Phase 2b Multicenter Trial Evaluating Zipalertinib in Advanced or Metastatic NSCLC with EGFR Exon 20 Insertion and Uncommon/Compound Mutations
- Trial ID
- 2023-503865-48-00
- Protocol
- TAS6417-201
- Sponsor
- Taiho Oncology Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **objective response rate (ORR)** of zipalertinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) characterized by EGFR exon 20 insertion mutations or other uncommon single or compound EGFR mutations. This is clinically relevant as it aims to determine the efficacy of zipalertinib in a specific subset of NSCLC patients, potentially offering a targeted therapeutic option for those with limited treatment alternatives.
Secondary objectives include: - Investigating the **safety and tolerability** of zipalertinib, which is crucial for understanding the risk-benefit profile of the treatment. - Further evaluating the **antitumor activity** of zipalertinib to assess its potential in reducing tumor burden. - Evaluating the **intracranial efficacy** of zipalertinib in Cohort C, which is important for patients with brain metastases. - Evaluating the **pharmacokinetics (PK)** of zipalertinib to understand its absorption, distribution, metabolism, and excretion characteristics.
Participants
The clinical trial involves a total of **171 participants** diagnosed with **locally advanced or metastatic non-small cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, who have provided written informed consent. Participants were selected based on specific inclusion criteria, including documented EGFR ex20ins or other uncommon single or compound EGFR mutations, and must have measurable disease per RECIST 1.1. The trial includes individuals with a stable neurological status, particularly those with brain metastases who have received CNS-directed therapy and show no evidence of progression. Participants are required to have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 and adequate organ function. Both males and females of reproductive potential must agree to use effective birth control during the study. The trial population is characterized by a diverse range of health statuses, with a focus on those who have progressed on or after systemic therapy targeting ex20ins mutations. Lifestyle considerations such as diet and physical activity are not specified, but participants must have a stable or decreasing dose of corticosteroids and/or anti-convulsant medications if applicable. The study does not include individuals with a history of uncontrolled seizures or leptomeningeal disease. The trial aims to evaluate the objective response rate of zipalertinib in this specific patient population.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **efficacy** of **Zipalertinib** in patients with **locally advanced or metastatic non-small cell lung cancer** (NSCLC) characterized by specific **EGFR** mutations. This is an open-label, Phase 2b, global multicenter cohort trial. The study will involve a randomized, controlled design, although it is not double-blind due to its open-label nature. The trial is expected to commence recruitment on October 31, 2023, and conclude by June 30, 2025, with the overall duration of the trial spanning approximately 20 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, confirmed diagnosis of NSCLC, and documented **EGFR** mutation status. The screening process will also involve assessments of organ function and performance status. Following successful screening, participants will be enrolled and commence treatment with **Zipalertinib**, administered orally in tablet form, with a maximum daily dose of 100 mg.
Throughout the trial, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include clinical evaluations, laboratory tests, and imaging studies to assess disease progression and any adverse events. The primary endpoint is the objective response rate (ORR), defined as the proportion of patients achieving a complete or partial response according to RECIST 1.1 criteria. Secondary endpoints include the assessment of adverse events, progression-free survival, overall survival, and intracranial response rates.
The expected length of participant involvement in the study is contingent upon individual response to treatment and disease progression, with a maximum treatment period of 21 days per cycle. Conditions that may lead to early termination from the study include unacceptable toxicity, disease progression, or withdrawal of consent. The end-of-study visit will occur after the final treatment cycle or upon early termination, during which final assessments will be conducted to evaluate the overall outcomes of the trial.
Treatment
The clinical trial involves the administration of **Zipalertinib**, a chemical entity developed by Taiho Pharmaceutical Co., Ltd. Zipalertinib is provided in the form of a **tablet** and is intended for **oral use**. The active substance in the medication is zipalertinib, which is chemically synthesized. The trial protocol specifies a maximum daily dose of 100 mg, with the total dose not exceeding 100 mg per day. The treatment period is set for a maximum of 21 days. The medication is not formulated for pediatric use and is not classified as an orphan drug. The primary objective of the trial is to evaluate the objective response rate of zipalertinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) characterized by exon 20 insertion or uncommon/single or compound epidermal growth factor receptor (EGFR) mutations.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on assessing the safety and efficacy of zipalertinib. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed as an open-label, Phase 2b, global multicenter cohort study, allowing for comprehensive evaluation across diverse patient populations.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which is defined as the proportion of patients experiencing the best overall confirmed response of Complete Response (CR) or Partial Response (PR) according to RECIST 1.1 criteria. Secondary endpoints include the evaluation of adverse events graded according to the NCI-Common Terminology Criteria of Adverse Events Version 5.0 (CTCAE v5.0), clinical laboratory tests, vital signs, ECGs, and echo/MUGA. Additional measures of antitumor activity will be assessed, including the duration of response, progression-free survival, and overall survival, with specific attention to intracranial response rates and durations as determined by RANO-BM criteria. The observed minimum concentration (Cmin) of zipalertinib in plasma will also be measured.
Inclusion and Exclusion Criteria
Inclusion Criteria
- A patient must meet ALL the following inclusion criteria to be eligible for enrollment to this study: Provide written informed consent
- Is ≥18 years of age (or meets the country’s regulatory definition of legal adult age, whichever is greater)
- Has pathologically confirmed, locally advanced or metastatic NSCLC meeting all the following criteria: a.Cohort A patients: i. Documented EGFR ex20ins status, as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US). ii. Progressed on or after systemic therapy with an agent targeting ex20ins, either alone or in combination with standard platinum-based chemotherapy for the treatment of advanced disease. Patients who discontinued previous treatment due to unacceptable toxicity are eligible. Permitted prior ex20ins therapies include: amivantamab, sunvozertinib (DZD9008), and BLU451. Other prior ex20ins-directed treatment may be discussed with the Sponsor for eligibility assessment. iii. Patients with brain metastasis must be neurologically stable. Patients must have received CNS-directed therapy and have no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period. Additionally, they must be on a stable or decreasing dose of corticosteroids and/or anti-convulsant medications for at least 2 weeks prior to the first dose of study treatment. Patients with a history of uncontrolled seizures or LMD are not eligible. b.Cohort B patients: i. Documented EGFR ex20 instatus, as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US). c. Patients who have not received prior treatment for advanced or metastatic disease and who are not appropriate candidates for first-line doublet platinum-based chemotherapy based on Investigator judgment or has refused first-line doublet platinum-based chemotherapy following discussion with the Investigator. Prior adjuvant/neoadjuvant treatment for early-stage disease must have been completed >6 months prior to the first dose of study treatment. iii. Patients with brain metastasis must be neurologically stable. Patients must have received CNS-directed therapy and have no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period, and they must be on a stable or decreasing dose of corticosteroids and/or anti-convulsant medications for at least 2 weeks prior to the first dose of study treatment. Patients with history of uncontrolled seizures or leptomeningeal disease are not eligible.
- Has pathologically confirmed, locally advanced or metastatic NSCLC meeting all the following criteria: c.Cohort C patients: i. Documented ex20ins or other uncommon single or compound EGFR non ex20ins status, as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US). ii. Presence of brain metastasis(es), characterized as at least one of the following: a. Newly diagnosed and/or progressive brain metastasis (es) measurable by RANO-BM criteria and not subjected to CNS-directed therapy, AND/OR b. Leptomeningeal disease (LMD) measurable by RANO-BM criteria and confirmed by a positive cerebrospinal fluid cytology, or unequivocal radiographic and/or clinical determination. iii. Patients may not require other immediate CNS-directed therapy or will likely require other CNS directed anti-tumor therapy during the first cycle of study treatment, as judged by the Investigator. d.Cohort D patients: i. Documented other uncommon single or compound EGFR non ex20ins status, (excluding C797S), as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US). A list of eligible mutations will be provided in a separate document. ii. Patients with brain metastasis must be neurologically stable. Patients must have received CNS-directed therapy and have no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period, and they must be on a stable or decreasing dose of corticosteroids and/or anti-convulsant medications for at least 2 weeks prior to the first dose of study treatment. Patients with history of uncontrolled seizures or leptomeningeal disease are not eligible. iii. Patients who have not received prior systemic therapy for their locally advanced or metastatic NSCLC disease. iv. Prior adjuvant/neoadjuvant treatment for early-stage disease must have been completed >6 months prior to the first dose of study treatment. Patients may not have received prior adjuvant/neoadjuvant treatment with any EGFR TKI.
- Measurable disease per RECIST 1.1.
- Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFRmt status and, where possible, other biomarkers (details provided in a laboratory manual). Patients with insufficient tissue may be eligible following discussion with the sponsor.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.
- Adequate organ function, as defined by the laboratory values: ANC: ≥1500/mm3 (≥1.5 ×109 /L); Platelets:≥100,000/mm3 (≥100 × 109 /L) without platelet transfusion within the last 14 days prior to the date of first dose of study treatment ; Hemoglobin: ≥9.0 g/dL without blood transfusion within 14 days prior to the date of the date of first dose of study treatment; Serum Creatinine/ Calculated CrCl: Serum creatinine <1.5 × upper limit of normal (ULN) OR CrCl ≥50 mL/min by Cockroft- Gault formula); Serum total bilirubin:≤1.5 × ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels >1.5 × ULN; or ≤3.0 × ULN for patients with documented, Gilbert’s syndrome; AST and ALT: ≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases.
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female patients are not considered to be of childbearing potential if they are post-menopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
- Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose of study drug and for 1 month after the last dose of study treatment.
Exclusion Criteria
- A patient must not meet any of the following exclusion criteria to be eligible for the study: Is currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged to be scientifically or medically incompatible with this study.
- Has received any of the following within the specific time frame specified: a. Zipalertinib (TAS6417/CLN081) at any time b. Thoracic radiotherapy ≤28 days or palliative radiation (gamma knife radiotherapy is allowed) ≤14 days prior to the first dose of study treatment c. Anticancer immunotherapy ≤28 days prior to the first dose of study treatment d. Major surgery (excluding placement of vascular access) ≤28 days prior to the first dose of study treatment e. All prescribed medication, over-the-counter medication, vitamin preparations and other food supplements, or herbal medications that are strong or moderate CYP3A4 inducers or inhibitors within 7 days prior to first dose of study treatment
- Have any unresolved toxicity of Grade ≥2 from previous anticancer treatment, except for Grade 2 alopecia or skin pigmentation. Patients with other chronic but stable Grade 2 toxicities may be allowed to enroll after agreement between the investigator and Sponsor.
- Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or evidence of clinically active interstitial lung disease.
- Impaired cardiac function or clinically significant cardiac disease including any of the following: a. History of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification b. Serious cardiac arrhythmias requiring treatment. c. Resting corrected QT interval (QTc) >470 msec using Fridericia’s formula (QTcF).
- Is unable to swallow tablets or has any disease or condition that may significantly affect gastrointestinal absorption of zipalertinib (eg, inflammatory bowel disease, malabsorption syndrome, or prior gastric/bowel resection).
- History of another primary malignancy ≤2 years prior to the date of first dose of study treatment unless at least one of the following criteria are met: a. Adequately treated basal or squamous cell carcinoma of the skin b. Cancer of the breast or cervix in situ c. Patients with previously treated malignancy if all treatment for that malignancy was completed at least 2 years prior to randomization and no evidence of disease d. Patients with concurrent malignancy clinically stable and not requiring tumor-directed treatment
- Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is not controlled with treatment.
- History of Coronavirus disease 2019 (COVID-19) infection within 4 weeks prior to enrollment and/or has persistent clinically significant pulmonary symptoms related to prior COVID-19 infection.
- Active bleeding disorders.
- Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class.
- Is pregnant, lactating or planning to become pregnant.
- The patient is, in the investigator’s opinion, unable or unwilling to comply with the trial procedures.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 31 Oct 2023 | 50 |
 Germany | Recruiting | 31 Oct 2023 | 20 |
 Italy | Recruiting | 31 Oct 2023 | 35 |
 Spain | Recruiting | 31 Oct 2023 | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Digoxin | Other | TABLET | ORAL USE | 250 | 3 | PRD12846059 |
Zipalertinib | Test | TABLET | ORAL USE | 200 | 21 | PRD10244860 |
Dextromethorphan | Other | CAPSULE | ORAL USE | 15 | 3 | PRD12846057 |
Midazolam | Other | SYRUP | ORAL USE | 2 | 3 | PRD12846058 |
Zipalertinib | Test | TABLET | ORAL USE | 200 | 21 | PRD10244859 |
Rosuvastatin | Other | TABLET | ORAL USE | 10 | 3 | PRD12846060 |