A Phase I/II, First-in-Human, Open-Label, Dose-Escalation and Dose-Extension Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of LM-061 Tablet in Subjects With Advanced Tumours
Overview
- Phase
- Phase 1
- Intervention
- LM-061
- Conditions
- Advanced Tumours
- Sponsor
- LaNova Medicines Limited
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a phase I/II, open-label, dose escalation and dose extension 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/II, open-label, dose escalation and dose extension 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 study, 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;
- •Dose Escalation 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;
- •Dose Extension patients with advanced solid tumors with abnormal c-Met, including EGFR-TKI-resistant non-small cell lung cancer and pulmonary sarcomatoid adenocarcinoma, diagnosed histologically or cytologically, who have failed standard therapy, or who do not have standard treatment regimens, or who are not suitable for standard therapy at this stage;Papillary renal cell carcinoma;Metastatic or locally advanced unresectable gastric adenocarcinoma with at least first-line standard treatment;
- •ECOG score 0-1;
- •C-MET abnormalities are defined by central laboratory as the situation that meets one of the following: Abnormal expression of c-Met immunohistochemistry (IHC) : strong staining (2+ or above) in more than 50% of tumor cells; MET amplification positive: MET/CEP 7 ≥2 or GCN ≥5; MET exon14-skipping mutation;
- •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) ≥90 ×109/L; 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; Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%; ECG is basically normal, and corrected QT interval (QTcF) ≤450 ms and 470 ms for male and female, respectively;
- •According to RECIST v1.1 criteria, there should be at least one evaluable tumor focus in the dose escalation phase;At least one measurable tumor was present during the dose expansion phase;
Exclusion Criteria
- •Have received chemotherapy, radiotherapy, biological therapy, endocrine therapy, immune checkpoint inhibitor therapy and other anti-tumour treatments within 4 weeks prior to first dose of IMP, except for the following items:
- •Subjects was diagnosed as acute promyelocytic leukemia (APL), breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (i.e., chronic myelogenous leukemia in blast crisis), active central nervous system leukemia, or AML secondary to prior chemotherapy for other neoplasms;
- •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 or 5 half-lives of the drugs prior to first dose of IMP (whichever is longer);
- •Have received other unmarketed clinical study 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 study 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 5 for details);
- •The histopathological type of the tumour is head and neck or lung squamous cell carcinoma, or other tumours 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
LM061 Dose Escalation Level 1, 2.5mg
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. first dose: 2.5mg QD, n=1;
Intervention: LM-061
LM061 Dose Escalation Level 2, 5mg
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. second dose: 5mg QD, n=3;
Intervention: LM-061
LM061 Dose Escalation Level 3, 10mg
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. third dose: 10mg QD, n=3;
Intervention: LM-061
LM061 Dose Escalation Level 4, 20mg
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. fourth dose: 20mg, n=3;
Intervention: LM-061
LM061 Dose Escalation Level 5, 30mg
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. fifth dose: 30mg, n=3;
Intervention: LM-061
LM061 Dose Escalation Level 6, 40mg
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. sixth dose: 40mg, n=9;
Intervention: LM-061
LM061 Dose Escalation Level 7, 60mg
The dose escalation scheme using the the accelerated titration design for dose 1 and the i3+3 design for the remaining doses. seventh dose: 60mg, n=15;
Intervention: LM-061
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD)
Time Frame: Cycle 1 of each cohort. Duration of one cycle is 28 days
MTD is defined as the dose for which the probability of DLT does not exceed the upper bound of the EI, 0.35, and is closest to the target toxicity probability p_T=0.3 during the DLT assessment period (from LM-061 single dose to the first treatment cycle of the multiple dose). The i3+3 design does not select a dose as the MTD unless at least 3 subjects have completed the safety assessment.
Number of participants with adverse events and serious adverse events
Time Frame: From screening up to 1.5 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-pulse rate
Time Frame: Baseline (Week 0) through approximately 1 year after first administration of LM061
Change in vital signs-pulse rate will be measured after the subject has been fully rested.
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)-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-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.
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.
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.
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.
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 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-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.
Secondary Outcomes
- Volume of distribution (Vd)(Up to 1.5 year)
- Terminal half-life (T1/2)(Up to 1.5 year)
- Dose proportionality(Up to 1.5 year)
- Maximum serum concentration (Cmax)(Up to 1.5 year)
- Volume of distribution at steady state (Vss)(Up to 1.5 year)
- Trough concentration before the next dose is administered (Ctrough)(Up to 1.5year)
- Time to reach maximum serum concentration (Tmax)(Up to 1.5 year)
- Clearance (CL)(Up to 1.5 year)
- Objective response rate (ORR)(Up to 1.5 year)
- Best of response (BOR)(Up to 1.5 year)
- Disease control rate (DCR)(Up to 1.5 year)
- Area under the serum concentration versus time curve within one dosing interval (AUCtau)(Up to 1.5year)