Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Adenocarcinoma
• Intervention / Treatment: Drug: Trastuzumab; Drug: Tucatinib

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Other
    • Brussels, Other, Belgium, 1200
      • Cliniques Universitaires Saint Luc
    • Edegem, Other, Belgium, 2650
      • Universitair Ziekenhuis Antwerpen
    • Leuven, Other, Belgium, 3000
      • Uz Leuven Campus Gasthuisberg
• France
  • Other
    • Besancon, Other, France, 25030
      • Hospitalier Jean Minjoz
    • Dijon, Other, France, 21000
      • Center Georges Francois Leclerc
    • Levallois-Perret, Other, France, 92300
      • Hopital Franco-Britannique - Fondation Cognacq-Jay
    • Lyon, Other, France, 69373
      • Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes
    • Paris, Other, France, 75012
      • Hopital Saint-Antoine
• Italy
  • Other
    • Milan, Other, Italy, 20141
      • Instituto Europeo di Oncologia
    • Milan, Other, Italy, 20162
      • Niguarda Ca' Granda Hospital
    • Pisa, Other, Italy, 56126
      • Azienda Ospedaliero-Universitaria Pisana - Ospedale S. Chiara
• Spain
  • Other
    • Barcelona, Other, Spain, 08035
      • Hospital Universitario Vall d'Hebron
    • L'Hospitalet de Llobregat, Other, Spain, 08907
      • Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
    • Madrid, Other, Spain, 28007
      • Hospital General Universitario Gregorio Marañon
    • Valencia, Other, Spain, 46010
      • Hospital Clínico Universitario de Valencia
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • Long Beach, California, United States, 90813
      • Pacific Shores Medical Group
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center / Samuel Oschin Comprehensive Cancer Institute
    • Los Angeles, California, United States, 90033
      • Keck Medical Center / University of Southern California
    • Palo Alto, California, United States, 94304
      • Stanford University School of Medicine
    • Santa Rosa, California, United States, 95403
      • Saint Joseph Heritage Medical Group
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers - Aurora
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Cancer Center / Georgetown University Medical Center
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists - South Region
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists - North Region
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute / Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute / Wayne State University
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University / University Hospitals Cleveland Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Northwest Cancer Specialists, P.C.
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology-Nashville/Sarah Cannon Research Institute
  • Texas
    • Beaumont, Texas, United States, 77702-1449
      • Texas Oncology - Beaumont
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Sammons Cancer Center
    • Lubbock, Texas, United States, 79410
      • Joe Arrington Cancer Research and Treatment Center
    • McAllen, Texas, United States, 78503
      • Texas Oncology - McAllen
    • San Antonio, Texas, United States, 78240
      • Texas Oncology - San Antonio Medical Center
    • Tyler, Texas, United States, 75702
      • Texas Oncology - Tyler
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Regional Medical Center Everett
    • Seattle, Washington, United States, 98109-1023
      • Seattle Cancer Care Alliance / University of Washington
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora Research Institute Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Trastuzumab; Given intravenously (into the vein; IV); Other Names: Herceptin; Drug: Tucatinib; Given orally; Other Names: ONT-380; TUKYSA; ARRY-380
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.	Drug: Trastuzumab; Given intravenously (into the vein; IV); Other Names: Herceptin; Drug: Tucatinib; Given orally; Other Names: ONT-380; TUKYSA; ARRY-380
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.	Drug: Tucatinib; Given orally; Other Names: ONT-380; TUKYSA; ARRY-380

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Objective Response Rate (cORR) Per RECIST v1.1 Per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B	cORR was defined as the percentage of participants with confirmed CR or PR according to RECIST v1.1. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to less than (<)1.0 centimeter (cm). PR was defined as at least a 30 percentage (%) decrease in post-baseline sum of the diameters (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of diameters.	Up to 46.6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR by 12 Weeks of Treatment Per RECIST v1.1 According to BICR Assessment	ORR per BICR by 12 Weeks was defined as the percentage of participants with CR or PR by 12 weeks of treatment, and before time of crossover (Cohort C), whichever came earlier. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to more than <1.0 cm. PR was defined as at least a 30% decrease in post-baseline sum of the diameters (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of diameter.	Up to 3 months
Duration of Response (DOR) Per RECIST v1.1 According to BICR Assessment	DOR was defined as the time from the first objective response (CR or PR that is subsequently confirmed) to documented PD per RECIST v1.1 or death from any cause, whichever occurred first. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to more than <1.0 cm. PR was defined as at least a 30% decrease in post-baseline sum of the diameters (PBSD) (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the BSD. PD was defined as: at least one new malignant lesion, which also includes any lymph node that was normal at baseline (<1.0 cm short axis) and increased to more than or equal to (>=)1.0 cm short axis during follow-up or at least a 20% increase in PBSD taking as reference the minimum sum of the diameters (MSD). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD.	Up to 64.1 months
Progression-Free Survival (PFS) Per RECIST v1.1 According to BICR Assessment for Pooled Cohorts A+B	PFS was 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 v1.1) or death from any cause, whichever occurred first. PD was defined as: at least one new malignant lesion, which also included any lymph node that was normal at baseline (<1.0 cm short axis) and increased to >=1.0 cm short axis during follow-up or at least a 20% increase in post-baseline sum of the diameters (PBSD) taking as reference the minimum sum of the diameters (MSD). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD.	Up to 64.1 months
Overall Survival (OS) in Pooled Cohorts A+B	OS was 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 71.8 months
Number of Participants With Adverse Events (AEs): Interim Analysis	AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs): Events that were 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). Serious AE (SAE): An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness was judged by investigator According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE.	Up to 49.3 months
Number of Participants With AEs: Final Analysis	AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Treatment emergent AEs (TEAEs): Events that were 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). SAE: An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness was judged by investigator According to NCI CTCAE version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE.	Up to 65.1 months
Number of Participants With AEs Resulting in Dose Modification: Interim Analysis	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 AEs Resulting in Dose Modification: Final Analysis	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. Drug interruption included infusion interrupted (full dose received within 24hrs).	Up to 65.1 months
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis	The following hematology laboratory parameters were assessed: Hemoglobin decreased; leukocytes decreased; neutrophils decreased and Platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities that were 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 v4.03 was used for the lab parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.	Up to 49.3 months
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis	The following hematology laboratory parameters were assessed: Hemoglobin decreased; hemoglobin increased; leukocytes decreased; lymphocytes decreased; neutrophils decreased and Platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities that were 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 v4.03 was used for the lab parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.	Up to 65.1 months
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis	The following chemistry laboratory parameters were assessed: Potassium increased; potassium decreased; aspartate aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased. Treatment emergent laboratory abnormalities were defined as abnormalities that were 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 was used for creatinine increased. NCI CTCAE v4.03 was used for the other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.	Up to 49.3 months
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis	The following chemistry laboratory parameters were assessed: Potassium increased; potassium decreased; aspartate aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased; albumin decreased; calcium corrected for albumin decreased; calcium corrected for albumin increased; glomerular filtration rate (GFR), estimated decreased; glucose decreased; glucose increased; sodium decreased; sodium increased; calcium and ionized increased. Treatment emergent laboratory abnormalities: Abnormalities that were 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 used for creatinine increased. NCI CTCAE v4.03 used for the other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening.	Up to 65.1 months
Number of Participants With Clinically Significant Vital Signs: Final Analysis	Vital signs included temperature, oxygen saturation, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and weight. Vital signs were considered clinically significant: temperature: >= 38 degree Celsius (C); oxygen saturation less than (<)88%; SBP >=120 millimeters of mercury (mmHg) or DBP >=80 mmHg; SBP >=140 mmHg or DBP >=90 mmHg; SBP >=160 mmHg or DBP >=100 mmHg and heart rate >100 beats per minute (bpm) and maximum decrease from baseline in weight in kilograms (kg).	Up to 65.1 months

Collaborators and Investigators

• Sponsor: Seagen Inc.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2017
• Primary Completion (Actual): March 28, 2022
• Study Completion (Actual): November 2, 2023

Study Registration Dates

• First Submitted: January 31, 2017
• First Submitted That Met QC Criteria: February 2, 2017
• First Posted (Estimated): February 6, 2017

Study Record Updates

• Last Update Posted (Estimated): November 26, 2024
• Last Update Submitted That Met QC Criteria: October 31, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Colorectal cancer; HER2; Seattle Genetics; ERBB2
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Trastuzumab; Tucatinib
• Other Study ID Numbers: SGNTUC-017; P30CA015083 (U.S. NIH Grant/Contract); NCI-2017-01107 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); ACCRU-GI-1617 (Other Identifier: Academic and Community Cancer Research United)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No