated curatively and have not recurred within 2 years prior to study entry or tumors treated with curative intent that have expected cure rates of >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.