A Study of Zipalertinib in Patients With Advanced Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions or Other Uncommon Mutation. (REZILIENT2)

• ClinicalTrials.gov Identifier: NCT05967689
• Recruitment Status: Recruiting
• First Posted: August 1, 2023
• Last Update Posted: May 20, 2024
• Sponsor: Taiho Oncology, Inc.
• Information provided by (Responsible Party): Taiho Oncology, Inc.

Tracking Information

• First Submitted Date: July 11, 2023
• First Posted Date: August 1, 2023
• Last Update Posted Date: May 20, 2024
• Actual Study Start Date: July 27, 2023
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: July 21, 2023): All Cohorts: objective response rate (ORR) [ Time Frame: Up to approximately 2 years ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 21, 2023)

• All Cohorts: The rate and severity of treatment emergent AEs [ Time Frame: Up to approximately 2 years ]
• All Cohorts: Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
  Antitumor activity is assessed by response evaluation criteria RECIST 1.1 by measuring
• All Cohorts: Disease control rate (DCR) [ Time Frame: Up to approximately 2 years ]
• All Cohorts: Duration of response (DoR) [ Time Frame: Up to approximately 2 years ]
• Progression-free survival (PFS) [ Time Frame: Up to approximately 2 years ]
• Cohort C: Intracranial (i) Overall Response Rate (iORR) [ Time Frame: Up to approximately 2 years ]
• Cohort C: intracranial duration of complete response (iDCR) [ Time Frame: Up to approximately 2 years ]
• Cohort C: intracranial duration of Response (iDoR) [ Time Frame: Up to approximately 2 years ]
• All Cohorts: Pharmacokinetic (PK) parameter [ Time Frame: Up to approximately 2 years ]
  Minimum Plasma Concentration (Cmin)

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 21, 2023)

• Pharmacokinetic (PK) parameter [ Time Frame: Up to approximately 2 years ]
  Minimum Plasma Concentration [Cmin]
• Pharmacokinetic (PK) parameter [ Time Frame: Up to approximately 2 years ]
  Maximum Plasma Concentration [Cmax]
• Pharmacokinetic (PK) parameter [ Time Frame: Up to approximately 2 years ]
  Area Under Curve [AUC]
• EGFR mutation status [ Time Frame: Up to approximately 2 years ]
  Local central tests results

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: A Study of Zipalertinib in Patients With Advanced Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions or Other Uncommon Mutation.
• Official Title: 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.
• Brief Summary: The purpose of this study is to evaluate the safety and efficacy of zipalertinib in patients with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations and other mutations.

Detailed Description

This study will evaluate the safety and efficacy of zipalertinib in patients with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations or other uncommon/single or compound EGFRmt.

Patients will be enrolled into 1 of the 4 following cohorts:

• Cohort A ("prior ex20ins treatment") will include patients harboring EGFR ex20ins mutations who have progressed on or after initial treatment with standard platinum-based chemotherapy and prior treatment with an ex20 agent for their advanced disease (administered together or separately).
• Cohort B ("1st line") will include patients harboring EGFR ex20ins mutations who have not received prior treatment for advanced disease.
• Cohort C ("active brain mets") will include patients harboring EGFR ex20ins or other uncommon single and compound mutations and active brain metastases. Patients may or may not have had prior treatment for advanced disease.
• Cohort D ("other uncommon EGFRmt") will include patients harboring other, non ex20ins uncommon single or compound EGFRmt who have progressed on or after treatment with standard systemic anticancer therapy.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

4 Cohorts based on eligibility criteria

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Advanced or Metastatic NSCLC Harboring Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion (ex20ins) Mutations

Intervention

Drug: TAS6417

Oral tablets/capsules

Other Names:

• CLN-081
• zipalertinib

Study Arms

• Experimental: Cohort A ("prior ex20ins treatment")
  Cohort A ("prior ex20ins treatment") participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.
  Intervention: Drug: TAS6417
• Experimental: Cohort B ("1st line treatment")
  Cohort B participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.
  Intervention: Drug: TAS6417
• Experimental: Cohort C ("active brain mets")
  Cohort C participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.
  Intervention: Drug: TAS6417
• Experimental: Cohort D ("other uncommon EGFRmt").
  Cohort D participants will receive zipalertinib orally twice a day (BID) continuously until documentation of PD or until other withdrawal criteria are met, whichever comes first.
  Intervention: Drug: TAS6417

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 21, 2023): 160
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 20, 2025
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Written informed consent
2. ≥18 years of age (or meets the country's regulatory definition of legal adult age, whichever is greater

3. Pathologically confirmed, locally advanced or metastatic NSCLC meeting all the following criteria:

   Cohort A patients:

   • Documented EGFR ex20ins mutation status, as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US).
   • 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.
   • 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.

   Cohort B patients:

   • Documented EGFR ex20ins mutation status, as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US).
   • Not received prior systemic therapy for locally advanced or metastatic disease. Prior adjuvant/neoadjuvant treatment for early-stage disease must have been completed >6 months prior to the first dose of study treatment.
   • 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.

   Cohort C patients:

   • Documented EGFR ex20ins mutation status, as determined by local testing performed at a CLIA certified (US) or locally certified laboratory (outside the US).

   • Presence of brain metastasis(es), which may be measurable or nonmeasurable by RANO-BM criteria, characterized as one of the following:

     • Newly diagnosed and/or progressive brain metastasis (es) not subjected to CNS-directed therapy, OR
     • Leptomeningeal disease (LMD) confirmed by a positive cerebrospinal fluid cytology, or unequivocal radiographic and/or clinical determination.

   Cohort D patients:

   • Documented other non-ex20ins uncommon single or compound EGFRmt status, 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 manual.
   • 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.
4. Measurable disease per RECIST 1.1.
5. 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.
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 17. Adequate organ function, as defined by the hematologic, renal and hepatic laboratory values

4. 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).

5. 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 6 months after the last dose of study treatment.

Exclusion Criteria:

1. Patient 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.

2. Has received any of the following within the specific time frame specified:

   1. Patient has received Zipalertinib (TAS6417/CLN081) at any time
   2. Thoracic radiotherapy ≤28 days or palliative radiation ≤14 days prior to the first dose of study treatment
   3. Anticancer immunotherapy ≤28 days prior to the first dose of study treatment
   4. Major surgery (excluding placement of vascular access) ≤28 days prior to the first dose of study treatment.
3. 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.
4. Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or evidence of clinically active interstitial lung disease.

5. Impaired cardiac function or clinically significant cardiac disease including any of the following:

   1. History of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification (Appendix A)
   2. Serious cardiac arrhythmias requiring treatment.
   3. Resting corrected QT interval (QTc) >470 msec using Fridericia's formula (QTcF).
6. Is unable to swallow tablets/capsules 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).

7. 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:

   1. Adequately treated basal or squamous cell carcinoma of the skin
   2. Cancer of the breast or cervix in situ
   3. Patients with previously treated malignancy if all treatment for that malignancy was completed at least 2 years prior to first dose and no evidence of disease
   4. Patients with concurrent malignancy clinically stable and not requiring tumor-directed treatment
8. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is not controlled with treatment.
9. History of COVID-19 infection within 4 weeks prior to enrolment and/or has persistent clinically significant pulmonary symptoms related to prior COVID-19 infection.
10. Active bleeding disorders.
11. Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class.
12. Is pregnant or lactating.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Taiho Oncology, INC; 609-250-7336; clinicaltrialinfo@taihooncology.com

• Listed Location Countries: Australia, Canada, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05967689
• Other Study ID Numbers: TAS6417-201; 2023-503865-48 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Taiho Oncology, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Taiho Oncology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Taiho Oncology, Inc.
• Verification Date: May 2024