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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04789096


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT04789096
Ethics application status
Date submitted
1/03/2021
Date registered
9/03/2021

Titles & IDs
Public title
Tucatinib Together With Pembrolizumab and Trastuzumab
Scientific 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
Secondary ID [1] 0 0
BCT 2102
Universal Trial Number (UTN)
Trial acronym
TUGETHER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
HER2-positive Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tucatinib
Treatment: Drugs - Pembrolizumab
Treatment: Drugs - Trastuzumab
Treatment: Drugs - Capecitabine

Experimental: TUGETHER Treatment - Participants 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.


Treatment: Drugs: Tucatinib
Oral tablet

Treatment: Drugs: Pembrolizumab
Intravenous

Treatment: Drugs: Trastuzumab
Intravenous

Treatment: Drugs: Capecitabine
Oral tablet
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective Response Rate (ORR) in the PD-L1 positive cohort
Timepoint [1] 0 0
Through to study completion, an average of 24 months
Secondary outcome [1] 0 0
Objective response rate (ORR) in the PD-L1 negative/unknown cohort
Timepoint [1] 0 0
Through to study completion, an average of 24 months
Secondary outcome [2] 0 0
Progression free survival (PFS) in each PD-L1 cohort
Timepoint [2] 0 0
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
Secondary outcome [3] 0 0
Duration of response (DoR) in each PD-L1 cohort
Timepoint [3] 0 0
From the time of registration to first documentation of progressive disease or death, assessed up to 24 months
Secondary outcome [4] 0 0
Clinical benefit rate (CBR) in each PD-L1 cohort
Timepoint [4] 0 0
From time of registration to CR or PR, assessed up to 24 months
Secondary outcome [5] 0 0
Overall survival (OS) in each PD-L1 cohort
Timepoint [5] 0 0
From time of registration until death from any cause, assessed at 24 months
Secondary outcome [6] 0 0
Incidence of treatment-emergent adverse events [Safety]
Timepoint [6] 0 0
From registration until 30 days after end of study treatment
Secondary outcome [7] 0 0
Incidence of treatment-emergent adverse events [Tolerability of tucatinib]
Timepoint [7] 0 0
From start of study treatment to the end of study treatment, assessed at 24 months
Secondary outcome [8] 0 0
Incidence of treatment-emergent adverse events [Tolerability of pembrolizumab]
Timepoint [8] 0 0
From start of study treatment to end of study treatment, assessed at 24 months

Eligibility
Key inclusion criteria
Inclusion Criteria (Pre-Registration):

1. Has provided written, informed consent to participate in the study.
2. Female or male, age = 18 years.
3. Local histologically confirmed HER2-positive unresectable loco-regional or metastatic breast cancer. HER2-positive according to ASCO CAP 2018 guidelines defined as:

1. ISH testing with ERBB2-amplification as demonstrated by ratio ERBB2/centromeres = 2.0 or mean gene copy number = 6 OR
2. 3+ staining by IHC.
4. 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.
5. 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.
6. 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.
7. Have a life expectancy of at least 6 months, in the opinion of the investigator.
8. 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.
9. 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.

Inclusion Criteria (Registration):

In addition to the above listed pre-registration inclusion criteria, participants must fulfill all the following criteria before registration:

1. 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
2. Have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
3. Have measurable disease assessable by RECIST v1.1.
4. Must have one of the following (based on screening brain MRI):

a) 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.

ii) 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.
5. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions.
6. 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.
7. Have adequate haematological, coagulation, hepatic and renal functions within 7 days before registration as defined as:

1. Absolute neutrophil count (ANC) = 1.5 x 10^9/L
2. Platelet count = 100 x 10^9/L
3. Haemoglobin = 90 g/L
4. 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:
5. 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
6. 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
7. 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).
8. 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:

1. 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.
2. 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria (Pre-Registration):

Any one of the following is regarded as a criterion for exclusion from pre-registration to the study:

1. Previously treated with:

1. Lapatinib within 12 months of registration OR
2. Neratinib or afatinib within 12 months of registration, unless ceased due to toxicity and not progression.
2. Prior anti-PD-1, anti-PD-L1/L2 or anti-CTLA4 therapy, including, but not limited to: pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab.
3. Previous severe hypersensitivity reaction to treatment with TKI or monoclonal antibody that is biologically similar to the study treatments.
4. Known leptomeningeal disease as documented/determined by the investigator.
5. Have poorly controlled (> 1/week) generalised or complex partial seizures, or manifest neurologic progression due to brain metastases despite CNS-directed therapy.
6. 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.
7. 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:

1. History of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible
2. Stable diabetes mellitus are eligible
3. 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:

i) 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.
8. Known human immunodeficiency virus (HIV) (HIV1/2antibodies) or active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).

1. 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
2. Participants positive for HCV antibody are eligible only if polymerase change reaction is negative for HCV RNA.
9. Pregnant, breastfeeding or planning a pregnancy; lactating participants must stop breast feeding before registration.
10. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed).
11. Unable to swallow pills or has significant gastrointestinal disease which would preclude the adequate oral absorption of medications.
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current active pneumonitis/interstitial lung disease.
13. History of current active tuberculosis.
14. Has had an allogenic tissue/solid organ transplant.
15. History of uncontrolled hypertension (= 180/110), dyspnoea at rest, or chronic therapy with oxygen.
16. 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.

Exclusion Criteria (Registration):

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:

1. 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.
2. Have any toxicity related to prior cancer therapies that has not resolved to = Grade 1, with the following exceptions:

1. Alopecia
2. Neuropathy, which must have resolved to = Grade 2
3. Menopausal symptoms.
3. Any untreated brain lesions > 2.0 cm in size, unless discussed with BCT and Study Chair and approval for registration is given.
4. 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.
5. 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.
6. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) = 450 ms from a single ECG.
7. 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.
8. 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.
9. Active infection requiring systemic therapy.
10. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
NA
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/03/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/09/2025
Actual
Sample size
Target
57
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC
Recruitment hospital [1] 0 0
Coffs Harbour Health Campus - Coffs Harbour
Recruitment hospital [2] 0 0
Gosford Hospital - Gosford
Recruitment hospital [3] 0 0
Nepean Cancer Care Centre - Kingswood
Recruitment hospital [4] 0 0
Macquarie University - Macquarie Park
Recruitment hospital [5] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [6] 0 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [7] 0 0
Westmead Hospital - Westmead
Recruitment hospital [8] 0 0
Wollongong Hospital - Wollongong
Recruitment hospital [9] 0 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [10] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [11] 0 0
Icon Cancer Centre Hobart - Hobart
Recruitment hospital [12] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [13] 0 0
Peter MacCallum Cancer Centre - Parkville
Recruitment hospital [14] 0 0
Epworth Richmond Hospital - Richmond
Recruitment hospital [15] 0 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 0 0
2450 - Coffs Harbour
Recruitment postcode(s) [2] 0 0
2250 - Gosford
Recruitment postcode(s) [3] 0 0
2747 - Kingswood
Recruitment postcode(s) [4] 0 0
2109 - Macquarie Park
Recruitment postcode(s) [5] 0 0
2031 - Randwick
Recruitment postcode(s) [6] 0 0
2310 - Waratah
Recruitment postcode(s) [7] 0 0
2145 - Westmead
Recruitment postcode(s) [8] 0 0
2500 - Wollongong
Recruitment postcode(s) [9] 0 0
4575 - Birtinya
Recruitment postcode(s) [10] 0 0
5000 - Adelaide
Recruitment postcode(s) [11] 0 0
7000 - Hobart
Recruitment postcode(s) [12] 0 0
3084 - Heidelberg
Recruitment postcode(s) [13] 0 0
3002 - Parkville
Recruitment postcode(s) [14] 0 0
3121 - Richmond
Recruitment postcode(s) [15] 0 0
3021 - St Albans

Funding & Sponsors
Primary sponsor type
Other
Name
Breast Cancer Trials, Australia and New Zealand
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Heath Badger
Address 0 0
Breast Cancer Trials, Australia and New Zealand
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Heath Badger
Address 0 0
Country 0 0
Phone 0 0
+61 2 4925 3022
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Refer to BCT Data Sharing Guidelines (contact [email protected] for further details).

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Analytic code
When will data be available (start and end dates)?
Data will be made available for request after publication of the main/final study results; no end date. Note that there may be additional circumstances preventing BCT from sharing requested data as outlined in the BCT Data Sharing Guidelines.
Available to whom?
Researchers need to submit a research proposal ([email protected]) and BCT Data Request Application, which is then assessed by BCT as having appropriate scientific value.
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04789096

Additional trial details provided through ANZCTR
Accrual to date
Recruiting in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC
Recruitment hospital [1] 113
Austin Health - Austin Hospital
Recruitment hospital [2] 114
Border Medical Oncology
Recruitment hospital [3] 115
Calvary Mater Newcastle
Recruitment hospital [4] 116
Coffs Harbour Base Hospital
Recruitment hospital [5] 117
Epworth Richmond
Recruitment hospital [6] 118
Gosford Hospital
Recruitment hospital [7] 119
Icon Cancer Centre Hobart
Recruitment hospital [8] 120
Nepean Hospital
Recruitment hospital [9] 121
Peter MacCallum Cancer Centre
Recruitment hospital [10] 122
Prince of Wales Hospital
Recruitment hospital [11] 123
The Royal Adelaide Hospital
Recruitment hospital [12] 124
Sunshine Coast University Hospital
Recruitment hospital [13] 125
Sunshine Hospital
Recruitment hospital [14] 126
Westmead Hospital
Recruitment postcode(s) [1] 114
3084
Recruitment postcode(s) [2] 115
2640
Recruitment postcode(s) [3] 116
2298
Recruitment postcode(s) [4] 117
2450
Recruitment postcode(s) [5] 118
3121
Recruitment postcode(s) [6] 119
2250
Recruitment postcode(s) [7] 120
7000
Recruitment postcode(s) [8] 121
2109
Recruitment postcode(s) [9] 122
2747
Recruitment postcode(s) [10] 123
3000
Recruitment postcode(s) [11] 124
2031
Recruitment postcode(s) [12] 125
5000
Recruitment postcode(s) [13] 126
4575
Recruitment postcode(s) [14] 127
3021
Recruitment postcode(s) [15] 128
2145
Funding & Sponsors
Primary sponsor
Other Collaborative groups
Primary sponsor name
Breast Cancer Trials
Primary sponsor address
PO Box 283
The Junction NSW 2291
Primary sponsor country
Australia
Ethics approval
Ethics application status
Approved
Ethics committee name [1] 56
Peter MacCallum Cancer Centre HREC
Address [1] 56
Ethics Coordinator Ethics Committee Secretariat Peter MacCallum Cancer Centre Locked Bag 1, A/Beckett Street Victoria 8006
Country [1] 56
Australia
Date submitted for ethics approval [1] 56
29/06/2022
Approval date [1] 56
02/10/2022
Ethics approval number [1] 56
HREC/86726/PMCC
 
Public notes

Contacts
Principal investigator
Title 241 0
Prof
Name 241 0
Sherene Loi
Address 241 0
Peter MacCallum Cancer Centre Locked Bag 1, A'Beckett Street Melbourne VIC 8006
Country 241 0
Australia
Phone 241 0
+61 2 4925 5235
Fax 241 0
Email 241 0
[email protected]
Contact person for public queries
Title 242 0
Ms
Name 242 0
Corinna Beckmore
Address 242 0
Breast Cancer Trials PO Box 283 The Junction NSW 2291
Country 242 0
Australia
Phone 242 0
+61 2 4925 5235
Fax 242 0
Email 242 0
[email protected]
Contact person for scientific queries
Title 243 0
Prof
Name 243 0
Sherene Loi
Address 243 0
Peter MacCallum Cancer Centre Locked Bag 1, A'Beckett Street Melbourne VIC 8006
Country 243 0
Australia
Phone 243 0
+61 2 4925 5235
Fax 243 0
Email 243 0
[email protected]