Advanced Thymic Carcinoma
Conditions
Keywords
Lucitanib, AL3810, Advanced recurrent or metastatic thymic carcinoma, Tyrosine kinase inhibitor
Brief summary
Indication: Patients with advanced recurrent or metastatic thymic carcinoma. Phase IIa (China only):Approximately 6 patients. Phase IIb (China only):Approximately 54 patients.
Detailed description
This study consists of two parts: a Phase IIa study and a Phase IIb study. Phase IIa study: A single-arm, open-label study to evaluate the safety and tolerability of Lucitanib administered at 15 mg once daily for three consecutive weeks followed by one week off treatment in patients with advanced solid tumors who have failed standard therapy, have no effective treatment options, or are unwilling to receive standard therapy. Phase IIb study: A randomized, double-blind, placebo-controlled, multicenter study to evaluate Lucitanib in patients with advanced, recurrent, or metastatic thymic carcinoma who have failed at least first-line chemotherapy and are not eligible for surgical resection or definitive radiotherapy.
Interventions
DRUGlucitanib 15 mg QD
Phase IIa: The investigational product will be orally administrated when fasting at dose level of lucitanib 15 mg, QD, 3 weeks on and 1 week off
DRUGlucitanib 10 mg QD
Phase IIb: The investigational product will be orally administrated when fasting at dose level of lucitanib 10 mg QD
DRUGplacebo QD
Phase IIb: The investigational product will be orally administrated when fasting at dose level of Placebo QD
Sponsors
Haihe Biopharma Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients eligible for enrollment in this study must meet all of the following criteria: 1. Be able to understand and voluntarily sign the written informed consent form (ICF); 2. Be male or female, aged 18 to 75 years; 3. Have histologically or cytologically confirmed advanced solid tumors for which standard treatment has failed (defined as disease progression during or after treatment or intolerance to treatment-related toxicities), or for which no effective standard treatment is available, or patients who are unwilling to receive standard treatment (applicable to patients in the Phase IIa study); 4. Have histologically or cytologically confirmed advanced, recurrent, or metastatic thymic carcinoma that is unresectable and not amenable to curative radiotherapy, and have failed at least one line of chemotherapy (applicable to patients in the Phase IIb study); * Definition of treatment failure: Disease progression during or after first-line systemic chemotherapy (which may include platinum- or taxane-based chemotherapy) or intolerance to treatment-related toxicities, with radiographic or clinical evidence confirming disease progression. * For neoadjuvant/adjuvant therapy (chemotherapy or chemoradiotherapy), disease progression occurring during treatment or within 6 months after discontinuation of treatment will be considered failure of first-line treatment. 5. Have at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. If a lesion that has previously received local treatment (e.g., radiotherapy, ablation, or vascular intervention) is the only measurable lesion, there must be clear radiographic evidence of disease progression in that lesion (applicable to patients in the Phase IIb study); 6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (applicable to patients in the Phase IIa study) or ≤2 (applicable to patients in the Phase IIb study); 7. Have adequate bone marrow, hepatic, and renal function, without blood transfusion, blood product transfusion, granulocyte colony-stimulating factor (G-CSF), or other hematopoietic growth factor support within 2 weeks prior to the first dose: * Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; * Hemoglobin ≥9 g/dL; * Platelet count ≥90 × 10⁹/L; * Serum total bilirubin ≤1.5 × the upper limit of normal (ULN); * Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN in patients with liver metastases); * Creatinine clearance ≥50 mL/min, calculated using the Cockcroft-Gault formula (see Appendix 4); * Urinary protein \<1+. If urinary protein is ≥1+, the quantitative 24-hour urinary protein must be \<1.0 g/24 h; * International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (APTT) ≤1.5 × ULN; 8. For females of childbearing potential, have a negative serum or urine pregnancy test within 7 days prior to the first dose. Male patients and female patients of childbearing potential must use adequate contraceptive measures from the time of signing the ICF until 6 months after the last dose of study drug; 9. Have a body weight ≥40 kg; 10. Have a life expectancy of ≥12 weeks, as judged by the investigator.
Exclusion criteria
* Patients who meet any of the following criteria will be excluded from the study: 1. Have unresolved toxicities related to previous anticancer treatment that have not recovered to ≤Grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), except for alopecia and ≤Grade 2 peripheral neuropathy due to oxaliplatin; 2. Have had other malignancies within the past 5 years, except for adequately controlled basal cell carcinoma of the skin or carcinoma in situ of the cervix; 3. Have central nervous system (CNS) metastases requiring clinical intervention or tumor-related epilepsy. Patients with previously treated and stable CNS metastases for ≥3 months without the need for corticosteroids or antiepileptic drugs, as well as patients with asymptomatic CNS metastases, may be enrolled; 4. Have received systemic anticancer therapy within 2 weeks prior to the first dose, including chemotherapy, molecularly targeted therapy, immunotherapy, biological therapy, hormone therapy, or traditional Chinese medicine for anticancer treatment (according to the indications specified in the relevant traditional Chinese medicine package insert). Patients who have completed a 2-week washout period may be eligible for enrollment; 5. Have received definitive radiotherapy within 4 weeks prior to the first dose (including radiotherapy involving \>25% of the bone marrow), or local palliative radiotherapy for bone metastases within 2 weeks prior to the first dose; 6. Have previously received treatment with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor or programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor; 7. Have clinically uncontrolled serous effusion, such as pleural effusion that cannot be adequately controlled by drainage or other interventions; 8. Have any of the following cardiovascular conditions: * Congestive heart failure of New York Heart Association (NYHA) functional class ≥II; * Serious cardiac arrhythmia requiring pharmacological treatment; * Acute myocardial infarction, severe or unstable angina pectoris, or coronary or peripheral arterial bypass surgery within 6 months prior to the first dose; * Left ventricular ejection fraction (LVEF) \<50%; * Corrected QT interval (QTc) \>450 ms in males or \>470 ms in females, or risk factors for torsades de pointes, such as clinically significant hypokalemia as judged by the investigator, a family history of long QT syndrome, or a family history of inherited arrhythmias (e.g., Wolff-Parkinson-White syndrome); * Uncontrolled hypertension, defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg despite standardized antihypertensive treatment; 9. Have experienced an arterial/venous thrombotic or embolic event within 6 months prior to the first dose, such as stroke (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism; 10. Have known human immunodeficiency virus (HIV) infection, active hepatitis B, or active hepatitis C. Active hepatitis B is defined as hepatitis B surface antigen (HBsAg) positivity with HBV DNA ≥10³ copies/mL or ≥200 IU/mL. Active hepatitis C is defined as positive hepatitis C virus (HCV) antibody and positive HCV RNA by polymerase chain reaction (PCR); 11. Have an active bacterial, fungal, or viral infection requiring systemic treatment within 1 week prior to the first dose; 12. Have received a strong cytochrome P450 (CYP) 2C8 and/or CYP3A4 inhibitor or a strong CYP3A4 inducer within 1 week or 5 half-lives of the drug, whichever is longer, prior to the first dose, or require continued treatment with any of these medications during the study; 13. Be unable to discontinue medications that may cause QTc prolongation or torsades de pointes (e.g., antiarrhythmic drugs) during the study; 14. Have experienced a bleeding event of ≥Grade 3 according to CTCAE within 4 weeks prior to the first dose or have a bleeding tendency. Patients with active duodenal ulcers, ulcerative colitis, intestinal obstruction, or other conditions considered by the investigator to potentially cause gastrointestinal bleeding or perforation are also excluded. Patients with a history of intestinal perforation or intestinal fistula that has not completely healed are also excluded; 15. Have multiple factors that may affect the absorption, distribution, metabolism, or elimination of oral study drug, such as inability to swallow medication, frequent vomiting, or chronic diarrhea; 16. Have any clinically significant systemic disease requiring treatment, as judged by the investigator, including but not limited to autoimmune diseases (except those requiring inhaled or topical treatment), thyroid disorders (patients with stable thyroid function on hormone replacement therapy may be enrolled), interstitial lung disease of ≥Grade 2 according to CTCAE, organ transplantation, or a history of psychiatric drug abuse, alcohol abuse, or illicit drug use; 17. Have poorly healing wounds, severe ulcers, or fractures; or have undergone major surgery (in China, major surgery is defined as Grade 3 or Grade 4 surgery according to the Administrative Measures for the Clinical Application of Medical Technologies, effective May 1, 2009) or experienced significant traumatic injury within 28 days prior to the first dose of study drug; 18. Have a known or suspected hypersensitivity to the study drug and/or any of its excipients; 19. Be pregnant or breastfeeding; 20. Be receiving treatment in another interventional clinical trial within 4 weeks prior to the first dose. Patients participating in a non-interventional clinical trial (e.g., an epidemiological study) may be eligible for enrollment. Patients who have entered the survival follow-up period of an interventional clinical trial may also be eligible for enrollment; 21. Have any other disease or medical condition that, in the investigator's judgment, is unstable or may affect patient safety or compliance with the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase IIa:Safety and Tolerability | From first dose through 28 days after the last dose | The safety and tolerability of lucitanib will be evaluated based on the incidence, type, severity, and outcome of adverse events (AEs) and treatment-emergent adverse events (TEAEs), including dose-limiting toxicities (DLTs) and other adverse events occurring during the treatment period. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03. |
| Phase IIb:Progression-free survival (PFS) by independent review committee | Up to approximately 24 months | Progression-free survival is defined as the time from the date of randomization to the date of disease progression or death from any cause, whichever occurs first, as assessed by independent review committee according to RECIST Version 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase IIa: Progression-free survival (PFS) by investigator | Up to approximately 24 months | Progression-free survival is defined as the time from the date of first dose of lucitanib to the date of disease progression or death from any cause, whichever occurs first, as assessed by the investigator according to RECIST Version 1.1 |
| Phase IIa: Objective response rate (ORR) | Up to approximately 24 months | Objective response rate is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR), as assessed by the investigator according to RECIST Version 1.1. |
| Phase IIa: Disease Control Rate (DCR) | Up to approximately 24 months | Disease control rate is defined as the proportion of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD), as assessed by the investigator according to RECIST Version 1.1. |
| Phase IIb: Progression-free survival (PFS) by investigator assessment | Up to approximately 24 months | Progression-free survival is defined as the time from the date of randomization to the date of disease progression or death from any cause, whichever occurs first, as assessed by the investigator according to RECIST Version 1.1. |
| Phase IIb: 6-month progression-free survival rate | 6 months after randomization | The 6-month progression-free survival rate is defined as the proportion of participants who remain alive and free of disease progression at 6 months after randomization, as assessed according to RECIST Version 1.1. |
| Phase IIb: Objective response rate (ORR) | Up to approximately 24 months | Objective response rate is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR), according to RECIST Version 1.1. |
| Phase IIb: Disease control rate (DCR) | Up to approximately 24 months | Disease control rate is defined as the proportion of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD), according to RECIST Version 1.1. |
| Phase IIb: Duration of response (DoR) | From the date of first documented response until disease progression or death, assessed up to approximately 24 months | Duration of response is defined as the time from the date of first documented complete response or partial response to the date of disease progression or death from any cause, whichever occurs first, as assessed according to RECIST Version 1.1. |
| Phase IIb: Overall survival (OS) | From the date of randomization until death from any cause, assessed up to approximately 48 months | Overall survival is defined as the time from the date of randomization to the date of death from any cause. |
| Phase IIb: Safety and tolerability | From first dose through 28 days after the last dose | The safety and tolerability of lucitanib will be evaluated based on the incidence, type, severity, and outcome of adverse events (AEs) and treatment-emergent adverse events (TEAEs) occurring during the treatment period and safety follow-up. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03. |
| Phase IIa:Area Under the Concentration-Time Curve from Time Zero to the Last Measurable Concentration (AUClast) | Day 1 and Day 15 | AUClast of lucitanib in plasma will be evaluated based on plasma concentrations of lucitanib collected pre-dose and at 30 min, 1, 2, 3, 4, 8, and 12 hours post-dose. |
| Phase IIa:Area Under the Concentration-Time Curve over 24 Hours (AUC24) | Day 1 and Day 15 | AUC24 of lucitanib in plasma will be evaluated based on plasma concentrations of lucitanib collected pre-dose and at 30 min, 1, 2, 3, 4, 8, and 12 hours post-dose. |
| Phase IIa:Maximum Observed Concentration (Cmax) | Day 1 and Day 15 | Maximum observed plasma concentration (Cmax) of lucitanib will be evaluated based on plasma concentrations collected pre-dose and at 30 min, 1, 2, 3, 4, 8, and 12 hours post-dose. |
| Phase IIa:Minimum Observed Concentration (Cmin) | Day 1 and Day 15 | Minimum observed plasma concentration (Cmin) of lucitanib will be evaluated based on plasma concentrations collected pre-dose and at 30 min, 1, 2, 3, 4, 8, and 12 hours post-dose. |
| Phase IIa:Accumulation Ratio (Racc) | Day 15 | Accumulation ratio (Racc) of lucitanib will be evaluated based on plasma concentrations on Day 1 and Day 15. |
| Phase IIa:Terminal Half-Life (t1/2) | Day 1 and Day 15 | Terminal half-life (t1/2) of lucitanib will be evaluated based on plasma concentrations collected following dosing. |
| Phase IIa:Clearance (CL) | Day 1 and Day 15 | Clearance (CL) of lucitanib will be evaluated based on plasma concentrations collected following dosing. |
Countries
China
Contacts
STUDY_DIRECTORHuiming Cai, MD
Haihe Biopharma
Outcome results
None listed