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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Taiho Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Feb 2024 → ongoing

Decision date (initial)

2023-11-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Taiho Oncology, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety, Pharmacogenomic

To evaluate the objective response rate (ORR) of zipalertinib in patients who have locally advanced or metastatic NSCLC with EGFR ex20ins or other uncommon single or compound EGFRmts

Secondary objectives 4

1. To investigate the safety and tolerability of zipalertinib
2. To further evaluate the antitumor activity of zipalertinib
3. To evaluate the intracranial efficacy of zipalertinib (Cohort C)
4. To evaluate the PK of zipalertinib.

Conditions and MedDRA coding

Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. A patient must meet ALL the following inclusion criteria to be eligible for enrollment to this study: Provide written informed consent
2. Is ≥18 years of age (or meets the country’s regulatory definition of legal adult age, whichever is greater)
3. 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.
4. 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.
5. Measurable disease per RECIST 1.1.
6. 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.
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.
8. 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.
9. 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).
10. 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 13

1. 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.
2. 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
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: 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).
6. 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).
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: 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
8. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is not controlled with treatment.
9. 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.
10. Active bleeding disorders.
11. Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class.
12. Is pregnant, lactating or planning to become pregnant.
13. The patient is, in the investigator’s opinion, unable or unwilling to comply with the trial procedures.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR, defined as the proportion of patients experiencing the best overall confirmed response of CR or PR, RECIST 1.1.

Secondary endpoints 5

1. Adverse events (AE) graded according to NCI-Common Terminology Criteria of Adverse Events Version 5.0 (CTCAE v5.0), clinical laboratory tests, vital signs, ECGs, and echo/MUGA
2. Antitumor activity will be evaluated per RECIST 1.1: -Duration of response defined the first objective response to progression or to death due to any cause, whichever occurs first - Progression-free survival defined the first treatment dose until the disease progression per death, whichever occurs first
3. Overall survival (OS), measured from the date of first dose of study treatment until the date of death from any cause
4. Intracranial (i) ORR (iORR), iDoR, and iDCR, as determined by RANO-BM criteria
5. Observed minimum concentration (Cmin) of zipalertinib in plasma

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Taiho Oncology Inc.

Sponsor organisation

Taiho Oncology Inc.

Address

101 Carnegie Center Suite 300

City

Princeton

Postcode

08540-6231

Country

United States

Scientific contact point

Organisation

Taiho Oncology Inc.

Contact name

Trial Information Desk

Public contact point

Organisation

Taiho Oncology Inc.

Contact name

Trial Information Desk

Third parties 7

Locations

4 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 71 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications