Clinical Trials

IRB Study Number 26-070

Status Recruiting

Phases Phase 1, Phase 2

Location Cleveland Clinic Main Campus

Institute Taussig Cancer Institute

Description

Dose Escalation (Part A) : To evaluate the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE) of HMPL-A251 in participants with previously treated HER2+ solid tumors

Dose Expansion/Optimization (Part B): To characterize the safety and preliminary efficacy of HMPL-A251 at RDEs to determine recommended dose(s) for phase 2 (RP2D) or phase 3 (RP3D) in participants with selected HER2-expressing solid tumors

Dose Escalation (Part A): To assess preliminary antitumor activity of HMPL-A251 in participants with previously treated HER2+ solid tumors

Dose Expansion/Optimization (Part B): To evaluate the preliminary antitumor activity of HMPL-A251 in participants with selected

For both Part A and Part B: To evaluate the pharmacokinetic (PK) profile of HMPL-A251, total anti-HER2 antibody, and HM5041609 in participants with advanced solid tumors

For both Part A and Part B: To evaluate the immunogenicity of HMPL-A251

For both Part A and Part B: To explore the exposure-response (ER) relationship in participants treated with HMPL-A251

To explore the effect of HMPL-A251 on corrected QT (QTc) interval

To explore the metabolite profile and conjugated payload concentration of HMPL-A251 in participants

Inclusion Criteria

Participants are eligible to be included in the trial only if all of the following criteria are met:

1. Understand this study and are able to voluntarily sign the informed consent form (ICF);
2. Male or female, aged ≥ 18 years;
3. Histologically confirmed unresectable advanced or metastatic disease:
   Part A: Histologically confirmed unresectable advanced or metastatic HER2+ (IHC 3+ or IHC2+/ISH+) solid tumors that have progressed on or were intolerant to all standard therapies or for which no standard treatment is available.
   Part B:
   -Cohort 1 (BC): HER2+ (IHC 3+ or IHC2+/ISH+) Breast Cancer that has progressed after no more than 4 lines of prior systemic therapies inclusive of prior anti-HER2 therapies;
   -Cohort 2 (GC/GEJ): HER2+ (IHC3+ or IHC2+/ISH+) Gastric or Gastroesophageal junction adenocarcinoma that has progressed after no more than 3 lines of prior therapies inclusive of platinum-based therapy and immune checkpoint inhibitor (ICI) if indicated;
   -Cohort 3 (Other): Tumor types may be adjusted based on signals
   • HER2-low (IHC 2+/ISH- or IHC 1+) Breast Cancer, progressed after no more than 4 lines of prior systemic therapy inclusive of prior anti-HER2 therapies if indicated;
   • HER2-overexpressed (IHC3+ or IHC2+) urothelial cancer, endometrial cancer, ovarian cancer or other solid tumors that progressed after no more than 3 prior linesof therapies, including platinum-based therapy and ICI if indicated.
   For both Part A and Part B, during screening, HER2 status must be confirmed by local pathological reports or central tests (for China only) to determine eligibility.
   The HER2 IHC or ISH scoring method will follow the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for BC and GC respectively; for other tumor types, the ASCO/CAP guideline for GC will be applied.
4. Are willing and able to provide adequate tumor sample (fresh biopsy or archival tissue) to central lab for PAM status testing, refer to Section 8.6.1 for details;
5. Have at least one measurable lesion per RECIST v1.1;
6. Life expectancy ≥ 12 weeks;
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1;
8. Weight ≥ 35 kg;
9. Adequate bone marrow function, renal function and hepatic function:
   • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, hemoglobin ≥ 9.0 g/dL, platelets ≥ 75 ×109/L (without receiving transfusions of granulocyte colony-stimulating factor or other hematopoietic growth factors within 14 days prior to laboratory examination, and without receiving transfusions of platelet within 7 days prior to laboratory examination);
   • Creatinine clearance > 60 mL/min, which can be calculated using the Cockcroft- Gault formula. (140 - Age) × (Weight in kg) × (0.85 if female) 72 × [Serum creatinine (mg/dl)]
   • Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN); or ≤ 3 × ULN if the elevation is due to Gilbert’s syndrome (isolated unconjugated hyperbilirubinemia) or liver metastases, in the absence of other hepatic dysfunction;
   • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN in participants without liver metastases; ≤ 5 × ULN for liver metastases;
   • International Standardized ratio (INR) ≤1.5×ULN, or activated partial thromboplastin time (APTT) ≤1.5×ULN;
10. Female participants of childbearing potential must agree to use an effective double contraception method starting from the screening period, throughout the treatment period, till 7 months after the last dose, and also agree not to donate ova (oocytes) for the purpose of reproduction during this period; male participants with partners of childbearing potential must also use an effective double contraception method during the study period and for 4 months after the final dose, and agree not to donate sperm during this period.

Female participants of non-childbearing potential are exempt from this criterion.

Exclusion Criteria

Participants are excluded from the trial if any of the following criteria are met:

1. An established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus.
   • Fasting plasma glucose (FPG) > 126 mg/dL (7.0 mmol/L) or Glycosylated Hemoglobin (HbA1c) > 6.4%.
2. Use of strong inhibitors of CYP3A4, and inhibitors of P-gp or BCRP within 5 elimination half-lives or 2 weeks (whichever is longer) before the first dose of study drug.
3. Toxicity from prior anti-tumor therapy has not recovered to Grade 1 or baseline prior to the first dose of study drug (except alopecia). Participants with chronic Grade 2 toxicities may be eligible after discussion between the investigator and Sponsor Medical Monitor (e.g., Grade 2 chemotherapy-induced neuropathy).
4. Baseline blood amylase or lipase exceeds the normal range and are judged by the investigators to be clinically significant.
5. Spinal cord compression, leptomeningeal disease, or clinically active central nervous system (CNS) metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
   • Participants with previously treated CNS metastases are permitted if asymptomatic or neurologically stable without steroids for at least 4 weeks prior to start of study treatment.
6. Interval between first dose of study drug and other prior anti-tumor therapies, including any other investigational therapies:
   • Cytotoxic chemotherapy: less than 21 days;
   • Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors): less than 28 days or 5 half-lives, whichever is shortest;
   • Nitrosourea: less than 6 weeks;
   • Antibody-based therapy: less than 28 days;
   • Radiotherapy:
   -Local radiotherapy: less than 14 days
   -Radioisotope therapy: less than 6 weeks
   -50% pelvic or total body radiotherapy: less than 12 weeks
7. Major surgery within 28 days prior to the first dose of study drug. Participants must have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study drug(s).
8. Clinically significant cardiovascular disease, including:
   • Acute myocardial infarction ≤ 6 months before the first dose of study drug
   • Unstable angina pectoris, or other cardiac chest pain defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before the first dose of study drug
   • Coronary artery bypass surgery within 6 months prior to enrollment
   • Congestive heart failure of New York Heart Association (NYHA) class ≥3 (including class 3), ≤ 6 months before the first dose of study drug; LVEF < 50%
   • Ventricular arrhythmia grade ≥2 in severity, ≤ 6 months before the first dose
   • Stroke or intracranial hemorrhage ≤ 6 months before the first dose
   • Uncontrolled hypertension that cannot be managed by standard antihypertension medications, which is specified as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg). The participant must have blood pressures below both limits. Repeated assessments are permitted.
   • Syncope or seizure ≤ 28 days before the first dose of study drug
9. Hereditary long QT syndrome or QTcF>450 msec in males and QTcF > 470 msec in females or taking drugs that may cause QT prolongation or torsades de pointes.
   Fridericia’s QT correction formula: 𝑄𝑇𝑐 =𝑄𝑇/RR1/3
10. A clinically significant intercurrent pulmonary illness including, but not limited to, any underlying pulmonary disorder (i.e., severe asthma, severe chronic obstructive pulmonary disorder, restrictive lung disease, severely impaired lung function, significant pleural effusion etc.), any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis etc.), and/or prior pneumonectomy (either partial or complete).
11. History of pulmonary embolism within 3 months prior to the first dose of study drug.
12. History of (non-infectious) pneumonitis/ILD that required steroids, has current pneumonitis/ILD, or where suspected pneumonitis/ILD cannot be ruled out by imaging at screening.
13. Active infection requiring systemic treatment.
14. Known history of human immunodeficiency virus (HIV) infection or syphilis.
15. Participants with untreated active hepatitis B (hepatitis B surface antigen [HbsAg] positive and HBV-DNA positive [HBV DNA>200 IU/mL or >1000 copies/mL or above the lower limit of detection, whichever is higher]) or for participants with hepatitis B who are required to receive anti-hepatitis B treatment during the study period or active hepatitis C at screening:
    • Participants who are HBsAg negative, hepatitis B surface antibody (HBsAb) positive and/or hepatitis B core antibody (HBcAb) positive, but with undetectable viral DNA (HBV DNA <200 IU/mL or <1000 copies/mL or below the lower limit of detection, whichever is lower) and normal ALT are eligible. Participants with hepatitis B with undetectable HBV DNA after treatment should be discussed with sponsor before enrollment.
    -These participants with undetectable HBV DNA should be monitored with HBV DNA at each cycle if enrolled;
    • Participants with a negative hepatitis C virus (HCV) antibody test at screening or a positive HCV antibody test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test should be performed only for participants who tested positive for the HCV antibody.
16. History of inflammatory gastrointestinal diseases (such as Crohn's disease or ulcerative colitis).
17. History of severe cutaneous reactions, such as Steven-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic syndrome (DRESS).
18. Known hypersensitivity to any component of the product.
19. History of severe hypersensitivity reactions or anaphylactic responses to any monoclonal antibodies.
20. Disease progression after prior treatment with PI3K inhibitors or AKT inhibitors.
21. For any other diseases, metabolic abnormalities, physical examination abnormalities or laboratory examination abnormalities of significant clinical significance, according to the judgment of the investigator, there is reason to suspect that the participant has a certain disease or condition that is not suitable for the use of HMPL-A251, or it may affect the interpretation of research results or put participants at a high risk.
22. Pregnant (positive pregnancy test) or lactating women.
23. Previous organ transplantation and stem cell transplantation.
24. Known past or current malignancies, other than inclusion diagnosis, except for malignancies with 5-year disease-free survival, completely resected non-melanotic skin cancer, or cured carcinoma in situ.