Clinical trial NCT05967689: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Advanced or Metastatic NSCLC Harboring Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion (ex20ins) Mutations
Keywords: NSCLC
Carcinoma
Non-Small Cell Lung
Lung disease
locally advanced/ metastatic
ex20ins mutation
Insertion Mutations
EGFR uncommon/ single mutation Phase 2, Phase 2b, Phase II Exon 20
TAS6417/ CLN-081
Lead sponsor: Taiho Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2023-08-01
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 4 Cohorts based on eligibility criteria
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and efficacy of zipalertinib in participants with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring EGFR ex20ins mutations and other mutations.

Detailed description: This study will evaluate the safety and efficacy of zipalertinib in participants with locally advanced or metastatic NSCLC harboring EGFR ex20ins mutations or other uncommon/single or compound Epidermal Growth Factor Receptor Proteins Mutations (EGFRmts).

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

* Cohort A ("prior ex20ins treatment") will include participants harboring EGFR ex20ins who have progressed on or after initial treatment with standard platinum-based chemotherapy and prior treatment with an ex20ins agent for their advanced disease (administered together or separately).
* Cohort B ("first-line") will include participants harboring EGFR ex20ins who have not received prior treatment for advanced or metastatic disease and are not appropriate candidates for first-line doublet platinum-based chemotherapy or have refused first-line doublet platinum-based chemotherapy.
* Cohort C ("active brain mets") will include participants harboring EGFR ex20ins or other uncommon single or compound EGFRmts and active brain metastases and/or leptomeningeal disease (LMD). Participants may or may not have had prior treatment for advanced disease.
* Cohort D ("other uncommon EGFRmts") will include participants harboring other non-ex20ins, excluding C797S (uncommon single or compound) EGFRmts who have not received prior systemic therapy for their locally advanced or metastatic NSCLC disease.

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 participants:
   * Documented EGFR ex20ins status, as determined by local testing performed at a Clinical Laboratory Improvement Amendments (CLIA) certified (United States \[US\]) 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. Participants who discontinued previous treatment due to unacceptable toxicity are eligible.

     i. Permitted prior ex20ins therapies include: amivantamab, sunvozertinib (DZD9008), and BLU451. Other prior ex20ins--directed treatment may be discussed with the Sponsor for eligibility assessment.
   * Participants with brain metastasis must be neurologically stable. Participants must have received central nervous system (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 (magnetic resonance imaging \[MRI\] or computed tomography \[CT\] 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. Participants with a history of uncontrolled seizures or LMD are not eligible.

   Cohort B participants:
   * Documented EGFR ex20instatus, as determined by local testing performed at a CLIA-certified (US) or locally certified laboratory (outside the US).
   * Participants 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.
   * Participants with brain metastasis must be neurologically stable. Participants 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. Participants with history of uncontrolled seizures or LMD are not eligible.

   Cohort C participants:
   * 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).
   * Presence of brain metastasis(es) characterized as at least one of the following:

     * Newly diagnosed and/or progressive brain metastasis(es) measurable by Response Assessment in Neuro-oncology Brain Metastases (RANO-BM) criteria and not subjected to CNS-directed therapy, AND/OR
     * LMD measurable or non-measurable by RANO-BM criteria and confirmed by a positive cerebrospinal fluid cytology, or unequivocal radiographic and/or clinical determination.
   * Participants 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.

   Cohort D participants:
   * 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.
   * Participants with brain metastasis must be neurologically stable. Participants 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. Participants with history of uncontrolled seizures or LMD are not eligible.
   * Participants who have not received prior systemic therapy for their locally advanced or metastatic NSCLC disease.
   * Prior adjuvant/neoadjuvant treatment for early-stage disease must have been completed \>6 months prior to the first dose of study treatment. Participants may not have received prior adjuvant/neoadjuvant treatment with any EGFR tyrosine kinase inhibitor (TKI).
4. Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (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). Participants with insufficient tissue may be eligible following discussion with the Sponsor.
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 17.
7. Adequate organ function, as defined by the hematologic, renal and hepatic laboratory values.
8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female participants 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).
9. 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:

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 (gamma knife radiotherapy is allowed) ≤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.
   5. 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. Participants 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.
   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 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. Participants 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. Participants 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.

Primary outcomes:
measure: All Cohorts: Objective Response Rate (ORR)
timeFrame: Up to approximately 2 years
Secondary outcomes:
measure: All Cohorts: Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0)
timeFrame: Up to approximately 2 years
measure: All Cohorts: Number of Participants with Clinically Significant Changes in Clinical Laboratory Parameters
timeFrame: Up to approximately 2 years
measure: All Cohorts: Number of Participants with Clinically Significant Changes in Vital Signs
timeFrame: Up to approximately 2 years
measure: All Cohorts: Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters
timeFrame: Up to approximately 2 years
measure: All Cohorts: Number of participants With Change in Left Ventricular Ejection Fraction (LVEF) Evaluated Using Electrocardiography (ECHO) and Multigated Acquisition (MUGA) Scan
timeFrame: Up to approximately 2 years
measure: All Cohorts: Disease control rate (DCR)
timeFrame: Up to approximately 2 years
measure: All Cohorts: Duration of response (DoR)
timeFrame: Up to approximately 2 years
measure: All Cohorts: Progression-free survival (PFS)
timeFrame: Up to approximately 2 years
measure: All Cohorts: Overall Survival (OS)
timeFrame: Up to approximately 2 years
measure: Cohort C: Intracranial (i) Overall Response Rate (iORR)
timeFrame: Up to approximately 2 years
measure: Cohort C: Intracranial Duration of Complete Response (iDCR)
timeFrame: Up to approximately 2 years
measure: Cohort C: Intracranial Duration of Response (iDoR)
timeFrame: Up to approximately 2 years
measure: All Cohorts: Minimum Plasma Concentration (Cmin) of Zipalertinib
timeFrame: Up to approximately 2 years
Other outcomes:
measure: Cmin of Zipalertinib
timeFrame: Up to approximately 2 years
measure: Maximum Plasma Concentration (Cmax) of Zipalertinib
timeFrame: Up to approximately 2 years
measure: Area Under Curve (AUC) of Zipalertinib
timeFrame: Up to approximately 2 years
measure: Number of Participants with EGFRmts
timeFrame: Up to approximately 2 years
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope - Duarte
state: California
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Cancer Center - Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Cancer Center - Monmouth
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Cancer Center - Bergen
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center - Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Cancer Center - Westchester
state: New York
city: Long Island City
country: United States
facility: MSK Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Cancer Center - Nassau
state: New York
city: Canton
country: United States
facility: Gabrail Cancer and Research Center
state: Ohio
city: Columbus
country: United States
facility: Zangmeister Cancer Center
state: Ohio
city: Toledo
country: United States
facility: The Toledo Clinic Cancer Center
state: Ohio
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Irving
country: United States
facility: Alliance Cancer Specialists PC
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specilalist
state: Virginia
city: Milwaukee
country: United States
facility: IDS Pharmacy
state: Wisconsin
city: Bankstown
country: Australia
facility: Bankstown-Lidcombe Hospital
state: New South Wales
city: Saint Leonards
country: Australia
facility: Genesis Care North Shore
state: New South Wales
city: Joondalup
country: Australia
facility: Joondalup Hospital Pharmacy
state: Western Australia
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Brampton
country: Canada
facility: William Osler Health System - Brampton Civic Hospital
city: Strasbourg
country: France
facility: Nouvel Hôpital Civil
state: Aslace
city: Caen cedex 9
country: France
facility: CHU Caen Normandie
state: Basse-Normandie
city: Paris
country: France
facility: Institut Curie
state: Ile-de-France
city: Limoges cedex
country: France
facility: Centre Hospitalier Universitaire Limoges
state: Limousin
city: Pessac
country: France
facility: Hopital Haut Leveque
state: Nouvelle-Aquitaine
city: Marseille
country: France
facility: Hôpital Nord Marseille
state: Provence Alpes Cote d´Azur
city: Lyon
country: France
facility: Centre Leon Berard
state: Rhone-Alpes
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Saint-Herblain
country: France
facility: Hopital Nord Laennec
city: Boulogne-Billancourt
country: France
facility: Hopital Ambroise Pare
state: Île-de-France
city: Esslingen
country: Germany
facility: Klinikum Esslingen GmbH
state: Baden-Wuerttemberg
city: Kassel
country: Germany
facility: Gesundheit Nordhessen Holding AG
state: Hassen
city: Dresden
country: Germany
facility: Uniklinik Dresden
city: Gießen
country: Germany
facility: UKGM Studienzentrale
city: Hamburg
country: Germany
facility: Asklepios Kliniken Hamburg
city: München
country: Germany
facility: LMU Klinikum - Apotheke
city: Regensburg
country: Germany
facility: UKR Innere Med II Pneumologie
city: Pok Fu Lam
country: Hong Kong
facility: Queen Mary Hospital
state: Hong Kong Island
city: Sha Tin
country: Hong Kong
facility: Prince of Wales Hospital
city: Firenze
country: Italy
facility: Azienda Ospedaliero - Universitaria Careggi
state: Florence
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
state: Forli-Cesena
city: Alessandria
country: Italy
facility: AOU di Alessandria
city: Bologna
country: Italy
facility: AOU Sant'Orsola Malpighi IRCCS
city: Catania
country: Italy
facility: Policlinico G.Rodolico-S.Marco
city: Cremona
country: Italy
facility: Azienda Socio-Sanitaria Territoriale di Cremona
city: Genova
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale Policlinico San Martino
city: Milan
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele
city: Modena
country: Italy
facility: Azienda Ospedaliero - Universitaria di Modena
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma
city: Piacenza
country: Italy
facility: Azienda Unità Sanitaria Locale - Piacenza
city: Ravenna
country: Italy
facility: Ospedale S. Maria delle Croci
city: Roma
country: Italy
facility: IFO Regina Elena
city: Nagoya
country: Japan
facility: Aichi Cancer Center
state: Aichi
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Fukuoka-shi
country: Japan
facility: NHO Kyushu Cancer Center
state: Hukuoka
city: Sendai
country: Japan
facility: Sendai Kousei Hospital
state: Miyagi
city: Niigata-shi
country: Japan
facility: Niigata Cancer Center Hospital
state: Niigata
city: Osakasayama
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Sunto-gun
country: Japan
facility: Shizuoka Cancer Center
state: Sizuoka
city: Chuo Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Koto-ku
country: Japan
facility: Cancer Institute Hospital of JFCR
state: Tokyo
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-Do
city: Suwon-si
country: Korea, Republic of
facility: Saint Vincent's Hospital
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
state: Gyeonggi-do
city: Jinju
country: Korea, Republic of
facility: Gyeongsang National University Hospital
state: Gyeongsangnamdo [Kyongsangnam-do]
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
state: Incheon Gwang'yeogsi [Inch'on-Kwangyokshi]
city: Hwasun-gun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi [Seoul-T'ukpyolshi]
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul Teugbyeolsi [Seoul-T'ukpyolshi]
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
state: Seoul Teugbyeolsi [Seoul-T'ukpyolshi]
city: Soeul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
state: Seoul Teugbyeolsi [Seoul-T'ukpyolshi]
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga - Hospital General
state: Malaga
city: Barcelona
country: Spain
facility: UOMi Clinica Mi Tres Torres
city: Barcelona
country: Spain
facility: Hospital Quirónsalud Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaen
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital La Paz
city: Cankaya
country: Turkey
facility: Ankara Bilkent Sehir Hastanesi
state: Ankara
city: Etlik
country: Turkey
facility: SBU Gulhane Egitim Ve Arastirma Hastanesi
state: Ankara
city: Esenyurt
country: Turkey
facility: Istinye Üniversite Hastanesi Liv Hospital Bahcesehir
state: Istanbul
city: Adana
country: Turkey
facility: Medical Park Seyhan Hastanesi
city: Adana
country: Turkey
facility: Adana Sehir Egitim ve Arastirma Hastanesi
city: Ankara
country: Turkey
facility: Memorial Ankara Hastanesi
city: Edirne
country: Turkey
facility: Trakya Üniversitesi Saglik Arastirma ve Uygulama Merkezi
city: Istanbul
country: Turkey
facility: Bagcilar Medipol Mega Universite Hastanesi
city: Istanbul
country: Turkey
facility: Prof. Dr. Suleyman Yalcin Sehir Hastanesi
city: Barnet
country: United Kingdom
facility: Royal Free Hospital NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
state: England
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: England
Study officials:
References: