Previously Treated, Locally-Advanced Unresectable or Metastatic Solid Tumors Driven by HER2 Alterations MedDRA version: 20.0 Level: PT Classification code 10008593 Term: Cholangiocarcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10017614 Term: Gallbladder cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Leve
Conditions
Sponsors
Seagen Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic solid tumor, including primary brain tumors 2.Prior therapy: a.Subjects with non-squamous NSCLC: Must have progressed during or after standard treatment or for which no standard treatment is available b.Subjects with other disease types: Must have pogressed during or after =1 prior line of systemic therapy for locally-advanced unresectable or metastatic disease •Subjects with metastatic HR+ HER2-mutated breast cancer must have received a prior CDK4/6 inhibitor in the metastatic setting •Subjects 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.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. •Subjects 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 9.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 with direct bilirubin =1.5 × ULN and normal AST and ALT are eligible 10.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 to 100 × 109/L may be included with approval from Medical Monitor c.Hemoglobin =9.0 g/dL; subjects with hemoglobin =8 and <9 g/dL may be included with approval from the Medical Monitor d.In subjects transfused before study entry, transfusion must be =14 days prior to start of therapy to establish adequate hematologic parameters independent from transfusion support 11.Estimated glomerular filtration rate (GFR) =30 mL/min/1.73 m² using the Modification of Diet in Renal Disease (MDRD) study equation 12.Left ventricular ejec
Exclusion criteria
Exclusion criteria: 1.Subjects with breast cancer, gastric or gastroesophageal junction adenocarcinoma, or CRC whose disease shows HER2 amplification/overexpression. 2.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 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, major surgery, 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: a.CD4+ T-cell count of <350 cells/µL b.Detectable HIV viral load c.History of an opportunistic infection within the past 12 months d.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 17.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 ca
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| Secondary end point(s): Disease control rate (DCR; confirmed CR or PR, or stable disease) per investigator assessment Duration of response (DOR; confirmed CR or PR) per investigator assessment Progression-free survival (PFS) per investigator assessment Overall survival (OS) Type, incidence, severity, seriousness, and relatedness of adverse events (AEs) Type, incidence, and severity of laboratory abnormalities Frequency of treatment interruptions, dose reductions, and treatment discontinuations due to AEs Other relevant safety variables including AEs of special interest (AESIs);Timepoint(s) of evaluation of this end point: Up to 3 years | — |
Countries
Belgium, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Poland, Spain, United Kingdom, United States
Contacts
Public ContactSeagen Clinical Trial Information
Seagen, Inc.
Outcome results
None listed