Tucatinib and trastuzumab in solid tumors with HER2 alterations
- Conditions
- Previously Treated, Locally-Advanced Unresectable or Metastatic Solid Tumors Driven by HER2 AlterationsMedDRA version: 20.0Level: PTClassification code 10008593Term: CholangiocarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: PTClassification code 10017614Term: Gallbladder cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.0Level: PTClassification code 10025697Term: Malignant neoplasm of ampulla of VaterSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: LLTClassification code 10064467Term: Urothelial carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: PTClassification code 10006187Term: Breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: PTClassification code 10008342Term: Cervix carcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 20.0Level: PTClassification code 10046766Term: Uterine cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-004873-29-NL
- Lead Sponsor
- Seagen Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 270
1.Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic solid tumor, including primary brain tumors
2.Subjects with disease types other than breast cancer, biliary tract cancer, non-squamous NSCLC, and cervical cancer: Disease progression on or after the most recent systemic therapy for locally-advanced unresectable or metastatic disease
3.Subjects with any breast cancer subtype:
a.Must have HER2-mutated disease which does not display HER2 overexpression/amplification
b.Must have progressed on or after =1 prior line of treatment (chemotherapy, endocrine therapy, or targeted therapy) for locally-advanced unresectable or metastatic breast cancer
c.Subjects with metastatic HR+ HER2-mutated disease must have received a prior CDK4/6 inhibitor in the metastatic setting
4.Subjects with biliary tract cancer: must have progressed on or after =1 prior line of treatment (chemotherapy, endocrine therapy, or targeted therapy)
5.Subjects with non-squamous NSCLC: has relapsed from or is refractory to standard treatment or for which no standard treatment is available
6.Subjects with cervical cancer:
a.Subjects with metastatic cervical cancer must have progressed on or after =1 prior line of systemic therapy (platinum-based chemotherapy with or without bevacizumab) in the metastatic setting
b.Subjects with locally advanced unresectable cervical cancer must have progressed on or after =1 prior lines of systemic therapy
7.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 (3+ immunohistochemistry IHC) (breast or gastric algorithms)
ii.HER2 amplification by in situ hybridization assay (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization signal ratio =2.0 or gene copy number >6)
iii.HER2 amplification in tissue by next generation sequencing (NGS) assay
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:
oExtracellular domain: G309A/E; S310F/Y; C311R/S; C334S
oKinase domain: T733I; L755P/S; I767M; L768S; D769N/Y/H; Y772; A775; G776; V777L/M; G778; T798; L841V, V842I; N857S, T862A, L869R, H878Y, R896C
oTransmembrane/juxtamembrane domain: S653C, I655V; V659E; G660D; R678Q; V697.
oSubjects with HER2 activating mutations not listed above may be eligible, if supported by scientific literature and approved by the medical monitor
8.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: subjects with known history of Gilbert’s Syndrome and normal direct bilirubin, AST, and ALT are eligible
9.Have adequate baseline hematologic parameters as defined by:
a.Absolute neutrophil count (ANC) =1.0 × 109/L
b.Platelet count =100 × 109/L; subjects with stable platelet count from 75 t
1. Subjects with breast cancer, GEC, or CRC whose disease shows HER2 amplification/overexpression.
2. Previous treatment with HER2-directed therapy; subjects with uterine serous carcinoma may have received prior trastuzumab
3. 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 subjects with HR+ HER2-mutated breast cancer
4. History of exposure to a >360 mg/m² doxorubicin-equivalent or >720 mg/m² epirubicin-equivalent cumulative dose of anthracyclines
5. Treatment with any systemic anti-cancer therapy, radiation therapy, or experimental agent within =3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial.
6. 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
7. 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
8. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
9. Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection (positive by polymerase chain reaction). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks
10. Presence of known chronic liver disease
11. 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
12. 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
13. Have inability to swallow pills
14. 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
15. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
16. 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
17. Subjects with known central nervous system (CNS) lesions must not have any of the following:
a. Any untreated b
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the antitumor activity of tucatinib given in combination with trastuzumab in subjects with previously treated, locally-advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) overexpressing/amplified or mutated solid tumors;Secondary Objective: To evaluate the safety and tolerability of tucatinib given in combination with trastuzumab with or without fulvestrant;Primary end point(s): 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;Timepoint(s) of evaluation of this end point: Up to 3 years
- Secondary Outcome Measures
Name Time Method Timepoint(s) of evaluation of this end point: Up to 3 years;Secondary end point(s): Disease control rate (DCR; confirmed CR or PR, or stable disease) per investigator assessment<br>Duration of response (DOR; confirmed CR or PR) per investigator assessment<br>Progression-free survival (PFS) per investigator assessment<br>Overall survival (OS)<br>Type, incidence, severity, seriousness, and relatedness of adverse events (AEs)<br>Type, incidence, and severity of laboratory abnormalities<br>Frequency of treatment interruptions, dose reductions, and treatment discontinuations due to AEs<br>Other relevant safety variables including AEs of special interest (AESIs)