An Open-label, Multicenter Phase Ib/II Study to Evaluate the Safety, Efficacy and Pharmacokinetic Characteristics of ANS014004 in Combination With EGFR-TKI in Patients With EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Sponsor
- Beijing Pearl Biotechnology Limited Liability Company
- Enrollment
- 253
- Locations
- 1
- Primary Endpoint
- Number of participants with dose-limiting toxicity (DLT) during the DLT observation period (Phase Ib Dose Escalation)
Overview
Brief Summary
Protocol Title
A Study to Evaluate ANS014004 in Combination with EGFR-TKI in Patients with EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
The main purpose of this research study is to
Find a safe and tolerable dose of two investigational drugs, ANS014004 and PLB1004, when used together.
Learn how effective this drug combination is at treating a type of lung cancer called "EGFR mutation-positive non-small cell lung cancer (NSCLC)" that has spread to other parts of the body (locally advanced or metastatic).
This study is trying to answer the following questions:
Safety & Dosing: What are the side effects of combining ANS014004 and PLB1004? What is the best dose to use that patients can tolerate well?
Effectiveness: Can this combination of drugs help shrink patients' tumors or stop them from growing?
Background Information
For patients with advanced lung cancer that has a specific gene change called an "EGFR mutation," targeted therapies known as EGFR-TKIs are a standard treatment. While these treatments often work well at first, most tumors eventually stop responding to the drug (this is called "acquired resistance"). The investigational drug ANS014004 is designed to block a protein called MET, which is one of the ways that tumors become resistant to EGFR-TKIs. The researchers believe that by combining ANS014004 with the EGFR-TKI PLB1004, they may be able to prevent or delay resistance, offering patients a more effective and longer-lasting treatment option.
How will the study be conducted?
This study is divided into two parts:
Part 1 (Dose Escalation and Optimization): A small number of participants will receive different dose levels of ANS014004 combined with a fixed dose of PLB1004. The goal is to find the safest and most tolerable dose combination.
Part 2 (Phase II Study): Once a recommended dose is identified, more participants will be enrolled to further evaluate how well the drug combination works against the cancer.
Throughout the study, participants' health will be closely monitored, and their tumors will be measured regularly using imaging scans (like CT scans) to see how they respond to the treatment.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
ANS014004+PLB1004
The Phase Ib study consists of two parts: dose escalation and dose optimization. The dose escalation part will enroll participants with EGFR mutation-positive locally advanced or metastatic NSCLC who have received prior standard therapy in order to evaluate the safety and tolerability of the combination therapy and determine the maximum tolerated dose (MTD) (if any); The dose optimization part will further expand the population to include participants with EGFR mutation-positive locally advanced or metastatic NSCLC who have not received prior systemic therapy for advanced disease or have received standard therapy to determine the recommended Phase 2 dose (RP2D).
Intervention: ANS014004 + PLB1004 (Drug)
ANS014004 + Osimertinib
participants will be enrolled in into two cohorts according to the prior anti-tumor treatment received.
- Cohort A: participants with EGFR mutation-positive (excluding exon 20 insertions) locally advanced or metastatic NSCLC who have not received prior standard systemic therapy for advanced disease. Participants who meet the inclusion criteria will be stratified according to baseline brain metastasis status (present vs. absent) and be randomized at a ratio of 2:1 to receive the combination treatment of ANS014004 and PLB1004 or the combination treatment of ANS014004 and Osimertinib.
- Cohort B: participants with EGFR mutation-positive (excluding exon 20 insertions) locally advanced or metastatic NSCLC who previously received standard systemic therapy. Participants who meet the inclusion criteria will be stratified according to baseline MET amplification and/or overexpression status (present vs. absent) and be randomized at a ratio of 2:1 to receive the combination treatment of ANS0140
Intervention: ANS014004 + Osimertinib (Drug)
Outcomes
Primary Outcomes
Number of participants with dose-limiting toxicity (DLT) during the DLT observation period (Phase Ib Dose Escalation)
Time Frame: 2 years.
To evaluate the tolerability of ANS014004 in combination with PLB1004. DLT is defined per NCI-CTCAE v5.0 (e.g., Grade 4 neutropenia lasting ≥7 days, febrile neutropenia, Grade 4 thrombocytopenia, Hy's Law-meeting hepatotoxicity, Grade ≥3 non-hematologic/non-hepatic toxicity excluding specified exceptions, etc.). The DLT observation period is the first 28 days after treatment initiation (including single-dose period and Cycle 1 of multiple-dose period). The outcome will be reported as the count and proportion of participants experiencing DLT in each dose group.
Maximum tolerated dose (MTD) of ANS014004 in combination with PLB1004 (Phase Ib Dose Escalation)
Time Frame: 2 years
To determine the MTD of the combination therapy. MTD is defined as the highest dose level where ≤1 of 3-6 evaluable participants experience DLT during the DLT observation period. The outcome will be reported as the specific dose of ANS014004 (e.g., 45 mg QD, 60 mg QD) combined with fixed 80 mg QD PLB1004 that meets the MTD definition.
Objective Response Rate (ORR) assessed by investigator per RECIST v1.1 (Phase Ib Dose Optimization, Phase II)
Time Frame: 2 years
To evaluate the anti-tumor activity of ANS014004 in combination with PLB1004 (Phase Ib Dose Optimization) or ANS014004 combined with PLB1004/Osimertinib (Phase II) in EGFR mutation-positive locally advanced or metastatic NSCLC. ORR is defined as the proportion of participants with confirmed Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Tumor assessments are performed every 6 weeks (±7 days) for the first year and every 12 weeks (±7 days) thereafter. The outcome will be reported as the proportion of participants achieving ORR, with 95% confidence intervals (CIs) calculated using the Clopper-Pearson method.
Recommended Phase 2 Dose (RP2D) of ANS014004 in combination with PLB1004 (Phase Ib Dose Optimization)
Time Frame: 2 years.
To identify the RP2D of the combination therapy. RP2D is determined based on comprehensive analysis of safety (incidence of AEs/DLTs), pharmacokinetic (PK) data, and preliminary efficacy (ORR, DCR) from the Phase Ib Dose Optimization period. The outcome will be reported as the specific dose of ANS014004 (e.g., 60 mg QD) combined with fixed 80 mg QD PLB1004 selected for Phase II.
Secondary Outcomes
- Incidence and severity of adverse events (AEs) assessed by NCI-CTCAE v5.0 (All Phases)(2 years)
- Plasma maximum observed concentration (Cmax) of ANS014004 (All Phases)(2 years)
- Plasma area under the concentration-time curve from time 0 to last quantifiable time point (AUC0-t) of ANS014004 (All Phases)(2 years)
- Disease Control Rate (DCR) assessed by investigator per RECIST v1.1 (Phase Ib Dose Optimization, Phase II)(2 years)
- Duration of Response (DoR) assessed by investigator per RECIST v1.1 (Phase Ib Dose Optimization, Phase II)(2 years)
- Progression-Free Survival (PFS) assessed by investigator per RECIST v1.1 (Phase Ib Dose Optimization, Phase II)(2 years)
- Overall Survival (OS) (Phase Ib Dose Optimization, Phase II)(2 years)
- Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) score (All Phases)(2 years)
- Functional Assessment of Chronic Illness Therapy (FACIT) GP5 question score (All Phases)(2 years)
- Plasma time to maximum observed concentration (Tmax) of ANS014004 (All Phases)(2 years)
- Plasma half-life (t1/2) of ANS014004 (All Phases)(2 years)