An Open-Label, Phase 2b, Global Multicenter Cohort Trial to Assess the Safety and Efficacy of Zipalertinib in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer with Exon 20 Insertion and Uncommon/Single or Compound Epidermal Growth Factor Receptor Mutations

Prior treatment

• 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.
• 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
• 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.

Other illness

• Active bleeding disorders.
• Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class.
• Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or evidence of clinically active interstitial lung disease.
• Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is not controlled with treatment.

Lab values

• 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).

Other

• 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.

• A patient must meet ALL the following inclusion criteria to be eligible for enrollment to this study: Provide written informed consent
• 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.
• 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).