Study of LM-061 in Subjects in Advanced Tumors

Study 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).

Official Title
-----------------
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

Conditions
-----------------
Advanced Tumours

Intervention / Treatment
-----------------
* Drug: LM-061
* Drug: Toripalimab


Participation Criteria
=================
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; 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; Eligible subjects with fertility (male and female) must agree to use reliable contraceptive methods (hormonal or barrier method or abstinence, etc.) with their partners during the trial period and at least 3 months after the last administration; women of childbearing age (Refer to Appendix 2 for definitions) The subject's serum pregnancy test must be negative within 7 days prior to the first administration. 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; The adverse reactions of previous anti-tumor treatments have not yet recovered to CTCAE 5.0 grade evaluation ≤1 (except for toxicity judged by the investigator to have no safety risk, such as hair loss, grade 2 peripheral neurotoxicity, etc.); Central nervous system metastasis or meningeal metastasis with clinical symptoms, or other evidence that the subject's central nervous system metastasis or meningeal metastasis has not been controlled, and the investigator judges it to be unsuitable for inclusion; Gastrointestinal perforation, abdominal fistula, or intra-abdominal abscess occurred within 6 months before the first dose of the IMP; or the investigator has determined that there are high-risk factors for the formation of cavity organ perforation/fistula (such as tumor infiltration in the cavity Outer layer of the wall); inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis; Unable to be dosed orally, or there are conditions that have been judged by the investigators to seriously affect the absorption of the gastrointestinal tract, such as dysphagia, nausea and vomiting that are difficult to control, intestinal obstruction, and gastric outlet obstruction; Have active infection 1 week before the first dose of IMP and currently need systemic anti-infective treatment; HIV infection, active HBV infection (HBV DNA exceeds the ULN), active HCV infection (HCV RNA exceeds the ULN); Have a history of serious cardiovascular and cerebrovascular diseases, including but not limited to: Severe heart rhythm or conduction abnormalities, such as ventricular arrhythmia that requires clinical intervention, grade Ⅱ-Ⅲ atrioventricular block, etc.; Thromboembolic events requiring therapeutic anticoagulation, or subjects with venous filters; According to the New York Heart Association (NYHA) standards, subjects with grade III IV cardiac insufficiency; Acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other cardiovascular and cerebrovascular events of grade 3 or above occurred within 6 months before the first administration of IMP; Clinically uncontrollable hypertension (blood pressure cannot be controlled at systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg after standard antihypertensive treatment); Any factors that increase the risk of QTc prolongation or arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, use of any concomitant drugs that are known or may prolong the QT interval (see Appendix 3 for details); The third gap effusion that cannot be controlled clinically is not suitable for inclusion in the study judged by the investigator; Known history of drug abuse; Subjects with mental disorders or poor compliance; Women who are pregnant or breastfeeding; Cannot tolerate venous blood sampling; Known to be allergic to LM-061 tablets or any of its excipients; Has history of other serious systemic diseases judged by the investigator, or other reasons are not suitable for participating in the study. （Combination escalation levels only ) Known history of intolerable to any prior anti-PD-1/PD-L1 or CTLA-4 therapy; (Combination escalation levels only) Known to take systemic corticosteroids (> 10 mg daily prednisone equivalents) or other systemic immunosuppressive medications (including, but not limited to, prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to the first dosing of LM-061 and toripalimab. Usage of topical, ocular, intra-articular, intranasal, and inhalational corticosteroids is allowed; (Combination escalation levels only) Have a known or suspected history of an autoimmune disorder; (Combination escalation levels only) Have a history of primary immunodeficiency; (Combination escalation levels only) Subjects from endemic area will be specifically screened for tuberculosis. Subjects with activetuberculosis are excluded; (Combination escalation levels only) History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis, or history of interstitial lung disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Interventional Model Description: Arm1: LM-061 single agent escalation Arm2: LM-061 combination escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LM-061 single agent escalation<br>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. | Drug: LM-061<br>* Oral dose with approximately 240 mL water in the fasting condition, and food will be forbidden 1 h prior to administration and 2h after dose. QD for continuous 28 days, and 4 weeks as one treatment cycle.<br>* Other names: Kinase inhibitor;|
| Experimental: LM-061 combination escalation<br>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 | Drug: LM-061<br>* Oral dose with approximately 240 mL water in the fasting condition, and food will be forbidden 1 h prior to administration and 2h after dose. QD for continuous 28 days, and 4 weeks as one treatment cycle.<br>* Other names: Kinase inhibitor;Drug: Toripalimab<br>* For subjects in combination escalation levels, toripalimab will be administered 240mg, IV, every 3 weeks<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events and serious adverse events | 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 | : From screening up to 1 year | 
| Dose-limiting toxicities (DLT) | DLT is defined as a toxicity (adverse event at least possibly related to LM061) occurring during the DLT observation period (the initial 21 days) | : Cycle 1 of each cohort. Duration of one cycle is 28 days | 
| Change in Vital Signs-ear temperature | Change in vital signs-ear temperature will be measured after the subject has been fully rested. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Change in Vital Signs-pluse rate | Change in vital signs-pluse rate will be measured after the subject has been fully rested. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Change in Vital Signs-blood pressure | Change in vital signs-blood pressure will be measured after the subject has been fully rested. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Change in Electrocardiogram (ECG)-RR interval | 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. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Change in Electrocardiogram (ECG)-QT interval | QT interval of 12-lead ECG will be performed in the supine position after the patients are fully rested at each timepoint for once. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Change in Electrocardiogram (ECG)-QRS duration | QRS duration of 12-lead ECG will be performed in the supine position after the patients are fully rested at each timepoint for once. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Incidence of Abnormal Clinical Laboratory Test Results-hematology | Number of participants with incidence of abnormal clinical lab test results like hematology will be assessed. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Incidence of Abnormal Clinical Laboratory Test Results-Biochemistry | Number of participants with incidence of abnormal clinical lab test results like Biochemistry will be assessed. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Incidence of Abnormal Clinical Laboratory Test Results-Urinalysis | Number of participants with incidence of abnormal clinical lab test results like Urinalysis will be assessed. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 
| Incidence of Abnormal Clinical Laboratory Test Results-Coagulation test | Number of participants with incidence of abnormal clinical lab test results like Coagulation test will be assessed. | Baseline (Week 0) through approximately 1 year after first administration of LM061 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7. Area under the serum concentration versus time curve within one dosing interval (AUCtau) | To determine the pharmacokinetics (PK) profile of LM061 Single dose: pre-dose (within 30 minutes before administration), and 1 h, 3 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h after administration on C0D1; Multiple dose: pre-dose (within 30 minutes before administration) on C1D1, C1D8, and C1D15; pre-dose (within 30 minutes before administration), and 1 h, 3 h, 6 h, 8 h, 10 h, 12 h, 24 h after administration on C1D22; The timepoints of PK sample may be adjusted base on the human PK data. The blood samples for PK analysis will be collected as much as possible if the subjects end of treatment/early withdraw. | Up to 1 year | 
| Volume of distribution (Vd) | To determine the pharmacokinetics (PK) profile of LM061 For AML, the efficacy will be evaluated by using the European LeukemiaNet (ELN) 2017 criteria. The complete blood count and bone marrow will be evaluated at screening visit and every 4 weeks ± 1 week (relative to C1D1) after the start of multiple administrations until the progressive disease judged by investigator or initiate new anti-tumour therapy or subject withdraw. The assessment results are divided into complete remission (CR), CR without minimal residual disease (CRMRD-)，CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MFLS), partial remission (PR), stable disease (SD), progressive disease (PD). | Up to 1 year | 
| Volume of distribution at steady state (Vss) | To determine the pharmacokinetics (PK) profile of LM061 | Up to 1 year | 
| Maximum serum concentration (Cmax) | To determine the pharmacokinetics (PK) profile of LM061 | Up to 1 year | 
| Trough concentration before the next dose is administered (Ctrough) | To determine the pharmacokinetics (PK) profile of LM061 | Up to 1 year | 
| Time to reach maximum serum concentration (Tmax) | To determine the pharmacokinetics (PK) profile of LM061 | Up to 1 year | 
| Clearance (CL) | To determine the pharmacokinetics (PK) profile of LM061 | Up to 1 year | 
| Terminal half-life (T1/2) | To determine the pharmacokinetics (PK) profile of LM061 | Up to 1 year | 
| Dose proportionality | To determine the pharmacokinetics (PK) profile of LM061 | Up to 1 year | 
| Objective response rate (ORR) | To assess the preliminary antitumor activity of LM102,The ORR, using RECIST 1.1 criteria, was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR; disappearance of all target lesions) or Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) at any time during the study, based on Investigator assessment. | Up to 1 year | 
| Best of response (BOR) | To assess the preliminary antitumor activity of LM061 | Up to 1 year | 
| Disease control rate (DCR) | To assess the preliminary antitumor activity of LM061 | Up to 1 year |