A Phase I Study of LX-039 Tablets

Study Overview
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Brief Summary
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This is a phase I dose escalation and expansion study in patients with ER+, HER2- advanced breast cancer to explore the tolerance, PK/PD(pharmacokinetics/pharmacodynamics) profiles and preliminary anti-tumor activity of different doses of LX-039 tablets. The trial consists of two parts, dose escalation and dose expansion. Part 1 is the dose escalation phase with initial 6 dose groups, and 3 + 3 design is used to explore MTD of the drug; Part 2 is the dose expansion phase with 2   3 doses selected for expansion according to the escalation results of Part 1, and more subjects are enrolled to further observe the tolerance and preliminary anti-tumor activity of the drug. After the completion of dose expansion, the recommended phase II dose (RP2D) will be determined after discussion based on the obtained tolerance and PK/PD data.

Official Title
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A Phase I Study of LX-039 Tablets in Postmenopausal Patients With ER+, HER2- Advanced Breast Cancer After Failure of Endocrine Therapy

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: LX-039 tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be able to read and sign the informed consent form. Adult females (aged ≥18 and ≤75 years). Be diagnosed with breast cancer confirmed by pathological examination. Be histologically or cytologically confirmed estrogen receptor positive (ER+≥1% positive staining). Be postmenopausal. Subjects who have previously received endocrine therapy and obtained benefit. ECOG(Eastern Cooperative Oncology Group) score ≤ 1. Subjects in part2 of the study need to have measurable lesions that meet RECIST 1.1 criteria. Has recovered from toxicity or injury from prior chemotherapy/radiotherapy . Enough hematology and organ function. Expected survival>3 months. Exclusion Criteria: Subjects with HER2-overexpressing breast cancer. Subjects with known brain metastases or other central nervous system metastases that are symptomatic or untreated. Patients with symptomatic advanced disease who have spread to the viscera and are at risk of life-threatening complications. Subjects who received second-line or above chemotherapy. Subjects with known allergy to this product or any of its components. Subjects who previously used other estrogen receptor down regulators than fulvestrant. Subjects who received endocrine therapy or other anti-tumor agent or radiotherapy within 4 weeks prior to study entry. Subjects who received cell therapy or tumor vaccine therapy; Subjects with severe immunosuppression . Severe or uncontrolled disease. Subjects with diseases or abnormalities that may affect the administration and absorption of drugs. Subjects with other malignancy within 5 years prior to study entry. Subjects with other high risks of thrombosis or require long-term use of antiplatelet drugs. Subjects with history of definite neurological or psychiatric disorders in the past. Subjects who are HIV(human immunodeficiency virus) antibody positive, HBsAg(hepatitis B surface antigen) positive or HCV(hepatitis C virus)antibody positive. Subjects with other uncontrolled malignant/non-malignant diseases, significant laboratory abnormalities, participation in the study may increase the risk.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part1：dose escalation<br>The investigational product for this study is LX-039 tablets,which can be administered orally. 6 8 ascending dose level until MTD and the specification included 50 mg, 100 mg, 200 mg, 400 mg, 600 mg , 800 mg,1050 mg and 1400 mg. LX-039 tablets will be administered in a therapeutic cycle of 28 days once a day orally. The subjects will continue therapy with LX-039 if good safety and tolerability were assessed by investigators after one cycle treatment. The treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. | Drug: LX-039 tablets<br>* orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, or study termination<br>|
| Experimental: Part 2：dose expansion<br>2 3 selected tolerable dose will be selected according to the tolerance and FES PET results of dose escalation phase.The subjects will continue therapy with LX-039 if good safety and tolerability were assessed by investigators after one cycle treatment. The treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. | Drug: LX-039 tablets<br>* orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, or study termination<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To explore the tolerance of LX-039 in ER +, HER2 - patients with advanced breast cancer | Incidence of dose limiting toxicities (DLTs) | DLT observation period(5 weeks for dose escalation, 4 weeks for dose expansion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of LX-039 in ER +, HER2 - patients with advanced breast cancer | Number of participants with treatment related. adverse events as assessed by CTCAE v5.0 | through study completion,an average of 1 year | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | Objective response rate (ORR) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | proportion of subjects with complete response (CR） | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | proportion of subjects with partial response (PR） | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | proportion of subjects with stable disease (SD) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | proportion of subjects with progressive disease (PD) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | duration of response (DoR) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | disease control rate (DCR) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | clinical benefit rate (CBR) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | time to progression (TTP) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | progression-free survival (PFS) | through study completion，an average of 1 year. | 
| To explore the efficacy of LX-039 in ER +, HER2 - patients with advanced breast cancer according to Recist 1.1. | overall survival (OS) | through study completion，an average of 1 year. | 
| Comparison of changes in maximum uptake ability of FES(progression free survival) in breast cancer lesions before and after treatment with LX-039 by PET(positron emission tomography) scan (performed in some subjects) | Decrease in SUVmax in comparison with that before treatment | Up to the third day of Cycle 2(each cycle is 28 days) | 
| PK profiles after a single dose of LX-039 | Peak Concentration (Cmax) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Peak Time (Tmax) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Elimination Half-life (t1/2) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Eliminate Rate Constant (Kel) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Mean Residence Time (MRT) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Area under plasma Concentration-time curve from 0 time to 24 hours (AUC0-24h) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Area under plasma Concentration-time curve from 0 time to sampling time t of the last measurable concentration (AUC0-last) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Area under plasma Concentration-time curve from administration (0) to infinity (AUC0-inf) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Apparent Total Clearance (CL/F) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after a single dose of LX-039 | Apparent Volume of Distribution (Vd/F) | Up to the third day of Cycle 0(Cycle 0 is 7 days) | 
| PK profiles after continuous administration of LX-039 | Trough Concentration at Steady State (Css, min) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Peak Concentration at Steady State (Css, max) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Average Concentration at Steady State (Css, av) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Peak Time (Tss, max) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Apparent Volume of Distribution at steady state (Vss/F) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Steady-state Clearance Half-life (tss,1/2) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Total Body Clearance (CLss/F) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Coefficient of Fluctuation (DF) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Area under Plasma Concentration-time Curve at Steady State (AUCss) | Up to the Second day of Cycle 2(each cycle is 28 days) | 
| PK profiles after continuous administration of LX-039 | Accumulation Coefficient (Rac) | Up to the Second day of Cycle 2(each cycle is 28 days) |