A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This study is being done to find out if tucatinib with other cancer drugs works better than standard of care to treat participants with HER2 positive colorectal cancer. This study will also test what side effects happen when participants take this combination of drugs. A side effect is anything a drug does to the body besides treating your disease. Participants in this study have colorectal cancer that has spread through the body (metastatic) and/or cannot be removed with surgery (unresectable). Participants will be assigned randomly to the tucatinib group or standard of care group. The tucatinib group will get tucatinib, trastuzumab, and mFOLFOX6. The standard of care group will get either: mFOLFOX6 alone, mFOLFOX6 with bevacizumab, or mFOLFOX6 with cetuximab mFOLFOX6 is a combination of multiple drugs. All of the drugs given in this study are used to treat this type of cancer.

Official Title
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An Open-label Randomized Phase 3 Study of Tucatinib in Combination With Trastuzumab and mFOLFOX6 Versus mFOLFOX6 Given With or Without Either Cetuximab or Bevacizumab as First-line Treatment for Subjects With HER2+ Metastatic Colorectal Cancer

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: tucatinib
* Drug: trastuzumab
* Drug: bevacizumab
* Drug: cetuximab
* Drug: oxaliplatin
* Drug: leucovorin
* Drug: levoleucovorin
* Drug: fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum which is locally advanced unresectable or metastatic Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides) obtained prior to treatment initiation to a central laboratory If archival tissue is not available, a newly-obtained baseline biopsy of an accessible tumor lesion is required within 35 days prior to start of study treatment HER2+ disease as determined by a tissue based assay performed at a central laboratory. Participant has rat sarcoma viral oncogene homolog wild-type (RAS WT) disease as determined by local or central testing. For central RAS analysis, tissue sample must be analyzed within 1 year of biopsy date. Radiographically measurable disease per RECIST v1.1 with: At least one site of disease that is measurable and that has not been previously irradiated, or If the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 CNS Inclusion - based on contrast brain magnetic resonance imaging, participants may have any of the following: No evidence of brain metastases Previously treated brain metastases which are asymptomatic Exclusion Criteria: Prior systemic anticancer therapy for colorectal cancer (CRC) in the metastatic setting; note that participants may have received a maximum of 2 doses of mFOLFOX6 in the locally advanced/unresectable or metastatic setting prior to randomization. Note: May have received chemotherapy for CRC in the adjuvant setting if it was completed >6 months prior to enrollment Radiation therapy within 14 days prior to enrollment (or within 7 days in the setting of stereotactic radiosurgery) Previous treatment with anti-HER2 therapy Ongoing Grade 3 or higher neuropathy GI perforation within 12 months of enrollment

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tucatinib Arm<br>Tucatinib + trastuzumab + mFOLFOX6 | Drug: tucatinib<br>* 300mg given by mouth (orally) twice daily<br>* Other names: TUKYSA, ONT-380, ARRY-380;Drug: trastuzumab<br>* 8mg/kg loading dose will be given into the vein (IV; intravenously) on Cycle 1 day 1, followed by 6mg/kg given by IV every 3 weeks thereafter.<br>* Other names: Herceptin;Drug: oxaliplatin<br>* 85mg/m2 given by IV every 2 weeks. Component of mFOLFOX6.<br>Drug: leucovorin<br>* 400mg/ m2 given by IV every 2 weeks. Component of mFOLFOX6.<br>Drug: levoleucovorin<br>* 200mg/ m2 given by IV every 2 weeks. May be given in place of leucovorin. Component of mFOLFOX6.<br>Drug: fluorouracil<br>* 400mg/m2 given by IV bolus then 2400mg/m2 given by continuous IV infusion (over 46-48 hours) every 2 weeks. Component of mFOLFOX6.<br>|
| Active Comparator: Standard of Care Arm<br>mFOLFOX6 + (bevacizumab OR cetuximab). Either (1) mFOLFOX6, (2) mFOLFOX6 and bevacizumab, or (3) mFOLFOX6 and cetuximab | Drug: bevacizumab<br>* 5mg/kg given by IV every 2 weeks<br>* Other names: Avastin;Drug: cetuximab<br>* 400mg/m2 loading dose will be given by IV on Cycle 1 day 1, followed by 250mg/m2 given by IV weekly<br>* Other names: Erbitux;Drug: oxaliplatin<br>* 85mg/m2 given by IV every 2 weeks. Component of mFOLFOX6.<br>Drug: leucovorin<br>* 400mg/ m2 given by IV every 2 weeks. Component of mFOLFOX6.<br>Drug: levoleucovorin<br>* 200mg/ m2 given by IV every 2 weeks. May be given in place of leucovorin. Component of mFOLFOX6.<br>Drug: fluorouracil<br>* 400mg/m2 given by IV bolus then 2400mg/m2 given by continuous IV infusion (over 46-48 hours) every 2 weeks. Component of mFOLFOX6.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) by Blinded Independent Central Review (BICR) | The time from the date of randomization to the BICR assessment of disease progression according to RECIST v1.1 or death from any cause | Up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The time from randomization to death from any cause | Up to approximately 6 years | 
| Confirmed objective response rate (cORR) per RECIST v1.1 by BICR | The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1, as assessed by BICR | Up to approximately 3 years | 
| PFS per RECIST v1.1 by investigator assessment | The time from the date of randomization to the investigator assessment of disease progression according to RECIST v1.1 or death from any cause | Up to approximately 3 years | 
| cORR per RECIST v1.1 by investigator assessment | The proportion of participants with confirmed CR or PR according to RECIST v1.1, as assessed by investigators | Up to approximately 3 years | 
| Duration of response (DOR) per RECIST v1.1 by BICR | The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of disease progression per RECIST v1.1 or death from any cause | Up to approximately 3 years | 
| DOR per RECIST v1.1 by investigator assessment | The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of disease progression per RECIST v1.1 or death from any cause | Up to approximately 3 years | 
| Time to second progression or death (PFS2) | The time from randomization to disease progression on the next-line of therapy, or death from any cause | Up to approximately 3 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. | Through 30 days after the last study treatment; approximately 1 year | 
| Incidence of dose alterations |  | Through 30 days after the last study treatment; approximately 1 year | 
| Trough concentration (Ctrough) | PK parameter | Approximately 4 months | 
| Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQC30) score | Change from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scores. Scale scores range from 0-100. For functioning and global health status/quality of life (QoL) scales, higher scores indicate better functioning or global health status/quality of life (QoL). For symptom scales, higher scores indicate greater symptom burden. | Through 30-37 days after the last study treatment; approximately 1 year | 
| Time to meaningful change in EORTC QLQ30 score | The time from baseline to the first onset of a ≥10-point changes in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scores. Scale scores range from 0-100. For functioning and global health status/QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Through 30-37 days after the last study treatment; approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer, CRC, Seattle Genetics