A Study of AK138D1 Alone or in Combination With Ivonescimab in Advanced Breast Cancer

This is a multicenter, open-label Phase Ib/II study of AK138D1 as monotherapy or in combination with ivonescimab in patients with advanced breast cancer. The Phase Ib portion is designed to evaluate the safety, tolerability, and preliminary antitumor activity of AK138D1 in combination with ivonescimab. The Phase II portion is designed to evaluate the safety and efficacy of AK138D1 as monotherapy or in combination with ivonescimab.

• AK138D1 (Drug): Enrolled subjects will receive intravenous infusion (IV) of AK138D1 according to the dosing regimen specified in their cohort.
• Ivonescimab (Drug): Enrolled subjects will receive intravenous infusion (IV) of ivonescimab according to the dosing regimen specified in their cohort.
• treatment of physician's choice (Drug): Enrolled subjects will receive treatment of physician's choice according to one of the protocol-specified regimens selected by the investigator, based on the investigator's decision.

Primary outcomes

• Adverse events (AEs) [Up to approximately 2 years]: Incidence and severity of participants with adverse events
• Overall Response Rate (ORR) assessed by investigator per RECIST v1.1 [Up to approximately 2 years]: ORR is the proportion of subjects with complete response(CR) or partial response(PR) , based on RECIST v1.1.

Secondary outcomes

• Peak Plasma Concentration (Cmax) [Up to approximately 2 years]: Derum drug concentrations in subjects at different time points after administration.
• Area under the plasma concentration versus time curve (AUC) [Up to approximately 2 years]: The definite integral of the concentration of AK138D1 in blood plasma as a function of time.
• Anti-drug antibodies (ADA) [Up to approximately 2 years]: Number of subjects with detectable anti-drug antibodies (ADA).
• Disease Control Rate (DCR) assessed by investigator per RECIST v1.1 [Up to approximately 2 years]: Disease control rate (DCR) assessed according to RECIST v1.1.
• Duration of response (DoR) assessed by the investigator per RECIST v1.1 [Up to approximately 2 years]: Duration of response (DoR) assessed according to RECIST v1.1.
• Progression Free Survival (PFS) assessed by investigator per RECIST v1.1 [Up to approximately 2 years]: PFS is defined as the time from randomization to the first documented disease progression (per RECIST v1.1 criteria) assessed by investigators or death due to any cause, whichever occurs first.
• Time to response (TTR) assessed by the investigator per RECIST v1.1 [Up to approximately 2 years]: Time to response (TTR) is defined as the time to response based on RECIST v1.1.
• Overall Survival (OS) [Up to approximately 2 years]: Overall Survival (OS) is defined as the time from randomization to death due to any cause.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. The subject must sign the written informed consent form (ICF) voluntarily;
2. At enrollment, aged ≥ 18 to ≤ 75 years, both males and females are eligible;
3. ECOG performance status score of 0 or 1;
4. Has a life expectancy of ≥ 3 months;
5. At least 1 measurable lesion as per RECIST v1.1 that is suitable for repeated accurate measurement.
6. Adequate organ function.

Exclusion Criteria:

1. Concomitant participation in another clinical study, unless it is a non-interventional clinical study or the follow-up period of an interventional study;
2. Presence of active central nervous system (CNS) metastases.
3. Live vaccines or attenuated live vaccines administered within 4 weeks prior to the first dose, or planned to be administered during the study; use of inactivated vaccines is allowed;
4. Untreated subjects with active hepatitis B or active hepatitis C;
5. Known active pulmonary tuberculosis (TB); subjects with suspected active TB must undergo appropriate clinical assessment to rule out the presence of active disease;
6. Known active syphilis infection;
7. Subjects with known allergy to any component of any study drug; and with a history of known severe hypersensitivity reactions to other monoclonal antibodies;
8. Other reasons for ineligibility as evaluated by the investigator.

• Fei Ma, Principal investigator, Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Tong Liu, Principal investigator, The Second Affiliated Hospital of Harbin Medical University
• Ting Luo, Principal investigator, West China Hospital