An Initial Evaluation of AN8025 in Solid Tumors

This is a first-in-human, open label, multi-center, multiple-ascending dose escalation, phase I study to test AN8025. After confirmation of meeting the study entry criteria, participants with advanced solid tumors will be in 1 of two parts of the study: Part A (dose escalation) and Part B (dose expansion). The study will take place in Australia and China, with approximately 4 sites in each country.

Each part of this study has 3 phases of participation: Screening Phase (up to 35 days prior to dosing), Treatment Phase (21-day cycles, dosing on the first day of each cycle), and a Follow Up Phase . Participants will have up to 35 days to enter the study (the screening phase), during which it will be determined if they qualify for the study. After confirmation of eligibility, participants will be enrolled into the treatment phase of the study for up to 24 months, or until experiencing drug toxicity, progressive disease, withdrawal of consent or death. Participant follow up will include an End of Treatment Visit (EoT), a 30-day safety follow up visit, and survival follow up contact every 3 months after the EoT visit until 6 months after EoT visit or 12 months from Cycle 1 Day1, whichever is longer. The study is projected to last approximately 50 months.

During the course of the study, treatment will be once every 21 days, with visits to the clinic required to undergo testing to determine the side effects, safety and efficacy of AN8025, including testing to characterized the drug level in a participants blood.

The goal of the study is to determine the dose level of AN8025 that is safe and tolerable to treat patients with advanced solid tumors. Once identified, the study will enroll in up 2, 20 patient expansion cohorts in advanced solid tumors (to be identified based on dose expansion). The pharmacokinetic (PK) profile of AN2025 will be determined in this population, along with any preliminary anti-tumor activity.

Inclusion criteria

• Aged ≥18 years old.
• Able to provide informed consent obtained before any study-related activities and according to local guidelines.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Have an estimated life expectancy ≥ 12 weeks, in the judgment of the investigator.
• Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic with progression after treatment with available standard therapies or are intolerant to or refuse standard therapies that are known to provide clinical benefit.
• Part A Dose Escalation only: Participants have unresectable advanced or metastatic solid tumors, with no preference of cancer type.
• Part B Dose Expansion only: Participants enrolled into tumor-specific cohorts have unresectable advanced metastatic disease. Participants must also have progressed after treatment with the appropriate targeted therapy. Participants must be primary refractory or non-responding to anti-PD-1 monotherapy as defined by:

• The participant has received at least 2 doses of an approved anti-PD-1/PD-L1 monoclonal antibody
• The participant has demonstrated progressive disease (PD) after anti-PD-1/PD-L1 therapy as defined by RECIST Version 1.1, which was subsequently confirmed by a second assessment no less than 4 weeks from the date of the first documented PD to rule out pseudo-progression.
• Participants who have received anti-PD-1/PD-L1 therapy as part of their adjuvant therapy but experienced recurrence with locally advanced or metastatic disease within 6 months after completing adjuvant therapy may be eligible for Part B.
• Part B Dose Expansion only: Participants enrolled into the expansion cohort must have documented PD-L1 tumor expression on ≥1% tumor cells (i.e. TPS or TC ≥1%) as assessed by validated immunohistochemistry (IHC) assay on archival or fresh tumor tissue.
• Participants have consented to provide archival tumor tissue collected within 5 years or a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Archival tumor tissue can be formalin-fixed, paraffin embedded (FFPE) tissue blocks or at least 15 freshly-sectioned slides. Tissue should be obtained from surgical resection or core needle biopsy. Fine-needle aspiration (FNA), pleural effusion, or ascitic fluid samples are not acceptable. FFPE blocks are preferred to slides and newly obtained biopsies are preferred to archival tissue. For participants who have consented to provide newly obtained fresh biopsy of baseline tumor tissue, the biopsy is required to be collected during the screening period. Tissue requirements may be waived on a case-by-case basis after discussion with the sponsor if tissue or biopsy is not available or feasible.
• Have at least one measurable lesion as defined per RECIST v1.1. Bone metastases are not considered measurable. Participants who only have non-measurable lesion(s) may be eligible for Part A, except for "back-filled" cohorts.
• Have adequate hematologic function and major organ function, defined by laboratory assessment documented within 7 days prior to first dose of study treatment:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
• Hemoglobin ≥ 9 g/dL (which may be reached by transfusion).
• Platelets ≥ 100 x 109/L (which may be reached by transfusion).
• International normalized ratio (INR) ≤ 1.5.
• Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if liver metastases are present.
• Total bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN if Gilbert's syndrome is present.
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCL) > 50 mL/min.
• Thyroid stimulating hormone (TSH) within normal limits. If TSH is not within normal limits at baseline, the participant will still be eligible if total T3 or free T3 (FT3) and free T4 (FT4) are within the normal limits.
• Have discontinued previous cancer treatment and recovered from the acute toxicity of therapy. Participants must have discontinued from previous treatment with length of time prior to first dose of study treatment.
• Fertile men and women of childbearing potential must agree to use an effective method of birth control from providing signed consent and for 180 days after the last study treatment administration. Women of childbearing potential include pre-menopausal women and women within the first 2 years of the onset of menopause. Women of childbearing potential must have a negative pregnancy test ≤ 7 days prior to the first dose of the study treatment.

Exclusion criteria

• Are currently enrolled in a clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
• Have a serious concomitant systemic disorder that, in the judgment of the investigator, would compromise the participant's ability to adhere to the protocol.
• Known human immunodeficiency virus (HIV) infection per HIV 1 and/or 2 antibodies.
• Participants with evidence of Hepatitis B or Hepatitis C infections (positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody) must fulfill the following criteria in order to be eligible for the study:

• Hepatitis B virus (HBV) viral load ≤2500 copies or ≤500 IU/mL before study enrollment, and participants with active HBV need to be on anti-HBV suppression ≥3 months, throughout treatment and for 6 months after; and
• Hepatitis C virus (HCV) viral load ≤lower limits of detection, participants with curable or controllable HCV infection are eligible. Participants with detectable HCV RNA can remain on continuous, effective antiviral therapy during the study.

Note: The necessity of conducting HBV DNA/HCV RNA quantitative testing is based on the local epidemiology and local clinical practice.

• Active tuberculosis.
• Active infection requiring intravenous therapy.
• Prior or second concurrent primary malignancies that, in the judgment of the investigator, may affect the interpretation of results. Participants with carcinoma in situ of any origin and participants with prior malignancies who are in remission and whose likelihood of recurrence is very low (such as basal cell carcinoma), as judged by the investigator, are eligible for this study.
• Have an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. This criterion does not apply to participants with:

• Resolved childhood asthma/atopy or who require intermittent use of bronchodilators or corticosteroid;
• Raynaud's syndrome; or
• Sjogren's syndrome. Use of topical, ophthalmic, inhaled, and intranasal corticosteroids are permitted.
• Evidence of (a) interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity (for example, interstitial lung disease); (b) active, noninfectious pneumonitis; or (c) history of noninfectious pneumonitis that required corticosteroid therapy or immune related pneumonitis.
• Moderate or severe cardiovascular disease, including:

• A myocardial infarction or any other arterial thrombotic event including cerebrovascular accident or transient ischemic attack within 6 months prior to enrollment;
• Unstable angina pectoris;
• New York Heart Association Class III/IV congestive heart failure;
• Aneurysm of major vessels or heart;
• Left ventricular ejection fraction <50% (evaluation based on institutional lower limit of normal);
• Uncontrolled hypertension;
• Severe, moderate, or clinically significant valvulopathy;
• Documented major ECG abnormalities that, in the judgment of the investigator, are clinically significant (for example, arrhythmia requiring treatment)
• Mean QTc ≥470 ms calculated using Fridericia's correction and confirmed by triplicate ECG.
• History of Grade ≥ 3 immune related Adverse Events (irAE) related to prior immune checkpoint inhibitor therapy or any active or unresolved AE from prior anti-cancer therapy that has not resolved to ≤ Grade 1 or baseline (except controlled endocrinopathies). Participants with a history of Grade ≥3 irAEs attributed to prior anti-CTLA4 (e.g. ipilimumab) combined with anti-PD(L)1 (e.g. pembrolizumab, nivolumab, atezolizumab) are eligible for enrollment if the irAE occurred during combination therapy, and they subsequently tolerated anti-PD(L)1 monotherapy without recurrence of Grade ≥3 irAEs.
• Participants permanently discontinued due to any immune-related toxicity requiring prolonged (≥10 weeks) high-dose corticosteroids (≥20 mg/day prednisone equivalent) or other immunosuppressants (e.g., infliximab, mycophenolate, cyclophosphamide) will be excluded.
• Have symptomatic central nervous system (CNS) malignancy or metastasis (screening not required). Participants with treated CNS metastases are eligible for this study if they are not requiring concurrent treatment, including but not limited to surgery, radiation, corticosteroids and/or anticonvulsants to treat CNS metastases, and their disease is asymptomatic and radiographically stable for at least 30 days.
• Have received a live vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (for example, FluMist®) are live attenuated vaccines and are not allowed.
• Are pregnant or planning to become pregnant during the study or within 6 months following the last dose of AN8025. Plan to be breastfeeding from C1D1 of study or within 6 months following the last dose of AN8025.
• Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Use of other herbal supplements, traditional medicines, or prescription medications that are known or suspected to interact with the investigational product or effect disease treatment/side effect management, as determined by the study investigator