A Phase I, First-in-Human, Open-Label, Dose Escalation Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of LM-061 Tablet in Subjects With Advanced Tumors
Overview
- Phase
- Phase 1
- Intervention
- LM-061
- Conditions
- Advanced Tumours
- Sponsor
- LaNova Medicines Limited
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Number of participants with adverse events and serious adverse events
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a phase I, open-label, dose escalation study to evaluate the safety, tolerability, PK, and preliminary efficacy of LM-061 in subjects with advanced tumors.
Detailed Description
This is a phase I, open-label, dose escalation study to evaluate the safety, tolerability, PK, and preliminary efficacy of LM-061 in subjects with advanced tumors. The study schedule includes screening visit (28 days prior to accept the investigational medicinal product (IMP)), treatment visit (accept IMP for the first time to the end of treatment (EOT)/early withdrawal), and follow-up visit (28 days after the EOT/early withdrawal).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Volunteer to participate in clinical trial, sign a written informed consent form, and be able to comply with clinical visits and study related procedures;
- •Male or female subjects 18 to 75 years old (both inclusive) when sign the informed consent;
- •Study population: the subjects with advanced malignant tumors confirmed by histology or cytology, and have failed standard treatment, or have no standard treatment, or not suitable for standard treatment at present;
- •ECOG score 0-1;
- •The estimated survival time is not less than 3 months;
- •The functional of bone marrow reserve and organs must meet the following requirements (without ongoing continuous supportive treatment):
- •Bone marrow reserve: Neutrophil count (NE#) ≥ 1.5×109/L, platelet count (PLT) ≥ 759 0 ×109/L; for patients with hematologic malignancies, platelet count ≥ 75 × 109/L, and hemoglobin (HGB) \> 9.0 g/dL (no blood transfusion or hematopoietic stimulating factor therapy within 14 days);
- •Coagulation function: activated partial thromboplastin time (APTT) prolong ≤ 1.5× upper limit of normal (ULN), and international standard ratio (INR) ≤ 1.5;
- •Liver function: total bilirubin (TBIL) ≤ 1.5×ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN (if there is liver metastasis, ALT or AST≤ 5×ULN);
- •Kidney function: Creatinine clearance rate ≥50 mL/min (using Cockcroft-Gault formula, see Appendix 1) or serum creatinine ≤1.5×ULN; qualitative urine protein ≤1+ or qualitative urine protein ≥2+, but 24-hour urine protein \<1g;
Exclusion Criteria
- •Have received chemotherapy, radiotherapy, biological therapy, endocrine therapy, immune checkpoint inhibitor therapy and other anti-tumor treatments within 4 weeks prior to first dose of IMP, except for the following items:
- •Have used nitrosourea or Mitomycin C within 6 weeks prior to first dose of IMP;
- •Have used oral fluorouracil and small molecule targeted drugs within 2 weeks prior to first dose of IMP or 5 half-lives of the IMP (whichever is longer);
- •Have used herbal therapy with anti-tumor indications are within 2 weeks prior to first dose of IMP;
- •Have received other Non-approved clinical trial drugs or treatments within 4 weeks prior to first dose of IMP;
- •Have undergone major organ surgery (excluding biopsy) or have had significant trauma or invasive dental procedures (such as tooth extraction, dental implant) within 4 weeks prior to first dose of IMP, or required elective surgery during the trial period;
- •Have serious unhealable wounds/ulcers/bone fractures within 4 weeks prior to first dose of IMP;
- •Are taking (or cannot be stopped at least 1 week prior to first dose of IMP) any drug that is known to strongly inhibit or induce CYP3A4 (see Appendix 3 for details);
- •The histopathological type of the tumor is head and neck or lung squamous cell carcinoma, or other tumors with bleeding tendency as judged by the investigator;
- •Bleeding events of grade 3 or above occurred within 6 months before the first dose of IMP or currently ≥grade 2 bleeding or factors judged by the investigator to have a high risk of bleeding (such as active peptic ulcer or esophageal varices) at present;
Arms & Interventions
LM-061 single agent escalation
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. The subject in single agent dose levels will be administered multiple oral doses of LM-061 once daily.
Intervention: LM-061
LM-061 combination escalation
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. The subjects in combination dose levels will be administered multiple oral doses once daily of LM-061 and Toripalimab fixed dose injections every 3 weeks
Intervention: LM-061
LM-061 combination escalation
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. The subjects in combination dose levels will be administered multiple oral doses once daily of LM-061 and Toripalimab fixed dose injections every 3 weeks
Intervention: Toripalimab
Outcomes
Primary Outcomes
Number of participants with adverse events and serious adverse events
Time Frame: : From screening up to 1 year
The safety profile of LM061 will be assessed by monitoring the adverse events (AE) per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Dose-limiting toxicities (DLT)
Time Frame: : Cycle 1 of each cohort. Duration of one cycle is 28 days
DLT is defined as a toxicity (adverse event at least possibly related to LM061) occurring during the DLT observation period (the initial 21 days)
Change in Vital Signs-ear temperature
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Change in vital signs-ear temperature will be measured after the subject has been fully rested.
Change in Electrocardiogram (ECG)-RR interval
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
RR interval of 12-lead ECG will be performed in the supine position after the patients are fully rested at each timepoint for once. RR is the standard heart rate which calculated by 60 divided by heart rate.
Incidence of Abnormal Clinical Laboratory Test Results-Biochemistry
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Number of participants with incidence of abnormal clinical lab test results like Biochemistry will be assessed.
Change in Vital Signs-blood pressure
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Change in vital signs-blood pressure will be measured after the subject has been fully rested.
Change in Electrocardiogram (ECG)-QRS duration
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
QRS duration of 12-lead ECG will be performed in the supine position after the patients are fully rested at each timepoint for once.
Incidence of Abnormal Clinical Laboratory Test Results-hematology
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Number of participants with incidence of abnormal clinical lab test results like hematology will be assessed.
Incidence of Abnormal Clinical Laboratory Test Results-Coagulation test
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Number of participants with incidence of abnormal clinical lab test results like Coagulation test will be assessed.
Change in Vital Signs-pluse rate
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Change in vital signs-pluse rate will be measured after the subject has been fully rested.
Change in Electrocardiogram (ECG)-QT interval
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
QT interval of 12-lead ECG will be performed in the supine position after the patients are fully rested at each timepoint for once.
Incidence of Abnormal Clinical Laboratory Test Results-Urinalysis
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Number of participants with incidence of abnormal clinical lab test results like Urinalysis will be assessed.
Secondary Outcomes
- Time to reach maximum serum concentration (Tmax)(Up to 1 year)
- Clearance (CL)(Up to 1 year)
- Terminal half-life (T1/2)(Up to 1 year)
- Dose proportionality(Up to 1 year)
- Best of response (BOR)(Up to 1 year)
- 7. Area under the serum concentration versus time curve within one dosing interval (AUCtau)(Up to 1 year)
- Volume of distribution (Vd)(Up to 1 year)
- Volume of distribution at steady state (Vss)(Up to 1 year)
- Trough concentration before the next dose is administered (Ctrough)(Up to 1 year)
- Maximum serum concentration (Cmax)(Up to 1 year)
- Objective response rate (ORR)(Up to 1 year)
- Disease control rate (DCR)(Up to 1 year)