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NCT Number: NCT03975647

A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer

This study is being done to see if tucatinib with ado-trastuzumab emtansine (T-DM1) works better than T-DM1 alone to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery.

Patients in this study will be randomly assigned to get either tucatinib or placebo (a pill with no medicine). This is a blinded study, so neither patients nor their doctors will know whether a patient gets tucatinib or placebo. All patients in the study will get T-DM1, a drug that is often used to treat this cancer.

Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills or placebo pills two times every day. Patients will get T-DM1 injections from the study site staff on the first day of every cycle.

Active, Not Recruiting

This study is active but is not currently recruiting participants.

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Key information

Conditions

HER2-positive Breast Cancer

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Patricia Ritchie Centre for Cancer Care and Research Mater Hospital Sydney, North Sydney, New South Wales, Australia

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About this study

This study is designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in participants with unresectable locally-advanced or metastatic HER2+ breast cancer who have had prior treatment with a taxane and trastuzumab in any setting. Prior pertuzumab treatment is permitted, but not required. Participants will be randomized in a 1:1 manner to receive 21-day cycles of either tucatinib or placebo in combination with T-DM1.

While on study treatment, participants will be assessed for progression every 6 weeks for the first 24 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions. Study treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study closure. After completion of study treatment and after occurrence of disease progression, participants in both arms of the study will continue to be followed for survival until study closure or withdrawal of consent.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

  • Inclusion Criteria:
  • Histologically confirmed HER2+ breast carcinoma as determined by a sponsor-designated central laboratory
  • History of prior treatment with a taxane and trastuzumab in any setting, separately or in combination
  • Have progression of unresectable locally advanced/metastatic breast cancer after last systemic therapy, or be intolerant of last systemic therapy
  • Measurable or non-measurable disease assessable by RECIST v1.1
  • ECOG performance status score of 0 or 1
  • CNS Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), participants must have at least one of the following:

(a) No evidence of brain metastases

(b) Untreated brain metastases not needing immediate local therapy

(c) Previously treated brain metastases

  • Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy
  • Participants treated with CNS local therapy for newly identified lesions or previously treated and progressing lesions may be eligible to enroll if all of the following criteria are met:

(i) Time since SRS is at least 7 days prior to first dose of study treatment, time since WBRT is at least 14 days prior to first dose, or time since surgical resection is at least 28 days.

(ii) Other sites of evaluable disease are present

  • Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
  • Exclusion Criteria:
  • Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib or neratinib within 12 months of starting study treatment (except in cases where they were given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity). Prior treatment with pyrotinib for recurrent of mBC (except in cases where pyrotinib was given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity).
  • CNS Exclusion - Based on screening contrast brain magnetic resonance imaging (MRI), participants must not have any of the following:
  • Any untreated brain lesions >2 cm in size
  • Ongoing use of corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent).
  • Any brain lesion thought to require immediate local therapy
  • Known or concurrent leptomeningeal disease as documented by the investigator
  • Poorly controlled generalized or complex partial seizures

Treatment and study plan

Tucatinib

Drug

300mg given twice per day by mouth (orally)

Other names: ONT-380

Placebo

Drug

Given twice per day orally

T-DM1

Drug

3.6 mg/kg given into the vein (IV; intravenously) every 21 days

Other names: Kadcyla

Primary outcomes

  1. Progression-Free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1 Based on Investigator Assessment

    Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)

    PFS as per investigator was defined as the time from the date of randomization to the investigator assessment of disease progression (PD) as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimiter (mm). Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment.

Secondary outcomes

  1. Overall Survival (OS)

    Time frame: Up to approximately 5 years

    OS was defined as the time from randomization to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on the date the participant was last known to be alive (i.e., the date of last contact).

  2. Progression-Free Survival as Per RECIST v1.1 in Participants With Brain Metastases at Baseline Based on Investigator Assessment

    Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 45 months)

    PFS as per investigator was defined as the time from the date of randomization to the investigator assessment of PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. PFS was analyzed in participants with presence or history of brain metastases.

  3. Objective Response Rate (ORR) as Per RECIST v1.1 Based on Investigator Assessment

    Time frame: From the date of first CR or PR until the date of the first documentation of PD or death, whichever occurred first (maximum up to 43 months)

    ORR was defined as the percentage of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<)10 mm. PR: a greater than equal (>=) 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For a response to be considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial response. ORR by investigator assessment is based on investigator response assessments. Two-sided 95% exact confidence interval, computed using the Clopper-Pearson method.

  4. Overall Survival in Participants With Brain Metastases at Baseline

    Time frame: Up to approximately 5 years

    OS was defined as the time from randomization to death due to any cause. For a participant who was not known to have died by the end of study follow-up, observation of OS was censored on the date the participant was last known to be alive (i.e., the date of last contact). OS was analyzed in participants with presence or history of brain metastases.

  5. Progression-Free Survival as Per RECIST v1.1 Determined by Blinded Independent Committee Review (BICR)

    Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)

    PFS as per BICR was defined as the time from the date of randomization to the centrally-reviewed documented PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documented progression of PD or death at the time of analysis were censored at the date of the last tumor assessment.

  6. Progression-Free Survival in Participants With Brain Metastases at Baseline as Per RECIST v1.1 Determined by BICR

    Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)

    PFS as per BICR was defined as the time from the date of randomization to the centrally-reviewed documented PD as per RECIST v1.1 or death from any cause, whichever occurred first. PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS was analyzed in participants with presence or history of brain metastases.

  7. Objective Response Rate as Per RECIST v1.1 Determined by BICR

    Time frame: From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to 43 months)

    ORR was defined as the percentage of participants with confirmed CR or PR according to RECIST v1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: A >= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR per BICR is based on BICR response assessments.

  8. Duration of Response (DOR) as Per RECIST v1.1 Based on Investigator Assessment

    Time frame: Up to approximately 5 years

    DOR was defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD as per RECIST v1.1 PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: A>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR per investigator was based on investigator response assessments.

  9. Duration of Response as Per RECIST v1.1 by BICR

    Time frame: Up to approximately 5 years

    DOR was defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD as per RECIST v1.1 PD: at least a 20 % increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants without documentation of PD, or death at the time of analysis were censored at the date of the last tumor assessment. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: A>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR per BICR was based on BICR response assessments.

  10. Clinical Benefit Rate (CBR) Per RECIST v1.1 Based on Investigator Assessment

    Time frame: Up to approximately 5 years

    CBR was defined as the percentage of participants with stable disease (SD) or non-CR or non-PD >= 6 months or best response of CR or PR according to RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: A >= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CBR was based on investigator assessment.

  11. Clinical Benefit Rate as Per RECIST v1.1 by BICR

    Time frame: Up to approximately 5 years

    CBR was defined as the percentage of participants with SD or non-CR or non-PD >= 6 months or best response of CR or PR according to RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: A >= 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CBR per BICR is based on BICR response assessments.

  12. Number of Participants With Treatment Emergent Adverse Events (AEs)

    Time frame: From start of treatment up to 30 days after the last study treatment (approximately 43 months)

    An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAE was defined as AE that is newly occurred or worsened after the start of study treatment.

Sponsors and collaborators

Lead sponsor

Seagen, a wholly owned subsidiary of Pfizer

Industry

Registry information

Official study title

Randomized, Double-blind, Phase 3 Study of Tucatinib or Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Subjects With Unresectable Locally-advanced or Metastatic HER2+ Breast Cancer (HER2CLIMB-02)

Important dates

Study start
2019
Primary completion
2023
Study completion
2029
First posted
Jun 5, 2019
Registry last updated
Jul 23, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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