A Phase 1 First-in-Human Study of CRPA1A2, a MAGE-A1/HLA-A*02:01 Bispecific T-Cell Engager, in Patients With Solid Tumors

A Phase I First-In-Human Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of CRPA1A2, a Bispecific T Cell Engager, in Patients With HLA-A*02:01 and MAGE-A1 Positive Advanced Solid Tumors

This is a Phase I, first-in-human, open-label study of CRPA1A2, a bispecific T-cell engager, in participants with HLA-A*02:01-positive and MAGE-A1-positive advanced solid tumors. The study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of CRPA1A2, and to identify recommended dose(s) for further evaluation.

The study consists of 2 parts: a dose escalation part (Part A) and a dose optimization part (Part B). In Part A, participants will receive escalating doses of CRPA1A2 to determine the recommended dose(s) for optimization, with additional backfill cohorts permitted. In Part B, 2 to 3 selected recommended dose(s) will be further evaluated in participants with selected tumor types to better characterize safety and preliminary anti-tumor activity.

CRPA1A2 will be administered by intravenous infusion in 28-day cycles, starting at 0.0003 mg/kg. Weekly dosing is planned, although alternative dosing schedules may be explored based on emerging data. Treatment will continue until disease progression, intolerable toxicity, initiation of new anti-tumor therapy, other discontinuation criteria are met, or study termination.

Inclusion Criteria:

1. Patients with a histological and/or cytological confirmed locally advanced or metastatic unresectable solid tumor (including but not limited to esophageal squamous cell carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma and lung squamous cell carcinoma) who have experienced disease progression following available standard therapy and for whom no further standard treatment options are available.
2. Patients with confirmed positive expression of MAGE-A1 (H-score ≥1, testing by IHC for FFPE) by central lab.
3. Patients with positive HLA-A*02:01 (confirmed by the central lab).
4. There must be at least one measurable lesion per RECIST v1.1 criteria. (Lesions that have received radiotherapy previously cannot be considered target lesions unless there is evident progression after radiotherapy).
5. Eastern Cooperative Oncology Group (ECOG) performance status: 0-1.
6. Life expectancy ≥ 3 months, in the opinion of the investigator.
7. Has adequate organ function, as demonstrated by laboratory values obtained during the screening period.
8. Participants (both males and females) of childbearing potential must agree to use highly efficient contraception from the time of signing the informed consent form until 6 months after the last dose of the investigational drug.

Exclusion Criteria:

1. Patients with history of other malignancies (within 2 years prior to signing the ICF) are excluded, except for those with cured stage IB or earlier stage cervical cancer, non-invasive basal cell or squamous cell skin cancer, malignant melanoma in complete remission (CR) for over 10 years, or other malignancies in complete remission (CR) for over 5 years.

2. Patients with positive HLA-A*02:05 (confirmed by the central lab).

3. Patients with known sensitivity or immediate hypersensitivity to any components of CRPA1A2 or ingredients of CRPA1A2 injection.

4. Patients who have been exposed to other MAGE-A1 targeted therapy.

5. With clinically significant cardiovascular diseases, including but not limited to:

   1. History of heart failure, myocardial ischemia or infarction, unstable angina, arrhythmias, or New York Heart Association (NYHA) Class III-IV within the past 6 months or currently.
   2. With prolonged QT/QTc intervals on the electrocardiogram during the screening period (QTcF: > 480 ms).
   3. Echocardiogram (ECHO) indicates a left ventricular ejection fraction (LVEF) of ≤50% at screening.
   4. Poorly controlled hypertension at screening (systolic blood pressure ≥150 mmHg, diastolic blood pressure ≥100 mmHg) despite pharmacological treatment.
   5. History of vascular angioplasty, coronary artery bypass grafting, or other cardiac surgical procedures.

6. With clinically significant active hepatitis B, HBsAg or HBcAb positive and have an HBV-DNA level above the detection limit at screening (i.e., the upper limit of normal values at each research center's laboratory). With the exception for those that have achieved HBV-DNA negativity after antiviral treatment and have received at least 2 weeks of antiviral therapy before the initial dosing. Additionally, they must be willing to continue antiviral therapy for hepatitis B throughout the study period. For patients with hepatocellular carcinoma, HBV DNA must be <1000 IU/mL for study eligibility.

7. Clinically significant active hepatitis C, indicated by positive HCV antibodies and HCV-RNA levels higher than the detection limit at screening (upper limit of normal values).

8. Positive Treponema pallidum antibodies (TP-Ab) and positive result for nonspecific syphilis antibodies titer (RPR) at screening.

9. Prior or concurrent therapies/procedures that may confound study evaluation or increase risk, including recent participation in another clinical study; recent anticancer therapy, investigational treatment, or invasive investigational medical device use; major surgery without full recovery; prior solid organ transplantation or allogeneic hematopoietic stem cell transplantation; recent autologous hematopoietic stem cell transplantation; or planned transplantation during the study period.

10. Active, uncontrolled, or clinically significant medical conditions that may increase the risk of study participation or interfere with study assessments, including severe infection; symptomatic or uncontrolled central nervous system or leptomeningeal metastases; clinically significant pulmonary disease (e.g., interstitial lung disease/pneumonitis); coagulation or bleeding disorders; autoimmune disease or immunodeficiency (including HIV infection); or significant neurologic or psychiatric disorders.

11. Unresolved toxicities or other conditions considered by the investigator to make the participant unsuitable for the study, including failure to recover adequately from prior anticancer treatment-related toxicities, prior Grade ≥2 ICANS after T-cell engager or CAR-T therapy, clinically significant abnormal laboratory findings, or other severe/uncontrolled acute or chronic diseases, alcohol abuse, or substance misuse.