A Study of AP601 in Patients With Locally Unresectable Advanced or Metastatic Solid Tumors

A Phase 1, Open-label Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of AP601 in Patients With Solid Tumors.

A Phase 1, Open-Label Study of the Safety, Tolerability,Pharmacokinetics, Pharmacodynamics and Clinical Activity of AP601 in Patients with Solid Tumours.The study is designed to find the highest dose of AP601 that can be given safely. Participants will be assigned to one of six cohorts. Each cohort will receive a different dose of the study medication, AP601, based on the body weight. Each cohort will initially enrol 1-3 participants. If no serious side effects are seen in the first participant(s), the next cohort will receive the next dose level.

Participants will receive a single infusion of AP601 once every 2 weeks (14 days) (Q2W) for up to 12 months.

Part 1 (Dose Escalation):

Part 1 is a dose escalation part, using an accelerated 3+3 design. Up to 6 dose levels are planned to be evaluated in Part 1.

Cohort 1 - 0.5mg/kg (1-6 participants) Cohort 2 - 1.25 mg/Kg (1-6 participants) Cohort 3 - 2.5 mg/Kg (3-6 participants) Cohort 4- 5.0 mg/Kg (3-6 participants) Cohort 5- 7.5 mg/Kg (3-6 participants) Cohort 6- 10.0 mg/Kg. (3-6 participants) At the first dose level, a single participant will be enrolled and observed for dose-limiting toxicities (DLTs) and adverse events (AEs) for 28 days (2 treatment cycles). If the participant does not experience any DLTs, then a new participant may be dosed at the next higher dose level and observed for the DLT period (28 days). There will be a maximum of 2 single-patient cohorts.

If in any of the single-patient cohorts a patient experiences a DLT, an additional 2 patients will be enrolled at that dose level and evaluated using 3+3 design rules.

Cohorts 3 and above will all use a standard 3+3 design, even if toxicity was not seen in the single-patient Cohorts 1 and 2.

Part 2 (Dose Expansion):

A dose expansion part may be initiated following completion of the dose escalation cohorts.

Inclusion Criteria: 1. Patients with histologically or cytologically proven locally unresectable advanced or metastatic solid tumors. Patients must be relapsed or refractory to at least one standard-of-care therapy, and/or have refused standard-of-care therapy.

2. Eastern Cooperative Oncology Group performance status of 0 to 1 at Screening, with an estimated life expectancy of at least 3 months.

3. Disease must have at least 1 assessable (long diameter ≥1 cm) lesion for evaluation of response by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

4. Patients with adequate organ and bone marrow function, in the absence of growth factors, including the specific laboratory findings of Absolute neutophil count, platelet count, Haemoglobin, AST, ALT, Serum total Bilirubin, Alkaline phosphatase, prothrombin time, INR or activated partial thromboplastin time, creatinine and albumin.

5. Female Volunteers must be of nonchild bearing potential i.e, surgically sterilised at least 6 weeks before Screening Visit or postmenopausal.

6. Females of childbearing potential must have a negative pregnancy test, agree not to attempt to become pregnant or donate Ova and agree to use contraception from one month prior to Screening until at least 90 days after last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle.

Male Vonuteers:

• Must agree not to donate sperm from signing the ICF until at aleast 90 days after the last dose of the study drug.
• If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception.
• Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Exclusion Criteria:

1. Has received concurrent antitumor treatment or IPs within 28 days of C1D1. The antitumor treatments include chemotherapy, radiotherapy, immunotherapy, targeted therapy, hormonal therapy, or cytokine therapy.

2. Has received prior CD73-targeted and/or CD137-targeted therapeutics.

3. Has had major surgery within 28 days prior to C1D1 (excluding prior diagnostic biopsy).

4. Any unresolved toxicity (except alopecia) from prior therapy of ≥CTCAE Grade 1, prior to the day of the first dose of IP. Participants with Grade 2 toxicity that is not CS (e.g., alopecia, vitiligo), or that is deemed stable or irreversible (e.g., peripheral neuropathy) can be enrolled.

5. History of any other malignancy, which has been active or treated within the past 2 years, with the exception of thyroid cancer, cervical intraepithelial neoplasia, basal cell carcinoma and squamous cell carcinoma.

6. Prior history of an irAE with immunotherapy-related toxicities that resulted in discontinuation of prior immunotherapy.

7. Current symptomatic leptomeningeal disease or uncontrolled, untreated brain metastasis.

8. Has received any organ transplantation including allogeneic stem cell transplantation.

9. Has received blood transfusions or growth factor support ≤ 14 days prior to screening.

10. Has any significant acute or chronic infections including:

    1. Infection requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days before first dose of AP601.
    2. Known active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.

11. Current active, or history of, any autoimmune disease that may relapse or immunodeficiencies.

12. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before first dose of AP601.

13. Known severe hypersensitivity reactions to monoclonal antibodies.

14. Breastfeeding (or planning to breastfeed) at any time during the study, and for 90 days following study completion.

15. Participants with a current or recent (within the past 12 months) diagnosis of alcohol or non-prescribed drug abuse, as defined by local guidelines.

16. Evidence of cardiac dysfunction (defined as myocardial infarction within the last 6 months, New York Heart Association Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias, or known left ventricular ejection fraction [LVEF] <55%) or other CS cardiac pathology likely to impair the participants ability to participate in the study.

17. Uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, uncontrolled diabetes, uncontrolled endocrinopathy, severe active peptic ulcer disease or gastritis.

18. Has received a live (or live attenuated) vaccination within 28 days of the first dose of AP601 and during the study period.

19. Any other condition or prior therapy that in the opinion of the PI (or delegate) would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.