Tucatinib and trastuzumab in solid tumors with HER2 alterations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Seagen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jul 2021 → 21 Jan 2026

Decision date (initial)

2024-04-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-511481-37-00

EudraCT number

2020-004873-29

ClinicalTrials.gov

NCT04579380

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Pharmacokinetic, Others, Efficacy, Pharmacodynamic

To evaluate the antitumor activity of tucatinib given in combination with trastuzumab in participants with previously treated, locally-advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) overexpressing/amplified or mutated solid tumors

Secondary objectives 1

1. To evaluate the safety and tolerability of tucatinib given in combination with trastuzumab with or without fulvestrant.

Conditions and MedDRA coding

Previously Treated, Locally-Advanced Unresectable or Metastatic Solid Tumors Driven by HER2 Alterations

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic solid tumor, including primary brain tumors
2. Prior therapy: a. Participants with non-squamous NSCLC: Must have progressed during or after standard treatment or for which no standard treatment is available b. Participants with other disease types: Must have progressed during or after ≥1 prior line of systemic therapy for locally-advanced unresectable or metastatic disease i. Participants with metastatic HR+ HER2-mutated breast cancer must have received a prior CDK4/6 inhibitor in the metastatic setting ii. Participants with metastatic cervical cancer must have received platinum-based chemotherapy with or without bevacizumab in the metastatic setting
3. Progression during or after, or intolerance of, the most recent line of systemic therapy
4. Disease demonstrating HER2 alterations (overexpression/amplification or HER2 activating mutations), as determined by local or central testing processed in a Clinical Laboratory Improvement Amendments (CLIA)- or International Organization for Standardization (ISO)-accredited laboratory, according to one of the following: a. HER2 overexpression/amplification from fresh or archival tumor tissue or blood utilizing one of the following tests, in subjects with tumor types other than breast cancer, GEC, or CRC: i. HER2 overexpression by immunohistochemistry (IHC): 3+ by breast or gastric algorithms ii. HER2 amplification by in situ hybridization (ISH) assay: fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) signal ratio ≥2.0 or gene copy number >6 iii. HER2 amplification in tissue by next generation sequencing (NGS) assay iv. iv. HER2 amplification in circulating tumor DNA (ctDNA) by blood-based NGS assay b. Known activating HER2 mutations detected in fresh or archival tumor tissue or blood by NGS assay, including: • Extracellular domain: G309A/E; S310F/Y; C311R/S; C334S • Kinase domain: T733I; L755P/S; I767M; L768S; D769N/Y/H; Y772; A775; G776; V777L/M; G778; T798; L841V, V842I; N857S, T862A, L869R, H878Y, R896C, other exon 20 insertions • Transmembrane/juxtamembrane domain: S653C, I655V; V659E; G660D; R678Q; V697. • Participants with HER2 activating mutations not listed above may be eligible, if supported by scientific literature and approved by the medical monitor
5. Have measurable disease per RECIST v1.1 criteria according to investigator assessment
6. Have adequate hepatic function as defined by the following: a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (≤5 × ULN if liver metastases are present) b. Total bilirubin ≤1.5 × ULN. Exception: participants with known history of Gilbert’s syndrome with direct bilirubin ≤1.5 × ULN and normal AST and ALT are eligible
7. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or multiple-gated acquisition scan (MUGA) documented within ≤28 days prior to first dose of study treatment

Exclusion criteria 17

1. Participants with breast cancer, gastric or gastroesophageal junction adenocarcinoma, or CRC whose disease shows HER2 amplification/overexpression.
2. Presence of known chronic liver disease
3. Subjects known to be positive for human immunodeficiency virus (HIV) are excluded if they meet any of the following criteria: • CD4+ T-cell count of <350 cells/µL • Detectable HIV viral load • History of an opportunistic infection within the past 12 months • On stable antiretroviral therapy for <4 weeks
4. Are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of any study drug, and, if applicable, for at least 2 years after the final dose of fulvestrant
5. Have inability to swallow pills
6. Have used a strong cytochrome P450 (CYP) 2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to start of treatment
7. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
8. History of another malignancy within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (eg, 5-year OS of ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
9. Previous treatment with HER2-directed therapy; subjects with uterine serous carcinoma or HER2-mutated gastric or gastroesophageal junction adenocarcinoma without HER2-overexpression/amplification may have received prior trastuzumab
10. Known hypersensitivity to any component of the drug formulation of tucatinib or trastuzumab (drug substance, excipients, murine proteins), or any component of the drug formulation of fulvestrant in participants with HR+ HER2-mutated breast cancer
11. History of exposure to a >360 mg/m² doxorubicin-equivalent or >720 mg/m² epirubicin-equivalent cumulative dose of anthracyclines
12. Treatment with any systemic anti-cancer therapy, radiation therapy, major surgery, or experimental agent within ≤3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial
13. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions: a. Alopecia b. Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely c. Anemia, which must have resolved to ≤ Grade 2
14. Have clinically significant cardiopulmonary disease such as: a. Ventricular arrhythmia requiring therapy b. Symptomatic hypertension or uncontrolled hypertension as determined by investigator c. Any history of symptomatic CHF d. Severe dyspnea at rest (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Grade 3 or above) due to complications of advanced malignancy e. Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea
15. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
16. Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection (positive by polymerase chain reaction). Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks
17. Please see protocol (page 37) for the full list.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Confirmed objective response rate (ORR; confirmed complete response [CR] or partial response [PR]) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 per investigator assessment

Secondary endpoints 7

1. Disease control rate (DCR; confirmed CR or PR, or stable disease) per investigator assessment
2. Duration of response (DOR; confirmed CR or PR) per investigator Assessment Progression-free survival (PFS) per investigator assessment
3. Overall survival (OS)
4. Type, incidence, severity, seriousness, and relatedness of adverse events (AEs)
5. Type, incidence, and severity of laboratory abnormalities
6. Frequency of treatment interruptions, dose reductions, and treatment discontinuations due to AEs
7. Other relevant safety variables including AEs of special interest (AESIs)

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Seagen Inc.

Sponsor organisation

Seagen Inc.

Address

21823 30th Drive Southeast

City

Bothell

Postcode

98021-3907

Country

United States

Scientific contact point

Organisation

Seagen Inc.

Contact name

Seagen Trial Information Support

Public contact point

Organisation

Seagen Inc.

Contact name

Seagen Trial Information Support

Third parties 9

Locations

3 EU/EEA countries · 8 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 30 files

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

Application history

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