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

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 - Basket study of tucatinib and trastuzumab in solid tumors.

Status

Active, not recruiting

Phases

Phase 2

Study type

Interventional

Source

NL-OMON

Registry ID

NL-OMON51882

Enrollment

Registered

2021-03-18

Start date

2021-06-01

Completion date

Unknown

Last updated

2025-09-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Metastasis Solid Tumor

Interventions

Tucatinib 300 mg will be administered PO BID continuously starting from Cycle 1 Day 1 onwards. Trastuzumab 8 mg/kg will be administered IV on Cycle 1 Day 1 and then will be administered at 6 mg/kg e

Eligibility

Age

18 Years to 99 Years

Inclusion criteria

Inclusion criteria: 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: o Extracellular domain: G309A/E; S310F/Y; C311R/S; C334S o Kinase domain: T733I; L755P/S; I767M; L768S; D769N/Y/H; Y772; A775; G776; V777L/M; G778; T798; L841V, V842I; N857S, T862A, L869R, H878Y, R896C o Transmembrane/juxtamembrane domain: S653C, I655V; V659E; G660D; R678Q; V697. o Subjects with HER2 activating mutations not listed above may be eligible, if supported by scientific literature and approved by the medical monitor 8. Have measurable disease per RECIST v1.1 criteria according to investigator assessment 9. Be at least 18 years of age at time of consent, or considered an adult by local regulations 10. Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 11. Have a life expectancy of at least 3 months, in the opinion of the investigator 12.

Exclusion criteria

Exclusion criteria: 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 =90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate canc

Design outcomes

Primary

Measure	Time frame
Efficacy Assessments Disease response will be assessed by the investigator according to RECIST v1.1. Treatment decisions will be made based upon local assessment of radiologic scans. Radiographic disease assessments will evaluate all known sites of disease, preferably using high quality spiral contrast computed tomography (CT) (with oral and/or IV contrast), and covering, at a minimum, the chest, abdomen, and pelvis. Positron emission tomography-CT scans (if high quality CT scan is included) and/or MRI scans may also be used as appropriate, as well as additional imaging of any other known sites of disease. In subjects with breast or lung cancer, a contrast MRI scan of the brain should be performed at screening. Subjects with known or suspected brain lesions should undergo brain MRIs during treatment and follow-up according to the same assessment schedule as for other disease assessments. If contrast is contraindicated (ie, in subjects with contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may be performed instead, with MRI scans of the abdomen and pelvis. For each subject, the same imaging modality as used at screening/baseline should be used throughout the study, unless otherwise clinically indicated. Images will be collected by an independent central review (ICR) facility for possible future analysis. Disease assessments will be done at screening/baseline, and every 6 weeks for first 24 weeks then every 12 weeks, irrespective of dose interruptions. Responses (CR or PR) will be confirmed with repeat scans at least 4 weeks after first documentation of response. The schedule for response assessments should not be adjusted after the confirmatory scan (eg, CR at Week 6, confirmatory scans at Week 10-12, next assessment due at Week 12). Tumor imaging should also be performed whenever disease progression is suspected. Subjects will be considered evaluable for response if they (1) had a baseline disease assessmen	—

Measure

Time frame

Efficacy Assessments Disease response will be assessed by the investigator according to RECIST v1.1. Treatment decisions will be made based upon local assessment of radiologic scans. Radiographic disease assessments will evaluate all known sites of disease, preferably using high quality spiral contrast computed tomography (CT) (with oral and/or IV contrast), and covering, at a minimum, the chest, abdomen, and pelvis. Positron emission tomography-CT scans (if high quality CT scan is included) and/or MRI scans may also be used as appropriate, as well as additional imaging of any other known sites of disease. In subjects with breast or lung cancer, a contrast MRI scan of the brain should be performed at screening. Subjects with known or suspected brain lesions should undergo brain MRIs during treatment and follow-up according to the same assessment schedule as for other disease assessments. If contrast is contraindicated (ie, in subjects with contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may be performed instead, with MRI scans of the abdomen and pelvis. For each subject, the same imaging modality as used at screening/baseline should be used throughout the study, unless otherwise clinically indicated. Images will be collected by an independent central review (ICR) facility for possible future analysis. Disease assessments will be done at screening/baseline, and every 6 weeks for first 24 weeks then every 12 weeks, irrespective of dose interruptions. Responses (CR or PR) will be confirmed with repeat scans at least 4 weeks after first documentation of response. The schedule for response assessments should not be adjusted after the confirmatory scan (eg, CR at Week 6, confirmatory scans at Week 10-12, next assessment due at Week 12). Tumor imaging should also be performed whenever disease progression is suspected. Subjects will be considered evaluable for response if they (1) had a baseline disease assessmen

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Secondary

Measure	Time frame
Pharmacokinetic Assessments Blood samples for PK assessment of trough tucatinib drug levels will be collected in all subjects on Day 1 of Cycles 2 to 6, prior to administration of tucatinib. On Day 1 of Cycle 3, PK assessments of peak levels of tucatinib will be performed 1 to 4 hours after administration of tucatinib. Plasma concentrations of tucatinib will be determined using validated liquid chromatography (LC)-mass spectrometry (MS)/MS methods. PK parameters will be summarized using descriptive statistics. HER2 Testing for Eligibility and Biomarker Assessments Study eligibility requirements for HER2 overexpressing/amplified disease and HER2-mutated disease are to be met by assays performed pre-study (assessments undertaken prior to any study-related actives) or in pre-screening, as follows: 1. Previously established HER2 alterations: HER2 eligibility can be demonstrated via HER2 overexpression or amplification in an IHC/ISH assay of tumor tissue or HER2 amplification or activating mutations in an NGS assay of ctDNA or tumor tissue, processed locally in a CLIA- or ISO-accredited laboratory before enrollment in the study. 2. Pre-screening for HER2 alterations: if HER2 alterations have not been detected in pre-study assessments, HER2 eligibility may alternatively be established during pre-screening, up to 3 months prior to the Screening visit, via an NGS assay of ctDNA evaluating the presence of HER2 amplification or mutations. 3. Additional samples for exploratory analyses: For exploratory analysis, all subjects will provide a blood sample for NGS assay of ctDNA and archival tumor tissue or a fresh tumor biopsy, if available. These will be provided either in pre-screening or, if pre-screening did not occur, at the Screening visit for tumor tissue and predose on Cycle 1 Day 1 for the blood sample. However, the blood sample does not need to be drawn if a pre-study NGS assay of ctDNA has previously been performed by the sponsor since the e	—

Measure

Time frame

Pharmacokinetic Assessments Blood samples for PK assessment of trough tucatinib drug levels will be collected in all subjects on Day 1 of Cycles 2 to 6, prior to administration of tucatinib. On Day 1 of Cycle 3, PK assessments of peak levels of tucatinib will be performed 1 to 4 hours after administration of tucatinib. Plasma concentrations of tucatinib will be determined using validated liquid chromatography (LC)-mass spectrometry (MS)/MS methods. PK parameters will be summarized using descriptive statistics. HER2 Testing for Eligibility and Biomarker Assessments Study eligibility requirements for HER2 overexpressing/amplified disease and HER2-mutated disease are to be met by assays performed pre-study (assessments undertaken prior to any study-related actives) or in pre-screening, as follows: 1. Previously established HER2 alterations: HER2 eligibility can be demonstrated via HER2 overexpression or amplification in an IHC/ISH assay of tumor tissue or HER2 amplification or activating mutations in an NGS assay of ctDNA or tumor tissue, processed locally in a CLIA- or ISO-accredited laboratory before enrollment in the study. 2. Pre-screening for HER2 alterations: if HER2 alterations have not been detected in pre-study assessments, HER2 eligibility may alternatively be established during pre-screening, up to 3 months prior to the Screening visit, via an NGS assay of ctDNA evaluating the presence of HER2 amplification or mutations. 3. Additional samples for exploratory analyses: For exploratory analysis, all subjects will provide a blood sample for NGS assay of ctDNA and archival tumor tissue or a fresh tumor biopsy, if available. These will be provided either in pre-screening or, if pre-screening did not occur, at the Screening visit for tumor tissue and predose on Cycle 1 Day 1 for the blood sample. However, the blood sample does not need to be drawn if a pre-study NGS assay of ctDNA has previously been performed by the sponsor since the e

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Countries

Netherlands

Outcome results

None listed

Source: NL-OMON (via WHO ICTRP)