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.
Male or female participants ≥18years of age at the time of signing the informed consent form.
Patients with histologically or cytologically confirmed diagnosis of unresectable locally advanced (Stage IIIB and IIIC) or metastatic (Stage IV) NSCLC (according to the lung cancer staging criteria, refer to the eighth edition of the American Joint Committee on Cancer [AJCC] Lung Cancer Staging).
Have a documented EGFR positive mutation (EGFR classic mutations including ex19del and ex21 L858R, uncommon mutations and ex20 insertion mutations) in tumor tissue samples or pleural fluid or blood samples.
For Phase Ib dose escalation: have disease progression after the existing standard of care or intolerance to the existing standard of care or inappropriate or no effective standard of care is available (standard of care is defined as treatment recommended by the National Comprehensive Cancer Network [NCCN] guidelines [including but not limited to chemotherapy, radiotherapy, targeted therapy based on mutation status, immunotherapy, and surgery]). For participants who are considered intolerant to or ineligible for available standard therapy, or for whom effective standard therapy does not exist, the documentation of these reasons is required.
Have other known primary driver gene alterations. For example, NSCLC with a targetable alteration in ALK, RET, ROS1, BRAF, KRAS, etc. The investigators should discuss enrollment with the sponsor regarding co-mutations.
Prior treated with hepatocyte growth factor (HGF) targeted therapy or other MET-TKIs (including Type I and Type II), e.g., gulmonertinib, savolitinib, capmatinib, tepotinib, bozitinib, cabozantinib, glenitinib and almonertinib.
Participation in other therapeutic clinical trials within 28 days prior to the first dose of study treatment.
Nitrosourea or mitomycin-C within 6 weeks prior to the first dose of study treatment.
Parallel
ANS014004 + PLB1004
Drug1. Drug: ANS014004 Investigational Type II MET tyrosine kinase inhibitor (oral tablets). Dosing: Phase Ib escalation (30 mg, 45 mg, 60 mg, 75 mg QD); optimization uses selected doses; Phase II uses RP2D. Administered QD (≥1h before/2h after meals) in 21-day cycles. Targets MET exon 14 skipping, amplification, overexpression, and fusions. 2. Drug: PLB1004 Investigational irreversible EGFR tyrosine kinase inhibitor (oral capsules). Fixed dose: 80 mg QD. Administered QD (≥1h before/2h after meals) in 21-day cycles. Targets EGFR classical mutations (Ex19del, L858R), rare mutations, Ex20ins, and T790M.
ANS014004 + Osimertinib
Drug1. Drug: ANS014004 (Same description as above, as the drug is identical across arms). 2. Drug: Osimertinib Market-approved third-generation EGFR tyrosine kinase inhibitor (oral tablets). Dosing: Per reference label (QD, with/without meals). Administered in 21-day cycles. Targets EGFR classical mutations (Ex19del, L858R) and T790M. Used as an active comparator.
Number of participants with dose-limiting toxicity (DLT) during the DLT observation period (Phase Ib Dose Escalation)
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)
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)
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)
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.
Incidence and severity of adverse events (AEs) assessed by NCI-CTCAE v5.0 (All Phases)
To evaluate the safety/tolerability of ANS014004 combinations. AEs include treatment-related AEs (TRAEs), serious AEs (SAEs), and AEs leading to dose modification/discontinuation. Severity is graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 (Grade 1-5). AEs are collected from the first dose of study treatment to 28 days after the last dose or before new anti-tumor treatment. The outcome will be reported as the count and proportion of participants with AEs by severity, system organ class (SOC), and preferred term (PT).
Plasma maximum observed concentration (Cmax) of ANS014004 (All Phases)
To characterize the PK profile of ANS014004 in combination with PLB1004/Osimertinib. Cmax is defined as the highest plasma concentration of ANS014004 measured after drug administration. PK blood samples are collected at pre-specified time points (e.g., pre-dose, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h post-dose in Phase Ib Dose Escalation). The outcome will be reported as descriptive statistics (arithmetic mean, geometric mean, standard deviation, minimum, maximum) of Cmax by study phase and dose group.
Plasma area under the concentration-time curve from time 0 to last quantifiable time point (AUC0-t) of ANS014004 (All Phases)
To characterize the PK profile of ANS014004. AUC0-t is defined as the area under the plasma concentration-time curve of ANS014004 from time 0 to the last time point with a quantifiable concentration. PK samples are collected per pre-specified schedules (e.g., Table 3-5 in the protocol). The outcome will be reported as descriptive statistics (arithmetic mean, geometric mean, coefficient of variation) of AUC0-t by study phase and dose group.
Disease Control Rate (DCR) assessed by investigator per RECIST v1.1 (Phase Ib Dose Optimization, Phase II)
To evaluate the anti-tumor efficacy of ANS014004 combinations. DCR is defined as the proportion of participants with confirmed CR, PR, or Stable Disease (SD) per RECIST v1.1. Tumor assessments follow the same schedule as ORR (every 6 weeks for the first year, every 12 weeks thereafter). The outcome will be reported as the proportion of participants achieving DCR, with 95% CIs.
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Beijing Pearl Biotechnology Limited Liability Company
Lead sponsor
Avistone Biotechnology Co., Ltd.
Collaborator
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