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Breast CancerPhase 2TUGETHERNCT04789096

Tucatinib Together With Pembrolizumab and Trastuzumab

A Phase 2 study testing Tucatinib, Pembrolizumab and Trastuzumab in people with Breast Cancer and HER2-positive Breast Cancer, run by Breast Cancer Trials, Australia and New Zealand at 15 sites in Australia.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

Women or men with HER2-positive, metastatic breast cancer, who have progressed on previous treatment, will receive tucatinib in combination with pembrolizumab and trastuzumab (PD-L1 positive). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Breast Cancer, HER2-positive Breast Cancer
What is being tested?
Tucatinib, Pembrolizumab and Trastuzumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
15 sitesAustralia
Study dates
7 Mar 2023to 4 Jun 2026
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Has provided written, informed consent to participate in the study.
  • Female or male, age ≥ 18 years.
  • Local histologically confirmed HER2-positive unresectable loco-regional or metastatic breast cancer. HER2-positive according to ASCO CAP 2018 guidelines defined as:
  • ISH testing with ERBB2-amplification as demonstrated by ratio ERBB2/centromeres ≥ 2.0 or mean gene copy number ≥ 6 OR
  • 3+ staining by IHC.
  • FFPE tumour samples (preferably two blocks) available from newly obtained biopsies of advanced disease for assessment of PD-L1, TILs status and correlative research. If new biopsies are not obtainable then primary/metastatic archival biopsies (preferably two samples) from within 12 months of registration may be provided.For those participants whose tissue is unavailable despite best efforts (e.g. inadequate sample or primary tumour lost/discarded), please discuss with BCT and the Study Chairs.
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  • Must have previously received taxane, trastuzumab, pertuzumab and an antibody-drug conjugate (ADC) in either the (neo) adjuvant or advanced disease setting. Any number of prior lines of anti-HER2 therapy is acceptable.
  • Have progression of unresectable locally advanced or metastatic breast cancer during or after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.
  • Have a life expectancy of at least 6 months, in the opinion of the investigator.
  • Women of childbearing potential (WOCBP) and men with partners of childbearing potential must agree to use a highly effective contraception from the signing of informed consent until 7 months after the last dose of protocol treatment.
  • Note: Use of oral, injectable or implant hormonal contraceptives or medicated IUD must stop before registration.
  • Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations during both the treatment and follow-up phases.
  • In addition to the above listed pre-registration inclusion criteria, participants must fulfill all the following criteria before registration:
  • Confirmed submission to the central laboratory of tumour tissue for PD-L1 status to determine cohort . For those participants whose tissue is unavailable for testing, individual cases must be discussed with BCT and the Study Chairs. Note: the first 10 participants will be reviewed for PD-L1 positivity rates
  • Have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  • Have measurable disease assessable by RECIST v1.1.
  • Must have one of the following (based on screening brain MRI):
  • No evidence of brain metastases OR b) Untreated brain metastases not needing immediate local therapy. Participants with CNS measurable disease by RECIST 1.1 criteria, with or without measurable extracranial disease by RECIST are eligible. For participants with untreated CNS lesions > 2.0 cm on screening MRI, discussion with and approval from BCT and the Study Chair is required before registration OR c) Previously treated brain metastases: i) Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local brain metastasis therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator.
  • Participants treated with CNS local therapy for newly identified lesions found on initial MRI performed during screening for this study may be eligible if the following criteria are met: (1) Time since whole brain radiation therapy (WBRT) is ≥ 14 days before registration, or (2) Time since stereotactic radiosurgery is ≥ 7 days before registration, or time since surgical resection is ≥ 28 days (3) Other sites of disease assessable by RECIST 1.1. are present.
  • Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions.
  • Have a left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 8 weeks before registration.
  • Have adequate haematological, coagulation, hepatic and renal functions within 7 days before registration as defined as:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
  • Platelet count ≥ 100 x 10^9/L
  • Haemoglobin ≥ 90 g/L
  • Creatinine ≤ 1.5 x ULN or serum creatinine clearance > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance:
  • Serum total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). In the case of known Gilbert's disease, serum total bilirubin < 2 x ULN is allowed
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5 x ULN
  • International normalised ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless on medication known to alter INR and aPTT (Note: Warfarin and other coumarin derivatives are prohibited).
  • Evidence of post-menopausal status, or negative urine or serum pregnancy test for female pre-menopausal participants. Women who have undergone surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy/tubal ligation, or hysterectomy) do not require pregnancy testing. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women < 50 years of age would be considered post-menopausal/non-fertile if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments or chemotherapy (whichever is most recent) and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution.
  • b) Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, or had chemotherapy-induced menopause with last menses > 1 year ago.

Who cannot join

  • Any one of the following is regarded as a criterion for exclusion from pre-registration to the study:
  • Previously treated with:
  • Lapatinib within 12 months of registration OR
  • Neratinib or afatinib within 12 months of registration, unless ceased due to toxicity and not progression.
  • Prior anti-PD-1, anti-PD-L1/L2 or anti-CTLA4 therapy, including, but not limited to: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab.
  • Previous severe hypersensitivity reaction to treatment with TKI or monoclonal antibody that is biologically similar to the study treatments.
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  • Known leptomeningeal disease as documented/determined by the investigator.
  • Have poorly controlled (> 1/week) generalised or complex partial seizures, or manifest neurologic progression due to brain metastases despite CNS-directed therapy.
  • History of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification ≥ 3), angina, myocardial infarction or ventricular arrhythmia. Have known myocardial infarction or unstable angina within 6 months before registration.
  • Active or history of autoimmune disease or immune deficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
  • History of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible
  • Stable diabetes mellitus are eligible
  • Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g. patients with psoriatic arthritis are excluded) are eligible provided ALL the following conditions are met:
  • Rash must cover < 10% of body surface area ii) Disease is well controlled at baseline and requires only low-potency topical corticosteroids iii) No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
  • Known human immunodeficiency virus (HIV) (HIV1/2antibodies) or active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).
  • Participants with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible
  • Participants positive for HCV antibody are eligible only if polymerase change reaction is negative for HCV RNA.
  • Pregnant, breastfeeding or planning a pregnancy; lactating participants must stop breast feeding before registration.
  • Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed).
  • Unable to swallow pills or has significant gastrointestinal disease which would preclude the adequate oral absorption of medications.
  • Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current active pneumonitis/interstitial lung disease.
  • History of current active tuberculosis.
  • Has had an allogenic tissue/solid organ transplant.
  • History of uncontrolled hypertension (≥ 180/110), dyspnoea at rest, or chronic therapy with oxygen.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
  • In addition to the above listed pre-registration exclusion criteria, any one of the following is regarded as a criterion for exclusion from registration to the study:
  • Have received treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation or experimental agent within 28 days of registration, except for participants with ER-positive breast cancer.
  • Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
  • Alopecia
  • Neuropathy, which must have resolved to ≤ Grade 2
  • Menopausal symptoms.
  • Any untreated brain lesions > 2.0 cm in size, unless discussed with BCT and Study Chair and approval for registration is given.
  • Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent). However, patients on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by BCT and the Study Chair.
  • Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related oedema may pose risk to patient (e.g. brain stem lesions). Participants who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under Registration Inclusion Criteria 4.
  • Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 450 ms from a single ECG.
  • Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days before the first dose of study treatment. Use of sensitive CYP3A substrates should be avoided 2 weeks before registration and during study treatment.
  • Treatment with botanical preparations (e.g. herbal supplements) and traditional Chinese medicines, intended for general health support or to treat the disease under study, within 7 days before registration.
  • Active infection requiring systemic therapy.
  • Administration of a live/live attenuated vaccine within 30 days before registration.
  • Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

Australia15 sites

  • Royal Adelaide Hospital

    Adelaide, South Australia, 5000

  • Sunshine Coast University Hospital

    Birtinya, Queensland, 4575

  • Coffs Harbour Health Campus

    Coffs Harbour, New South Wales, 2450

  • Gosford Hospital

    Gosford, New South Wales, 2250

  • Austin Hospital

    Heidelberg, Victoria, 3084

  • Icon Cancer Centre Hobart

    Hobart, Tasmania, 7000

  • Nepean Cancer Care Centre

    Kingswood, New South Wales, 2747

  • Macquarie University

    Macquarie Park, New South Wales, 2109

  • Peter MacCallum Cancer Centre

    Parkville, Victoria, 3002

  • Prince of Wales Hospital

    Randwick, New South Wales, 2031

  • Epworth Richmond Hospital

    Richmond, Victoria, 3121

  • Sunshine Hospital

    St Albans, Victoria, 3021

  • Calvary Mater Newcastle

    Waratah, New South Wales, 2310

  • Westmead Hospital

    Westmead, New South Wales, 2145

  • Wollongong Hospital

    Wollongong, New South Wales, 2500

Other trials in Australia

About this study

Official title: A Phase II, Two-arm, Non-comparative, Multicentre Study of Tucatinib (ONT-380), Pembrolizumab and Trastuzumab in Patients With Pre-treated Advanced HER2-positive Breast Cancer

Women or men with HER2-positive, metastatic breast cancer, who have progressed on previous treatment, will receive tucatinib in combination with pembrolizumab and trastuzumab (PD-L1 positive).

Read the detailed description

Despite significant advances in systemic treatment options, advanced HER2-positive breast cancer post treatment with trastuzumab, pertuzumab and T-DM1 still remains incurable, with brain metastases remaining a major cause of patient morbidity and mortality.

HER2-positive breast cancers have relatively high tumour infiltrating lymphocytes (TILs) that may be targeted with immune checkpoint blockade. Studies in metastatic breast cancer with PD1 or PD-L1 inhibition have shown an overall survival (OS) benefit for those that are enriched for pre-existing immunity, such as positive expression of PD-L1 protein or TILs present.

One of the main areas of disease progression in HER2 positive disease is in the central nervous system (CNS), supporting the need to find an effective combination for patients with brain metastases.

Tucatinib (ONT-380) is a potent, highly selective, oral HER2 small molecule tyrosine kinase inhibitor (TKI) with demonstrated clinical benefit notable for its minimal inducement of EGFR-type toxicities when administered in combination-type studies including proven intra-cranial efficacy in studies of patients with brain metastases.

The investigators hypothesise that the combination of tucatinib with trastuzumab and PD-1 inhibition will result in a similar ORR as that seen in HER2CLIMB, along with comparable PFS and duration of response, particularly through prevention and treatment of CNS metastases. The potential advantage of adding PD-1 inhibition and omitting capecitabine in the PD-L1 positive group is to increase the durability of the response, with hopefully less added toxicity for patients. The investigators believe this regimen will result in comparable outcomes as those seen in HER2CLIMB, with fewer adverse events. Importantly, the side effect profiles of all agents in our proposed combination are non-overlapping and this combination provides a unique opportunity for excellent tolerability and durable disease control in this patient group. The study design initially included two treatment cohorts, with the PD-L1 negative/unknown cohort being treated with the HER2CLIMB regimen with the addition of pembrolizumab (MK-3475), under the hypothesis that the anti-tumour activity of this regimen will overcome the lower immunogenicity of this subgroup. However, Protocol Amendment 2 will omit capecitabine in the PD-L1 negative/unknown cohort due to a high frequency of liver test abnormalities within the first seven participants in this cohort.

Being tested
Tucatinib, Pembrolizumab, Trastuzumab, Capecitabine
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TucatinibDrug

    Also called Tukysa

    Oral tablet

  • PembrolizumabDrug

    Also called Keytruda

    Intravenous

  • TrastuzumabDrug

    Also called Herceptin

    Intravenous

  • CapecitabineDrug

    Also called Xeloda

    Oral tablet

Study groups in NCT04789096
Study groupRoleWhat they receive
TUGETHER TreatmentExperimentalParticipants will receive: * Tucatinib (oral) at a dose of 300 mg BD on day 1-21 of each 21-day cycle * Pembrolizumab will be administered at a dose of 200 mg IV on day 1 of each 21 day cycle * Trastuzumab will be given as a loading dose of 8 mg/kg IV (if loading required, otherwise 6 mg/kg) on day 1 followed by 6 mg/kg on day 1 of each 21 day cycle. Participants registered to PD-L1 negative/unknown cohort prior to Protocol Amendment 2 received Capecitabine 1000 mg/m^2 day 1-14 of each 21 day cycle.
Receives: Drug: Tucatinib; Drug: Pembrolizumab; Drug: Trastuzumab; Drug: Capecitabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective Response Rate (ORR) in the PD-L1 positive cohort

    Defined as complete response (CR) or partial response (PR) assessed as per RECIST 1.1

    Measured: Through to study completion, an average of 24 months

Secondary outcomes (8)

  1. Objective response rate (ORR) in the PD-L1 negative/unknown cohort

    Defined as complete response (CR) or partial response (PR) assessed as per RECIST 1.1

    Measured: Through to study completion, an average of 24 months

  2. Progression free survival (PFS) in each PD-L1 cohort

    Defined as the time from start of study treatment until documented disease progression by RECIST 1.1 or death due to any cause (whichever occurs first) based on local investigator assessment.

    Measured: From the time of registration until documented disease progression by RECIST 1.1 or death due to any cause (whichever occurs first), assessed up to 24 months

  3. Duration of response (DoR) in each PD-L1 cohort

    Defined as the time from first documentation of CR or PR by RECIST 1.1 to first documentation of progressive disease or death, in the subset of participants with objective response.

    Measured: From the time of registration to first documentation of progressive disease or death, assessed up to 24 months

  4. Clinical benefit rate (CBR) in each PD-L1 cohort

    Defined as stable disease (SD) for >= 6 months after starting study treatment, or best response of CR or PR.

    Measured: From time of registration to CR or PR, assessed up to 24 months

  5. Overall survival (OS) in each PD-L1 cohort

    Defined as from the time from start of study treatment to death from any cause

    Measured: From time of registration until death from any cause, assessed at 24 months

  6. Incidence of treatment-emergent adverse events [Safety]

    Assessed as worst grade of adverse events (AEs) and serious adverse events (SAE) documented using NCI-CTCAE 5.0.

    Measured: From registration until 30 days after end of study treatment

  7. Incidence of treatment-emergent adverse events [Tolerability of tucatinib]

    Assessed by tucatinib dose holding, dose reduction, drug discontinuation.

    Measured: From start of study treatment to the end of study treatment, assessed at 24 months

  8. Incidence of treatment-emergent adverse events [Tolerability of pembrolizumab]

    Assessed by pembrolizumab dose holding, dose reduction, drug discontinuation.

    Measured: From start of study treatment to end of study treatment, assessed at 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Mar 2021
  2. Study start7 Mar 2023
  3. Primary completion4 Jun 2025
  4. Study completion4 Jun 2026

Why it stopped: Stopped on the recommendation of the BCT Independent Data and Monitoring Committee

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04789096
Sponsor's protocol ID
BCT 2102
Acronym
TUGETHER
Status last verified
Sep 2026
First submitted
1 Mar 2021
Last updated
30 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Refer to BCT Data Sharing Guidelines (contact concept@bctrials.org.au for further details).

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tucatinib, Pembrolizumab and Trastuzumab in people with Breast Cancer and HER2-positive Breast Cancer, run by Breast Cancer Trials, Australia and New Zealand at 15 sites in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 30 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Stopped on the recommendation of the BCT Independent Data and Monitoring Committee). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response Rate (ORR) in the PD-L1 positive cohort (time frame: Through to study completion, an average of 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04789096.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2026.

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