A Phase I Study of LX-039 Tablets

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: LX-039 tablets

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Fudan University Shanghai Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Be able to read and sign the informed consent form.
2. Adult females (aged ≥18 and ≤75 years).
3. Be diagnosed with breast cancer confirmed by pathological examination.
4. Be histologically or cytologically confirmed estrogen receptor positive (ER+≥1% positive staining).
5. Be postmenopausal.
6. Subjects who have previously received endocrine therapy and obtained benefit.
7. ECOG(Eastern Cooperative Oncology Group) score ≤ 1.
8. Subjects in part2 of the study need to have measurable lesions that meet RECIST 1.1 criteria.
9. Has recovered from toxicity or injury from prior chemotherapy/radiotherapy .
10. Enough hematology and organ function.
11. Expected survival>3 months.

Exclusion Criteria:

1. Subjects with HER2-overexpressing breast cancer.
2. Subjects with known brain metastases or other central nervous system metastases that are symptomatic or untreated.
3. Patients with symptomatic advanced disease who have spread to the viscera and are at risk of life-threatening complications.
4. Subjects who received second-line or above chemotherapy.
5. Subjects with known allergy to this product or any of its components.
6. Subjects who previously used other estrogen receptor down regulators than fulvestrant.
7. Subjects who received endocrine therapy or other anti-tumor agent or radiotherapy within 4 weeks prior to study entry.
8. Subjects who received cell therapy or tumor vaccine therapy;
9. Subjects with severe immunosuppression .
10. Severe or uncontrolled disease.
11. Subjects with diseases or abnormalities that may affect the administration and absorption of drugs.
12. Subjects with other malignancy within 5 years prior to study entry.
13. Subjects with other high risks of thrombosis or require long-term use of antiplatelet drugs.
14. Subjects with history of definite neurological or psychiatric disorders in the past.
15. Subjects who are HIV(human immunodeficiency virus) antibody positive, HBsAg(hepatitis B surface antigen) positive or HCV(hepatitis C virus)antibody positive.
16. Subjects with other uncontrolled malignant/non-malignant diseases, significant laboratory abnormalities, participation in the study may increase the risk.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part1：dose escalation; 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; orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, or study termination
Experimental: Part 2：dose expansion; 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; orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, or study termination

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Shandong Luoxin Pharmaceutical Group Stock Co., Ltd.

Publications and helpful links

General Publications

• Lu J, Chan CC, Sun D, Hu G, He H, Li J, Dong J, Liu K, Shen L, Hu L, Gu Q, Chen S, Wang T, Gong T, Tang W, Li X, Zhu X, Zeng X, Zhu Y, Xia Y, Huang Y, Zhu Y, Liu Z, Ding CZ. Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD). Bioorg Med Chem Lett. 2022 Jun 15;66:128734. doi: 10.1016/j.bmcl.2022.128734. Epub 2022 Apr 15.

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2020
• Primary Completion (Actual): August 8, 2022
• Study Completion (Actual): February 7, 2023

Study Registration Dates

• First Submitted: July 29, 2019
• First Submitted That Met QC Criteria: September 18, 2019
• First Posted (Actual): September 20, 2019

Study Record Updates

• Last Update Posted (Actual): May 1, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: OE861801

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No