Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer

Phase 2

Completed

• Conditions: Metastatic Colorectal Adenocarcinoma
• Interventions: Drug: Trastuzumab; Drug: Tucatinib

• Registration Number: NCT03043313
• Lead Sponsor: Seagen Inc.

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 available

Study Timeline

• Study First Submitted: 2017-01-31
• Study First Submitted QC: 2017-02-02
• Study First Posted: 2017-02-06
• Study Start: 2017-06-23
• Primary Completion: 2022-03-28
• Results First Submitted: 2023-01-27
• Results First Submitted QC: 2023-03-27
• Results First Posted: 2023-04-18
• Study Completion: 2023-11-02
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-31
• Last Update Posted: 2024-11-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 117

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A: Tucatinib + Trastuzumab	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.
Cohort A: Tucatinib + Trastuzumab	Tucatinib	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.
Cohort B: Tucatinib + Trastuzumab	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.
Cohort C: Tucatinib Monotherapy	Tucatinib	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.
Cohort B: Tucatinib + Trastuzumab	Tucatinib	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.

Primary Outcome Measures

Name	Time	Method
Confirmed Objective Response Rate (cORR) Per RECIST v1.1 Per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B	Up to 46.6 months	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.

Secondary Outcome Measures

Name	Time	Method
ORR by 12 Weeks of Treatment Per RECIST v1.1 According to BICR Assessment	Up to 3 months	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.
Duration of Response (DOR) Per RECIST v1.1 According to BICR Assessment	Up to 64.1 months	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.
Progression-Free Survival (PFS) Per RECIST v1.1 According to BICR Assessment for Pooled Cohorts A+B	Up to 64.1 months	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.
Overall Survival (OS) in Pooled Cohorts A+B	Up to 71.8 months	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.
Number of Participants With Adverse Events (AEs): Interim Analysis	Up to 49.3 months	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.
Number of Participants With AEs: Final Analysis	Up to 65.1 months	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.
Number of Participants With AEs Resulting in Dose Modification: Interim Analysis	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 AEs Resulting in Dose Modification: Final Analysis	Up to 65.1 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. Drug interruption included infusion interrupted (full dose received within 24hrs).
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis	Up to 49.3 months	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.
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis	Up to 65.1 months	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.
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis	Up to 49.3 months	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.
Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis	Up to 65.1 months	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.
Number of Participants With Clinically Significant Vital Signs: Final Analysis	Up to 65.1 months	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).

Trial Locations

Locations (56)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Banner MD Anderson Cancer Center; 🇺🇸 Gilbert, Arizona, United States

Mayo Clinic Arizona; 🇺🇸 Phoenix, Arizona, United States

Pacific Shores Medical Group; 🇺🇸 Long Beach, California, United States

Keck Medical Center / University of Southern California; 🇺🇸 Los Angeles, California, United States

Cedars Sinai Medical Center / Samuel Oschin Comprehensive Cancer Institute; 🇺🇸 Los Angeles, California, United States

Stanford University School of Medicine; 🇺🇸 Palo Alto, California, United States

Saint Joseph Heritage Medical Group; 🇺🇸 Santa Rosa, California, United States

Rocky Mountain Cancer Centers - Aurora; 🇺🇸 Aurora, Colorado, United States

Lombardi Cancer Center / Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

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