Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT03043313
• Recruitment Status: Completed
• First Posted: February 6, 2017
• Results First Posted: April 18, 2023
• Last Update Posted: November 13, 2023
• Sponsor: Seagen Inc.
• Collaborators: National Cancer Institute (NCI); Academic and Community Cancer Research United
• Information provided by (Responsible Party): Seagen Inc.

Tracking Information

• First Submitted Date: January 31, 2017
• First Posted Date: February 6, 2017
• Results First Submitted Date: January 27, 2023
• Results First Posted Date: April 18, 2023
• Last Update Posted Date: November 13, 2023
• Actual Study Start Date: June 23, 2017
• Actual Primary Completion Date: March 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 27, 2023)

Confirmed Objective Response Rate (cORR) Per RECIST 1.1 Per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B [ Time Frame: Up to 46.6 months ]

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).

Original Primary Outcome Measures (submitted: February 2, 2017)

Objective Response Rate (ORR) defined as achieving Complete Response (CR) or Partial Response (PR) [ Time Frame: Through study completion, an average of 7 months ]

ORR is defined as a complete response (CR) or partial response (PR) measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 over the treatment period, with the exception that 4-week confirmatory scans will not be required. The primary hypothesis will be tested in the cohort of eligible patients.

Current Secondary Outcome Measures (submitted: January 27, 2023)

• ORR by 12 Weeks of Treatment Per RECIST 1.1 According to BICR Assessment [ Time Frame: Up to 3 months ]
  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.
• Duration of Response (DOR) Per RECIST 1.1 According to BICR Assessment [ Time Frame: Up to 44.7 months ]
  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.
• Progression-Free Survival (PFS) Per RECIST 1.1 According to BICR Assessment for Pooled Cohorts A+B [ Time Frame: Up to 46.6 months ]
  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.
• Overall Survival (OS) in Pooled Cohorts A+B [ Time Frame: Up to 53 months ]
  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.
• Number of Participants With Adverse Events (AEs) [ Time Frame: Up to 49.3 months ]
  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).
• Number of Participants With AEs Resulting in Dose Modification [ Time Frame: Up to 49.3 months ]
  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.
• Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology) [ Time Frame: Up to 49.3 months ]
  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.
• Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry) [ Time Frame: Up to 49.3 months ]
  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.

Original Secondary Outcome Measures (submitted: February 2, 2017)

• Clinical Best Response (CBR) [ Time Frame: Up to 3 years ]
  Stable disease (SD) ≥6 months or best response of CR or PR estimated by 95% confidence interval estimates
• Overall Survival (OS) [ Time Frame: Up to 3 years ]
  Time from registration to time of death
• Progression Free Survival (PFS) [ Time Frame: Up to 3 years ]
  Time from registration to earliest date documentation off disease progression
• Duration of Response [ Time Frame: Up to 3 years ]
  For all eligible patients who have achieved an objective response, duration of response is defined as time from patient's earliest best objective status noted to be either CR or PR to the earliest date progression is documented.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Colorectal Adenocarcinoma

Intervention

• Drug: Trastuzumab
  Given intravenously (into the vein; IV)
  Other Name: Herceptin
• Drug: Tucatinib
  Given orally
  Other Names:

  • ARRY-380
  • ONT-380
  • TUKYSA

Study Arms

• Experimental: Cohort A: Tucatinib + Trastuzumab
  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.
  Interventions:

  • Drug: Trastuzumab
  • Drug: Tucatinib
• Experimental: Cohort B: Tucatinib + Trastuzumab
  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.
  Interventions:

  • Drug: Trastuzumab
  • Drug: Tucatinib
• Experimental: Cohort C: Tucatinib Monotherapy
  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.
  Intervention: Drug: Tucatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 30, 2021): 117
• Original Estimated Enrollment (submitted: February 2, 2017): 35
• Actual Study Completion Date: November 2, 2023
• Actual Primary Completion Date: March 28, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Italy, Spain, United States

Administrative Information

• NCT Number: NCT03043313
• Other Study ID Numbers: SGNTUC-017; NCI-2017-01107 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ACCRU-GI-1617 ( Other Identifier: Academic and Community Cancer Research United ); P30CA015083 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Seagen Inc.
• Original Responsible Party: Academic and Community Cancer Research United
• Current Study Sponsor: Seagen Inc.
• Original Study Sponsor: Academic and Community Cancer Research United

Collaborators

• National Cancer Institute (NCI)
• Academic and Community Cancer Research United

Investigators

• Study Chair: John H Strickler; Academic and Community Cancer Research United
• Study Director: Jorge Ramos, DO; Seagen Inc.

• PRS Account: Seagen Inc.
• Verification Date: November 2023