HMPL-453 Tartrate Combined With Chemotherapy or Teriprizumab in Patients With Advanced Solid Tumors

• Status: Not yet recruiting
• Trial end date: 2025-08-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a phase Ib/II clinical study evaluating the safety, tolerability and preliminary efficacy of HMPL-453 combined with chemotherapy or teriprizumab in patients with advanced solid tumors. This study includes a dose exploration phase and a dose expansion phase.

The dose exploration phase includes 5 cohort studies (cohorts A, B, C, D, E), and a total of about 24 to 60 patients with advanced solid tumors were enrolled in this stage (cohorts B and C enrolled about 3 to 12 cases, others The cohort was enrolled in about 6-12 cases) and received HMPL-453 combined chemotherapy or teriprizumab treatment to evaluate the tolerability, safety and PK characteristics of HMPL-453 combined treatment. In the process of dose exploration, chemotherapeutics and teriprizumab will use a fixed dose, and only the dose/administration method of HMPL-453 will be adjusted. Each cohort and method of administration can be expanded to up to 12 patients.

About 60 to 81 patients were enrolled in the dose expansion stage to evaluate the initial efficacy of HMPL-453 combination therapy. After the RP2D and the mode of administration are determined in the dose exploration stage, the safety and preliminary effectiveness of HMPL-453 combination therapy will be further evaluated in patients with advanced solid tumors accompanied by specific FGFR gene changes.

All patients will receive the corresponding treatment until the disease progresses, the toxicity is intolerable, the informed consent is withdrawn, or other reasons that need to stop the study treatment occur (whichever occurs first). The sponsor can decide whether to further expand the enrollment based on PK, preliminary efficacy and safety data.

During the entire study period, the longest period of gemcitabine and cisplatin was no more than 24 weeks, and the use time of teriprizumab was no more than 24 months.

In this study, patients were evaluated on tumor imaging according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients will undergo tumor imaging evaluation every 6 weeks (±7 days) within 48 weeks after the first medication, and every 12 weeks (±7 days) after 48 weeks, until disease progression occurs. Initiation of new anti-tumor treatment, withdrawal of informed consent, loss of follow-up, death or termination of the study, whichever occurs first.

All SAEs need to be collected from the patient signing the pre-screening informed/informed consent form to before the first medication; after the first medication to 30 days after the last medication, or before the start of a new anti-tumor treatment (whichever occurs first), collect all SAEs All adverse events (Adverse Event, AE)/SAE. 30 days after the last administration or after the start of a new anti-tumor treatment (whichever occurs first), only SAEs that the investigator judges to be reasonably likely to be related to the study drug are reported. All AEs will be graded according to the National Cancer Institute Common Adverse Events Evaluation Criteria (NCI CTCAE) version 5.0.

After the study treatment is terminated and the treatment is completed, patients will undergo safety follow-up (30 days ± 7 days after the last medication) and survival follow-up (every 12 weeks ± 7 days).

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Hutchison Medipharma Limited

Criteria

Inclusion Criteria

Inclusion criteria for dose-exploration phase:

Patients with locally advanced, recurrent or metastatic advanced solid tumors who have failed histologically or cytologically confirmed standard treatment;

Inclusion criteria for Dose Expansion Phase:

Cohort I (intrahepatic cholangiocarcinoma with FGFR2 fusion)

• Histologically or cytologically confirmed surgically unresectable locally advanced, recurrent, or metastatic intrahepatic cholangiocarcinoma;

• Patients who have not received any first-line standard treatment for advanced cholangiocarcinoma (patients who have previously received postoperative adjuvant chemotherapy with gemcitabine combined with chemotherapy, but whose radiologically confirmed disease progression occurs 6 months after the last treatment, or patients who have undergone transcatheter arterial chemoembolization, cryoablation of liver metastases, or local anti-tumor therapy such as radiofrequency ablation can enter this clinical trial for prescreening/screening);

• Confirmed FGFR2 gene fusion/rearrangement;

Cohort II (gastric or gastroesophageal junction adenocarcinoma with FGFR2 amplification or FGFR2 overexpression)

• Histologically or cytologically confirmed surgically unresectable locally advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma;

• Patients who have failed or cannot tolerate first-line standard treatment (patients with PD or recurrence within 6 months after the end of previous systemic neoadjuvant or adjuvant chemotherapy can enter this study for prescreening or screening);

• Confirmed with FGFR2 gene amplification or FGFR2 overexpression;

• No prior treatment with paclitaxel/paclitaxel or radiographic progression after 6 months of last treatment;

Cohort III (urothelial carcinoma with FGFR2 translocation or FGFR3 mutation/translocation)

• Histologically or cytologically confirmed surgically unresectable locally advanced, recurrent, or metastatic urothelial carcinoma;

• Patients who have failed or cannot tolerate first-line standard treatment (patients with PD or recurrence within 6 months after the end of previous systemic neoadjuvant or adjuvant chemotherapy can enter this study for prescreening or screening);

• With FGFR2/3 gene translocation or FGFR3 gene mutation (R248, S249, G370, Y 373);

• Be able to provide tumor tissue samples to assess PD-L1 expression;

• No previous treatment with immune checkpoint inhibitors (including anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (or any other antibody acting on T-cell costimulation or checkpoint pathways);

Inclusion criteria to be met in both dose-finding and expansion phases:

• Aged 18 to 75 years, inclusive;

• Sign written informed consent, and be able to comply with protocol-specified visits and related procedures;

• Had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1;

• At least 1 measurable lesion according to RECIST v1.1;

• Adequate organ and bone marrow function, defined as follows:

• Blood routine: absolute neutrophil count (ANC) ≥ 1.5 × 109/L; platelet count (PLT) ≥ 100 × 109/L; hemoglobin (HGB) ≥ 100 g/L;

• Liver function: For patients without liver metastasis, serum total bilirubin (TBIL) ≤ 1.5 × ULN (UpperLimitofNormalvalue, ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. Requirements for patients with liver metastasis (or hepatocellular carcinoma): serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN;

• Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance rate (CCr) ≥ 50ml/min; urine routine results show urine protein < 2 +; for patients with urine protein ≥ 2 + in urine routine at baseline, 24h urine collection should be performed and the protein content in urine within 24h should be < 1g;

• Coagulation function: international normalized ratio (INR) ≤ 1.5, and partial thromboplastin time (PT) or activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

• Life expectancy ≥ 12 weeks;

• Female patients of childbearing age who are not surgically sterile must have a negative serum HCG test within 72 hours before the first treatment; female patients of childbearing age or male patients with partners of childbearing age must take effective contraceptive measures throughout the treatment period and 6 months after the treatment period.

Exclusion Criteria

• Patients who previously received selective FGFR target therapy (e.g., AZD4547, Debio1347, ARQ087, JNJ42756493, INCB054828, TAS120, BGJ398, LY2874455, BAY1163877, FPA144, etc.);

• Concurrent participation in another interventional clinical study, unless participating in an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study;

• History of blood transfusion or treatment with erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), thrombopoietin (TPO) or IL-11 within 2 weeks prior to the first study treatment;

• Received anti-tumor therapy (chemotherapy, endocrine therapy, targeted therapy, immunotherapy or tumor embolization, etc.) within 4 weeks before the first study treatment or Received radiotherapy within 2 weeks before the first study treatment;

• Take drugs (such as calcium, phosphate, vitamin D, parathyroid hormone, etc.) that may lead to increased blood phosphorus/calcium time within 2 weeks before the first treatment;

• Patients who have used immunosuppressive drugs before the first treatment with HMPL-453 combined with terepril or tislelizumab, excluding topical glucocorticoids by nasal spray, inhalation or other routes or physiological doses of systemic glucocorticoids (i.e., no more than 10 mg/day prednisone or equivalent doses of other glucocorticoids); prophylactic corticosteroids are allowed to avoid allergic reactions (e.g., pretreatment before intravenous contrast agent or chemotherapeutic drugs);

• Patients with active or suspected autoimmune diseases or a history of such diseases in the past 2 years prior to the first treatment with HMPL-453 combined with terepril or tislelizumab (patients with vitiligo, psoriasis, alopecia or Grave's disease requiring no systemic treatment in the past 2 years, patients with hypothyroidism requiring only thyroid hormone replacement therapy and patients with type I diabetes requiring only insulin replacement therapy can be excluded);

• Patients who received live vaccines 30 days before the first dose of study drug and during the study. Allowed to receive inactivated viral vaccines against seasonal influenza but not attenuated intranasal influenza vaccines;

• Major surgical procedures (craniotomy, thoracotomy or laparotomy) within 4 weeks prior to the first study treatment or expected to require major surgery or unhealed wound, ulcer or bone fracture during study treatment;

• Toxicities caused by previous anti-tumor therapy that have not recovered to NCICTCAEv5.0 grade 1 prior to the first study treatment (excluding alopecia);

• Prior or screening central nervous system (CNS) metastases;

• Patients with keratopathy confirmed by ophthalmic examination, including but not limited to bullous keratitis, band corneal degeneration, corneal abrasion, corneal ulcer and keratitis;

• Patients with current history of retinal detachment;

• Patients with a history of clinically significant abnormal calcium and phosphorus metabolism (e.g., parathyroid disease, history of parathyroidectomy, tumor lysis, tumor calcification, etc.) and/or serum phosphorus results in the screening period exceeding the upper limit of normal with clinical significance;

• The patient has any disease or condition that affects drug absorption, or the patient cannot take the drug orally;

• Patients who have received strong CYP3A inhibitors or strong inducers within 2 weeks or 5 half-lives (whichever is the time period, it takes 3 weeks for Forsythia suspensa) before the first dose;

• Known history of primary immunodeficiency;

• Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;

• Patients with human immunodeficiency virus (HIV) infection (HIV1/2 antibody positive), known syphilis infection requiring treatment;

• Symptomatic congestive heart failure (New York Heart Association Class II to IV), symptomatic or poorly controlled arrhythmia; presence or history of clinically significant electrocardiogram (ECG) changes in the opinion of the investigator; screening QTc interval > 480 ms;

• Hypertension uncontrolled even after standard treatment (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg);

• Uncontrolled metabolic disorders or other non-malignant organ or systemic diseases or reactions secondary to cancer, which may lead to high medical risk and/or uncertainty in survival evaluation;

• Patients with acute or chronic active hepatitis B or C infection, who are positive for hepatitis B virus surface antigen (HBsAg) and/or hepatitis B virus core antibody (HbcAb), hepatitis B virus (HBV) DNA > 104 copies/mL or 2000 IU/mL; patients with positive hepatitis C virus (HCV) antibody and positive HCV RNA (for patients with hepatocellular carcinoma, hepatitis C antibody positive and HCV RNA ≤ 103 copies/ml can be enrolled); patients lower than the above criteria after nucleotide antiviral therapy can be enrolled;

• Patients with a second primary tumor within 5 years before randomization, except for adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, local prostate cancer after radical resection, ductal carcinoma in situ after radical resection, or papillary thyroid carcinoma (applicable for dose expansion phase);

• Female patients who are pregnant or lactating;

• Patients with any other medical condition or clinically significant laboratory abnormality judged by the investigator that would make the patient inappropriate for the study.