Tucatinib Together with Pembrolizumab and Trastuzumab
- Conditions
- Breast CancerHER2-positive Breast Cancer
- Interventions
- Registration Number
- NCT04789096
- Lead Sponsor
- Breast Cancer Trials, Australia and New Zealand
- Brief 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).
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 57
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description TUGETHER Treatment Tucatinib 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. TUGETHER Treatment Pembrolizumab 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. TUGETHER Treatment Trastuzumab 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. TUGETHER Treatment Capecitabine 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.
- Primary Outcome Measures
Name Time Method Objective Response Rate (ORR) in the PD-L1 positive cohort Through to study completion, an average of 24 months Defined as complete response (CR) or partial response (PR) assessed as per RECIST 1.1
- Secondary Outcome Measures
Name Time Method Progression free survival (PFS) in each PD-L1 cohort 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 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.
Clinical benefit rate (CBR) in each PD-L1 cohort From time of registration to CR or PR, assessed up to 24 months Defined as stable disease (SD) for \>= 6 months after starting study treatment, or best response of CR or PR.
Overall survival (OS) in each PD-L1 cohort From time of registration until death from any cause, assessed at 24 months Defined as from the time from start of study treatment to death from any cause
Incidence of treatment-emergent adverse events [Safety] From registration until 30 days after end of study treatment Assessed as worst grade of adverse events (AEs) and serious adverse events (SAE) documented using NCI-CTCAE 5.0.
Objective response rate (ORR) in the PD-L1 negative/unknown cohort Through to study completion, an average of 24 months Defined as complete response (CR) or partial response (PR) assessed as per RECIST 1.1
Duration of response (DoR) in each PD-L1 cohort From the time of registration to first documentation of progressive disease or death, assessed up to 24 months 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.
Incidence of treatment-emergent adverse events [Tolerability of pembrolizumab] From start of study treatment to end of study treatment, assessed at 24 months Assessed by pembrolizumab dose holding, dose reduction, drug discontinuation.
Incidence of treatment-emergent adverse events [Tolerability of tucatinib] From start of study treatment to the end of study treatment, assessed at 24 months Assessed by tucatinib dose holding, dose reduction, drug discontinuation.
Trial Locations
- Locations (15)
Peter MacCallum Cancer Centre
🇦🇺Parkville, Victoria, Australia
Macquarie University
🇦🇺Macquarie Park, New South Wales, Australia
Nepean Cancer Care Centre
🇦🇺Kingswood, New South Wales, Australia
Sunshine Coast University Hospital
🇦🇺Birtinya, Queensland, Australia
Epworth Richmond Hospital
🇦🇺Richmond, Victoria, Australia
Gosford Hospital
🇦🇺Gosford, New South Wales, Australia
Prince of Wales Hospital
🇦🇺Randwick, New South Wales, Australia
Calvary Mater Newcastle
🇦🇺Waratah, New South Wales, Australia
Icon Cancer Centre Hobart
🇦🇺Hobart, Tasmania, Australia
Coffs Harbour Health Campus
🇦🇺Coffs Harbour, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Wollongong Hospital
🇦🇺Wollongong, New South Wales, Australia
Sunshine Hospital
🇦🇺St Albans, Victoria, Australia
Austin Hospital
🇦🇺Heidelberg, Victoria, Australia