Irinotecan Hydrochloride Liposome Injection (LY01610) For Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is a Phase I, open-label, non-randomized, dose-escalation study to evaluate the safety and tolerability, the maximum tolerated dose (MTD) and the dose limited toxicity(DLT) of LY01610 monotherapy and combine with 5-Fu in patients with advanced solid tumors. Additionally, the pharmacokinetics and preliminary efficacy of LY01610 monotherapy and combine with 5-Fu will be investigated in this study.

Detailed Description
-----------------
This study will be conducted in two stages: In the first stage, ascending doses of LY01610 will be administered as monotherapy in participants with solid tumors. The starting dose was 30 mg/m2 and the subsequent dose was increased according to the protocol of 60 mg/m2, 90 mg/m2, 120 mg/m2, 150 mg/m2, 180mg/m2. Each subject received only one dose of the drug, and the next dose group study could only be performed if the previous dose group was completed 21 days of observation after the first dose and safe tolerance was confirmed. According to the subjects' tolerance, appropriate doses will be selected and the safety, PK characteristics and initial efficacy of LY01610 were further evaluated in additional 6 - 8 patients. The interval between the first dose and the second dose was 3 weeks, followed by 2 weeks.Another 8 subjects were enrolled and given CAMPTO® (180 mg/m2) once every 2 weeks to perform the pharmacokinetic profiles. The second stage is a dose escalation study of LY01610 combined with 5-Fu. Based on the results of the first stage, three doses of low, medium and high doses were selected in combination with a fixed dose of 5-Fu to determine the DLT and MTD. Similarly, according to the subjects' tolerance, appropriate dose will be selected and the safety, PK characteristics and initial efficacy of LY01610 combined with a fixed dose of 5-Fu were further evaluated in 6 - 8 patients. The drug was administered every 2 weeks.

Official Title
-----------------
PhaseⅠStudy of Irinotecan Hydrochloride Liposome Injection (LY01610) About the Safety, Tolerability, Pharmacokinetics (PK)and Preliminary Efficacy in Patients With Advanced Solid Tumors

Conditions
-----------------
Advanced Solid Tumor

Intervention / Treatment
-----------------
* Drug: LY01610 ( Irinotecan hydrochloride liposome injection )
* Drug: LY01610 ( Irinotecan hydrochloride liposome injection ) with 5-Fu（Fluorouracil Injection）
* Drug: Irinotecan Hydrochloride Injection（CAMPTO®）


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients aged 18 to 70 years (18 years and 70 years are inclusive). Histologically or cytologically confirmed solid tumor for which failed or could not •tolerate standard treatment, or standard effective treatment does not exist. The patient should have at least one measurable lesion as the target lesion (according to RECIST 1.1 criteria). The predictable survival duration ≥ 3 months. The Eastern Cooperative Oncology Group (ECOG) performance status score < 2 point. Laboratory results during screening: Hematology: Absolute neutrophil count ≥ 1.5× 109/L, platelet count≥ 100× 109/L and hemoglobin≥ 90 g/L; Liver function: Total bilirubin（TBIL）≤ 1.5×upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN for the subjects without liver metastasis; ALT and AST≤ 5×ULN for the subjects with liver metastasis; Kidney function: Serum creatinine ≤ 1.5 ×ULN or creatinine clearance rate ≥ 50 mL/min(Cockcroft-Gault formula); The subject has voluntarily signed the written informed consent form (ICF) and can comply with the study protocol; The female subjects of childbearing age and male subjects with fertility potential female partner agree to take reliable contraceptive measures (such as abstinence, sterilizing operation, contraceptives, injection of the contraceptive drug •medroxyprogesterone acetate or subdermal implant of contraceptives) during the study period and within 6 months after infusion of the study drugs. Exclusion Criteria: Patients with brain malignant tumor, lymphoma or other malignant blood diseases; The subjects with symptomatic brain metastasis; Other malignant tumors within 5 years prior to screening (except for stage Ib or lower cervical cancer, non-invasive basal cells or squamous cell skin cancer that have been cured); Patients with uncontrollable ascites, pleural effusion; Ongoing or active systemic infection need intravenous antibiotic treatment; Medical history of the following diseases within 6 months before screening: myocardial infarction, unstable angina, history of coronary revascularization, congestive heart failure (New York Heart Association classification ≥ grade II), severe unstable ventricular arrhythmia, serious arrhythmia which needs drug treatment; The patient with hepatitis B surface antigen (HBsAg) positive and the peripheral blood HBV DNA titer ≥1× 103 copies/mL or 200 IU/ml The subject is eligible to be enrolled if HBsAg is positive and peripheral blood hepatitis B virus (HBV) DNA titer <1×103 copies/ml or 200 IU/ml and the investigator considers that the subject is at the stable stage of chronic hepatitis and the risk will not be increased for the subjects;the patient with hepatitis C virus (HCV) antibody and human immunodeficiency virus (HIV) antibody positive; Patients still with clinically significant electrolyte disorders that were diagnosed by the investigator before drug administration;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY01610-Dose Escalation<br>The starting dose was 30 mg/m2 IV and the subsequent dose was increased according to the protocol of 60 mg/m2, 90 mg/m2, 120 mg/m2, 150 mg/m2, 180mg/m2. The interval between the first dose and the second dose was 3 weeks, followed by 2 weeks. | Drug: LY01610 ( Irinotecan hydrochloride liposome injection )<br>* Part1-Dose Escalation and Part1-Dose Extension : subjects take LY01610;<br>|
| Experimental: LY01610-Dose Extension<br>According to the subjects' tolerance, appropriate dose will be selected and the safety, PK characteristics and initial efficacy of LY01610 were further evaluated in 6 - 8 patients. The interval between the first dose and the second dose was 3 weeks, followed by 2 weeks. | Drug: LY01610 ( Irinotecan hydrochloride liposome injection )<br>* Part1-Dose Escalation and Part1-Dose Extension : subjects take LY01610;<br>|
| Experimental: LY01610 with 5-Fu -Dose Escalation<br>Dose Escalation: Based on the results of the first stage, three doses of low, medium and high doses were selected in combination with a fixed dose of 5-Fu to determine the DLT, MTD, PK characteristics and the preliminary efficacy. 5-Fu, 400mg/m2 will be administered intravenously on days 1, followed by 600 mg/m2 given as a 22-hour continuous infusion on day 1 and 2, every 2 weeks. | Drug: LY01610 ( Irinotecan hydrochloride liposome injection ) with 5-Fu（Fluorouracil Injection）<br>* Part2-Dose Escalation and Part2-Dose Extension : subjects take LY01610 with 5-Fu;<br>|
| Experimental: LY01610 with 5-Fu -Dose Extension<br>Similarly, according to the subjects' tolerance, appropriate dose will be selected and the safety, PK characteristics and initial efficacy of LY01610 combined with a fixed dose of 5-Fu were further evaluated in additional 6 - 8 patients. In dose escalation and dose extension stages, both LY01610 and fixed dose 5-Fu will be given once every 2 weeks. | Drug: LY01610 ( Irinotecan hydrochloride liposome injection ) with 5-Fu（Fluorouracil Injection）<br>* Part2-Dose Escalation and Part2-Dose Extension : subjects take LY01610 with 5-Fu;<br>|
| Active Comparator: Hydrochloride Injection- pharmacokinetics comparative study<br>After receiving the MTD of LY01610, another 8 subjects were enrolled and given Irinotecan Hydrochloride Injection（captol ®） (180mg/m2) once every 2 weeks. Upon completion of the pharmacokinetics study, the sponsor will continue to provide the study drug treatment free of charge, and the researcher will conduct treatment and examination according to the subject's situation, without collecting any safety and efficacy data of the subject. | Drug: Irinotecan Hydrochloride Injection（CAMPTO®）<br>* Irinotecan Hydrochloride Injection（CAMPTO®） pharmacokinetics comparative study<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | The DLT of LY01610 monotherapy was obtained through the dose-increasing study of LY01610 | 21 days for the LY01610 monotherapy (first treatment cycle of every subjects) | 
| Dose limiting toxicity (DLT) | The DLT of combination of LY01610 and 5-fu was obtained through the dose-increasing study of LY01610 and 5-Fu | 14 days for the LY01610 combined 5-Fu (first treatment cycle of every subjects) | 
| Maximum tolerated dose(MTD) | The MTD of LY01610 monotherapy was obtained through the single-drug dose increase study | 21 days for the LY01610 monotherapy (first treatment cycle of every subjects) | 
| Maximum tolerated dose(MTD) | The MTD of combination of LY01610 and 5-fu was obtained through the combined dose increase study | 14 days for the LY01610 combined 5-Fu (first treatment cycle of every subjects) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | The AUC of LY01610 monotherapy was obtained through the dose escalation and extension study，the AUC of active comparator CAMPTO® was obtained through the study，and the AUC of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| t1/2 | The t1/2 of LY01610 monotherapy was obtained through the dose escalation and extension study，the t1/2 of active comparator CAMPTO® was obtained through the study，and the t1/2 of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| Cmax | The Cmax of LY01610 monotherapy was obtained through the dose escalation and extension study，the Cmax of active comparator CAMPTO® was obtained through the study，and the Cmax of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| tmax | The tmax of LY01610 monotherapy was obtained through the dose escalation and extension study，the tmax of active comparator CAMPTO® was obtained through the study，and the tmax of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| Vd | The Vd of LY01610 monotherapy was obtained through the dose escalation and extension study，the Vd of active comparator CAMPTO® was obtained through the study，and the Vd of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| CL | The CL of LY01610 monotherapy was obtained through the dose escalation and extension study，the CL of active comparator CAMPTO® was obtained through the study，and the CL of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| MRT | The MRT of LY01610 monotherapy was obtained through the dose escalation and extension study，the MRT of active comparator CAMPTO® was obtained through the study，and the MRT of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| Kel | The Kel of LY01610 monotherapy was obtained through the dose escalation and extension study，the Kel of active comparator CAMPTO® was obtained through the study，and the Kel of LY01610 combined with 5-fu was obtained through the dose escalation and extension study. | 22 days for the LY01610 monotherapy (first treatment cycle of every subjects)，5 days for the active comparator CAMPTO® (first treatment cycle of every subjects)，and 15 days for the LY01610 combined with 5-fu(first treatment cycle of every subjects) | 
| Best Objective Response Rate | Preliminary efficacy evaluation of LY01610 and LY01610 combined with 5-fu | 8 weeks from enrollment | 
| Progression Free Survival | Preliminary efficacy evaluation of LY01610 and LY01610 combined with 5-fu | from the date of enrollment to the date of disease progression or death up to 24 months from randomisation of the subject | 
| Overall Survival | Preliminary efficacy evaluation of LY01610 and LY01610 combined with 5-fu | from the date of enrollment to the date of death up to 24 months from randomisation of the subject | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LY01610, 5-Fu, Safety, Tolerability, Pharmacokinetics