Basket Study of Tucatinib and Trastuzumab in Solid Tumors With HER2 Alterations

Study Overview
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Brief Summary
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This trial studies how well tucatinib works for solid tumors that make either more HER2 or a different type of HER2 than usual (HER2 alterations) The solid tumors studied in this trial have either spread to other parts of the body (metastatic) or cannot be removed completely with surgery (unresectable). All participants will get both tucatinib and trastuzumab. People with hormone-receptor positive breast cancer will also get a drug called fulvestrant. The trial will also look at what side effects happen. A side effect is anything a drug does besides treating cancer.

Detailed Description
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There are multiple cohorts in this trial: 5 tumor specific cohorts with HER2 overexpression/amplification (cervical cancer, uterine cancer, biliary tract cancer, urothelial cancer, and non-squamous non-small cell lung cancer [NSCLC]) 2 tumor specific cohorts with HER2 mutations (non-squamous NSCLC and breast cancer) 2 cohorts which will enroll all other HER2 amplified/overexpressed solid tumor types (except breast cancer, gastric or gastroesophageal junction adenocarcinoma [GEC], and colorectal cancer [CRC]) or HER2-mutated solid tumor types.

Official Title
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A Phase 2 Basket Study of Tucatinib in Combination With Trastuzumab in Subjects With Previously Treated, Locally Advanced Unresectable or Metastatic Solid Tumors Driven by HER2 Alterations

Conditions
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Uterine Neoplasms, Uterine Cervical Neoplasms, Biliary Tract Neoplasms, Urologic Neoplasms, Carcinoma, Non-Small-Cell Lung, HER2 Mutations Breast Neoplasms

Intervention / Treatment
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* Drug: tucatinib
* Drug: trastuzumab
* Drug: fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic solid tumor, including primary brain tumors Participants with non-squamous NSCLC must have progressed during or after standard treatment or for which no standard treatment is available Participants with other disease types must have progressed during or after ≥1 prior line of systemic therapy for locally-advanced unresectable or metastatic disease Disease progression during or after, or intolerance of, the most recent line of systemic therapy 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: HER2 overexpression/amplification from fresh or archival tumor tissue or blood Known activating HER2 mutations detected in fresh or archival tumor tissue or blood Have measurable disease per RECIST v1.1 criteria according to investigator assessment Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Exclusion Criteria Participants with breast cancer, gastric or gastroesophageal junction adenocarcinoma, or CRC whose disease shows HER2 amplification/overexpression. Previous treatment with HER2-directed therapy; participants with uterine serous carcinoma or HER2-mutated gastric or gastroesophageal junction adenocarcinoma without HER2-overexpression/amplification may have received prior trastuzumab 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 History of exposure to a 360 mg/m² doxorubicin-equivalent or >720 mg/m^2 epirubicin-equivalent cumulative dose of anthracyclines 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. There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tucatinib + Trastuzumab (+ Fulvestrant)<br>Tucatinib + trastuzumab (+ fulvestrant in hormone-receptor positive HER2-mutant breast cancer only) | Drug: tucatinib<br>* 300 mg orally twice daily<br>* Other names: TUKYSA, ARRY-380, ONT-380;Drug: trastuzumab<br>* Given into the vein (intravenously; IV). 8mg/kg IV on Cycle 1 Day 1, and 6mg/kg every 21 days starting on Cycle 2 Day 1<br>* Other names: Herceptin;Drug: fulvestrant<br>* Given into the muscle (intramuscular; IM) once every 4 weeks starting from Cycle 1 Day 1, plus one dose on Cycle 1 Day 15. Only administered to participants with hormone-receptor positive breast cancer.<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed objective response rate (cORR) per investigator assessment | cORR is defined as the proportion of participants with best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | From start of treatment up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) per investigator assessment | DCR is defined as the proportion of participants with confirmed CR, confirmed PR, or stable disease according to RECIST v1.1 | From start of treatment up to approximately 2 years | 
| Duration of response (DOR) per investigator assessment | DOR is defined as the time from first documentation of objective response of confirmed CR or confirmed PR to the first documentation of disease progression per RECIST v1.1 or death from any cause, whichever occurs first. | From start of treatment up to approximately 2 years | 
| Progression-free survival (PFS) per investigator assessment | PFS is defined as the time from the date of treatment initiation to the date of disease progression according to RECIST v1.1 or death from any cause, whichever occurs first. | From start of treatment up to approximately 2 years | 
| Overall survival (OS) | OS is defined as the time from treatment initiation to death due to any cause. | From start of treatment up to approximately 4 years | 
| Incidence of adverse events (AEs) | Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | From start of treatment up to approximately 2 years | 
| Incidence of laboratory abnormalities | To be summarized using descriptive statistics. | From start of treatment up to approximately 2 years | 
| Incidence of dose alterations |  | From start of treatment up to approximately 2 years | 
| Maximum concentration (Cmax) | To be summarized using descriptive statistics. | Approximately 4 months, during first 6 cycles of treatment | 
| Trough concentration (Ctrough) | To be summarized using descriptive statistics. | Approximately 4 months, during first 6 cycles of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical cancer, Uterine cancer, Biliary tract cancer, Urothelial cancer, Non-squamous non-small cell lung cancer, Non-squamous NSCLC, Breast cancer, Colorectal cancer, Ampullary cancer, Solid tumors, Solid tumors harboring somatic HER2 mutations, Seattle Genetics