Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer

Study Overview
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Brief Summary
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This trial studies how well the drug tucatinib works when given with trastuzumab and when given by itself. The participants in this trial have HER2-positive (HER2+) metastatic colorectal cancer (mCRC). 'Metastatic' means that the cancer has spread to other parts of the body. In the first part of this study, participants enrolled into Cohort A and received both tucatinib and trastuzumab. In the second part of this study, participants are randomly assigned to either Cohort B or Cohort C. Participants in Cohort B will receive tucatinib and trastuzumab. Participants in Cohort C will receive tucatinib. Participants in Cohort C who do not respond to therapy may have an option to receive tucatinib plus trastuzumab.

Official Title
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MOUNTAINEER: A Phase II, Open Label Study of Tucatinib Combined With Trastuzumab in Patients With HER2+ Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Adenocarcinoma

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Tucatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically and/or cytologically documented adenocarcinoma of the colon or rectum that is metastatic and/or unresectable Unless contraindicated, participants must have received and failed regimens containing the following agents: fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody (bevacizumab, ramucirumab, or ziv-aflibercept), and an anti-PD-(L)1 therapy (nivolumab or pembrolizumab) if tumor has deficient mismatch repair proteins or is MSI-High. Have progression of unresectable or metastatic CRC after the last systemic therapy, or be intolerant of last systemic therapy Have RAS wild-type in primary or metastatic tumor tissue, based on expanded RAS testing Willing and able to provide the most recently available tissue blocks obtained prior to treatment initiation. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor Have confirmed HER2-positive mCRC, as defined by having tumor tissue tested at a Clinical Laboratory Improvement Act (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory, meeting at least one of the following criteria: HER2+ overexpression (3+ immunohistochemistry [IHC]) by an FDA-approved or Conformité Européene (CE)-marked HER2 ICH test HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved or CE-marked HER2 in situ hybridization assay (FISH or chromogenic in situ hybridization [CISH])) HER2 (ERBB2) amplification by CLIA-certified or ISO-accredited next generation sequencing (NGS) sequencing assay Have radiographically measurable disease assessable by RECIST 1.1, 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 (PS) of 0, 1, or 2 Life expectancy greater than 3 months Have adequate hematological, hepatic, renal, coagulation, and cardiac function Exclusion Criteria Previous treatment with anti-HER2 targeting therapy Previous treatment with any systemic anticancer therapy, non-central nervous system radiation, or experimental agent within 3 weeks of first dose of study treatment Toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions: Alopecia and neuropathy, which must have resolved to ≤ Grade 2 Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely Anemia, which must have resolved to ≤ Grade 2 Decreased ANC, which must have resolved to ≤ Grade 2 Have clinically significant cardiopulmonary disease Have known myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery within 6 months prior to first dose of study treatment Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to enrollment (≤56 days for hepatectomy, open thoracotomy, or major neurosurgery) or anticipation of need for major surgical procedure during the study Serious, non-healing wound, ulcer, or bone fracture Known to be positive for hepatitis B by surface antigen expression Known to have active hepatitis C infection Exception for participants with a documented sustained virologic response of 12 weeks Known to be positive for human immunodeficiency virus (HIV) Subjects who are pregnant, breastfeeding, or planning a pregnancy Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications Have used strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP2C8 or CYP3A4 inducer within 5 days prior to first dose of study treatment History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death Subjects with known active CNS metastasis Irradiated or resected lesions are permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for at least 30 days

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: Cohort A: Tucatinib + Trastuzumab<br>Non-randomized cohort. Participants take tucatinib twice per day orally on Days 1-21 and trastuzumab intravenously (into the vein; IV) on Day 1. Cycles repeat every 21 days. | Drug: Trastuzumab<br>* Given intravenously (into the vein; IV)<br>* Other names: Herceptin;Drug: Tucatinib<br>* Given orally<br>* Other names: TUKYSA;|
| Experimental: Cohort B: Tucatinib + Trastuzumab<br>Randomized cohort. Participants take tucatinib twice per day orally on Days 1-21 and trastuzumab intravenously (into the vein; IV) on Day 1. Cycles repeat every 21 days. | Drug: Trastuzumab<br>* Given intravenously (into the vein; IV)<br>* Other names: Herceptin;Drug: Tucatinib<br>* Given orally<br>* Other names: TUKYSA;|
| Experimental: Cohort C: Tucatinib Monotherapy<br>Randomized cohort. Participants take tucatinib twice per orally every day. Participants who do not respond to therapy may have the option to receive tucatinib and trastuzumab. | Drug: Tucatinib<br>* Given orally<br>* Other names: TUKYSA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (cORR) Per RECIST 1.1 Per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B | cORR is defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). | Up to 46.6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR by 12 Weeks of Treatment Per RECIST 1.1 According to BICR Assessment | ORR per BICR by 12 Weeks is defined as the percentage of participants with CR or PR by 12 weeks of treatment, and before time of crossover (Cohort C), whichever comes earlier. | Up to 3 months | 
| Duration of Response (DOR) Per RECIST 1.1 According to BICR Assessment | DOR is defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST 1.1 or death from any cause, whichever occurs first. | Up to 44.7 months | 
| Progression-Free Survival (PFS) Per RECIST 1.1 According to BICR Assessment for Pooled Cohorts A+B | PFS is defined as the time from start of study treatment (Cohort A) or date of randomization (Cohort B) to documented disease progression (as determined by BICR per RECIST 1.1) or death from any cause, whichever occurs first. | Up to 46.6 months | 
| Overall Survival (OS) in Pooled Cohorts A+B | OS is defined as the time from start of study treatment (Cohort A) or randomization (Cohort B) to date of death due to any cause. | Up to 53 months | 
| Number of Participants With Adverse Events (AEs) | An AE is any untoward medical occurrence in a patient or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs) are defined as events that are new or worsened on or after receiving the first dose of study treatment (tucatinib or trastuzumab) and up through 30 days after the last dose of study treatment (tucatinib or trastuzumab). | Up to 49.3 months | 
| Number of Participants With AEs Resulting in Dose Modification | Dose modification included dose reduction and dose withheld by investigator due to AEs. Dose holds were defined as any instances where planned administration of the study drug was temporarily withheld or interrupted at the direction of the treating physician. Dose reductions of trastuzumab were not allowed; if trastuzumab could not be restarted after being held for a TEAE, it was discontinued. | Up to 49.3 months | 
| Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology) | Treatment emergent laboratory abnormalities are defined as abnormalities that are new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. NCI CTCAE v5.0 is used for creatinine increased. NCI CTCAE v4.03 is used for the other lab parameters. | Up to 49.3 months | 
| Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry) | Treatment emergent laboratory abnormalities are defined as abnormalities that are new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. NCI CTCAE v5.0 is used for creatinine increased. NCI CTCAE v4.03 is used for the other lab parameters. | Up to 49.3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, ERBB2, Colorectal cancer, Seattle Genetics