A study of zipalertinib and chemotherapy compared with chemotherapy alone in patients with advanced Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Exon 20 insertion

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

23 Jan 2024 → ongoing

Decision date (initial)

2023-11-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Taiho Onclology Inc.

External identifiers

EU CT number

2023-503575-21-00

ClinicalTrials.gov

NCT05973773

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacogenetic, Safety, Pharmacokinetic, Efficacy, Dose response

PART A: To determine the recommended dose of zipalertinib in combination with pemetrexed and a platinum agent to be studied in the Phase 3 portion of the Study
PART B To compare the progression-free survival (PFS) between treatment arms

Secondary objectives 1

1. PART A: to further assess the safety profile of zipalertinib in combination with pemetrexed and a platinum agent/ to evaluate he antitumor activity of zipalertinib in combination with pemetrexed and a platinum agent based on investigator assessment. PART B: to further compare the efficacy between treatment arms/ to evaluate the safety and tolerability of Zipalertinib in combination with chemotherapy verus chemotherapy alone/for patients receiving zipalertinib, to evaluate the PK profile of zipalertinib in combination with pemetrexed and platinum agent / to compare the patient reported outcomes (PROs) between treatment arms

Conditions and MedDRA coding

Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Provide written informed consent
2. ≥18 years of age (or meets the country’s regulatory definition for legal adult age, whichever is greater).
3. Pathologically confirmed, locally advanced or metastatic nonsquamous NSCLC
4. Has not received any prior systemic treatment for their locally advanced or metastatic nonsquamous NSCLC. Prior adjuvant/neoadjuvant treatment for advanced or metastatic disease >6 months prior to first dose of study treatment is allowed for early-stage NSCLC. Prior monotherapy with an approved EGFR TKI (ie, gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib) as nonstandard first-line therapy for the treatment of locally advanced or metastatic disease is allowed if all of the following criteria are met: a.Treatment duration did not exceed 8 weeks; b.Lack of disease response was documented (radiographically) by an increase in tumor burden (a copy of the computerized tomography [CT] report showing increase in tumor burden from baseline should be submitted); c.Associated toxicities have resolved to baseline; and d. The EGFR TKI was discontinued at least 2 weeks or 4 half-lives prior to randomization, whichever is longer. Prior therapy with EGFR TKI agents targeting exon20ins mutations including amivantamab, mobocertinib, sunvozertinib, furmonertinib, and poziotinib is not allowed.
5. Documented EGFR mutation status, as determined by local testing performed at a CLIA certified (US) or accredited (outside of the US) local locallaboratory, defined as follows: a. Part A: EGFR ex20ins or other common single or compound EGFR mutation b. Part B: EGFR ex20ins mutation
6. Archival tumor tissue available for submission, with minimum quantity sufficient to evaluate EGFR mutation status and, where possible, other biomarkers. Patients with insufficient tissue (details provided in laboratory manual) may be eligible following discussion with the sponsor; a fresh biopsy will not be required.
7. Patients with brain metastasis(es) who have previously received definitive local treatment and have and stable CNS disease (defined as being neurologically stable and receiving a stable and off corticosteroid for at least 2 weeks prior to enrollment) are eligible If brain metastases are diagnosed on screening imaging, the patient may be rescreened for eligibility after definitive treatment. b. Asymptomatic brain metastases ≤2 cm in size can be eligible for inclusion if, in the opinion of the Investigator, immediate definitive treatment is not indicated
8. At least one measurable lesion as determined per RECIST 1.1 for patients enrolling to Part B. Patients enrolling to Part A may be enrolled without measurable disease.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
10. Adequate organ function, as defined by the laboratory value
11. Have a life expectancy of at least 3 months as assessed by the investigator.
12. 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 postmenopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
13. Both males and females of reproductive potential must agree to use effective birth control during the study prior to the first dose and for 6 months after the last dose of study treatment or longer, based on local requirements.

Exclusion criteria 15

1. Is currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study.
2. Active bleeding disorders.
3. Known hypersensitivity to the ingredients in zipalertinib or any drugs similar in structure or class. To platinum-containing drugs (ie, cisplatin, carboplatin), pemetrexed, or any known excipients of these drugs. b. Contraindications toning drugs (ie, cisplatin, carboplatin) or pemetrexed according to the respective local labels.
4. Is unable or unwilling to take dexamethasone, folic acid, and/or vitamin B12 supplementation during treatment with pemetrexed.
5. History of leptomeningeal disease and spinal cord compression
6. The patient is, in the investigator’s opinion, unable or unwilling to comply with the trial procedures.
7. Prior treatment with any of the following within the specific time frame specified: a. Zipalertinib (TAS6417/CLN-081) at any time. b.Thoracic radiotherapy ≤28 days, palliative radiation of nonthoracic disease ≤14 days, or palliative radiation of a single lesion ≤7 days prior to first dose of study treatment. c.Major surgery (excluding placement of vascular access) ≤28 days prior to first dose of study treatment., d.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.
8. Have any unresolved toxicity of Grade ≥2 from previous anticancer treatment in the neoadjuvant or adjuvant setting, 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.
9. Past medical history of interstitial lung disease, treatment-related pneumonitis (any grade), or any evidence of clinically active interstitial lung disease.
10. 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 calculated using Fridericia's formula (QTcF).
11. Unable to swallow tablets or has any disease or condition that may significantly affect gastrointestinal (GI) absorption of zipalertinib (such as inflammatory bowel disease, malabsorption syndrome, or prior GI resection).
12. 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. Previously treated malignancy, if all treatment for that malignancy was completed at least 2 years prior to first dose of study treatment, and no current evidence of disease d. Concurrent malignancy determined to be clinically stable and not requiring tumordirected treatment
13. Known history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) that is unstable or not controlled with treatment.
14. History of COVID-19 infection within 4 weeks prior to enrolment and/or have persistent, clinically significant pulmonary symptoms related to prior COVID-19 infection.
15. Is pregnant or lactating or planning to become pregnant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. PART A: Incidence of dose-limiting toxicities (DLTs) graded according to the NCI-Common Terminology Criteria of Adverse Events (CTCAE) v5.0 during Cycle 1
2. PART B: PFSS, defined as the time from the date of randomization to the date of death (any cause) or disease progression per RECIST 1.1, whichever occurs first as assessed by blinded independent central review (BICR)

Secondary endpoints 10

1. 1.Adverse events (AE) graded according to NCI-CTCAE v5.0, clinical laboratory tests, vital signs, ECGs, and echo/MUGA
2. Antitumor activity will be evaluated for patients with at least one measurable lesion per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) as follows: 1.Objective response rate (ORR) defined as the proportion of patients experiencing a best overall response of partial response (PR) or complete response (CR)
3. 2.Antitumor activity will be evaluated for patients with at least one measurable lesion per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) as follows: 2.Disease control rate (DCR) defined as the proportion of patients experiencing a best overall response of stable disease (SD), PR, or CR
4. 3.Antitumor activity will be evaluated for patients with at least one measurable lesion per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) as follows: 3.Duration of response (DoR) defined as the time from the first documentation of objective response (CR or PR) to progression or to death due to any cause, whichever occurs first
5. 4.Antitumor activity will be evaluated for patients with at least one measurable lesion per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) as follows: 4.Intracranial ORR (iORR), iDCR, iDoR
6. PART B 1. Efficacy will be evaluated per RECIST 1.1 as follows: a.PFS based on investigator assessment b.ORR, DoR, and DCR, by BICR and investigator assessment c.iORR, iDCR, and iDoR with measurable CNS disease by BICR and investigator assessment
7. 2.Overall survival (OS) defined as the time from the date of randomization to date of death
8. 3.Adverse events (AE) graded according to NCI-CTCAE v5.0, clinical laboratory tests, vital signs, ECGs, and echo/MUGA
9. 4.Minimum observed concentration (C min)
10. 5.Measured by EQ5D-3L, EORTC QLQ-C30 and NSCL-CSAQ

Investigational products

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

Test 1

Comparator 3

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 10

Locations

10 EU/EEA countries · 64 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 205 files

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

Application history

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