Ignite Creation Date:
2025-12-25 @ 1:34 AM
Ignite Modification Date:
2025-12-25 @ 11:48 PM
Study NCT ID:
NCT07193394
Status:
NOT_YET_RECRUITING
Last Update Posted:
2025-09-25
First Post:
2025-09-12
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer
Sponsor:
Institut Curie
Organization:
Study Overview
Official Title:
Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer: a Proof of Concept Study (H3RAKLES)
Status:
NOT_YET_RECRUITING
Status Verified Date:
2025-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
H3RAKLES
Brief Summary:
The H3RAKLES trial would allow patients with a progressive metastatic breast cancer to have access to one more line of systemic therapy. Patients included in this trial will have already received at least two lines of chemotherapy (and potentially several lines of endocrine therapy for patients with a HR+ disease). In this setting, few treatments have demonstrated a clinically meaningful benefit, and any additional option is valuable. Furthermore, the pre-clinical and clinical rationale indicate a high probability of clinical benefit, as previously shown in Table 1, with all patients treated with trastuzumab and a TKI targeting HER2 displaying a response. Besides, with several years of hindsight for the combination of lapatinib, trastuzumab and capecitabine, we expect excellent tolerance with the same treatment without capecitabine.
The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation. To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles.
The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation. To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles.
Detailed Description:
For breast cancers in which HER2 is not overexpressed, activating mutations in the ERBB3 gene, coding for the HER3 tyrosine kinase receptor, have an oncogenic role, and targeting them may offer new perspectives of treatment.
Pre-clinical data suggest that HER2 is essential for the pro-tumoral effect of HER3, which does not have a functional tyrosine kinase domain and requires heterodimerization with other members of the HER family of tyrosine kinase receptors for signaling. There is limited clinical evidence of the activity of drugs targeting HER2 in cancers harboring ERBB3 mutations, but few patients with breast cancer have been evaluated. Furthermore, the distribution of ERBB3 mutations seems to differ in breast carcinoma when compared to other cancer types. A few patients with a HER2 non-amplified metastatic breast cancer were treated at Institut Curie with the combination of a HER2-directed antibody and of a HER2 tyrosine kinase inhibitor (TKI) and all responded, warranting further explorations in this setting.
The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody, with a Bayesian design in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation.
To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles, until cancer progression, inacceptable toxicity or patient's withdrawal from the trial.
Tumor radiological assessments will be performed every 6 weeks during the 6 first months (first 8 cycles), then every 9 weeks until disease progression. In addition, Quality of Life will be evaluated throughout the treatment.
Blood samples (at baseline, cycles 1, 2 and 3, and at end of treatment) and tissue samples (at baseline and optionally at progression) will be collected as part as exploratory objective analyses on biomarkers (ctDNA monitoring and next-generation sequencing (NGS)).
Pre-clinical data suggest that HER2 is essential for the pro-tumoral effect of HER3, which does not have a functional tyrosine kinase domain and requires heterodimerization with other members of the HER family of tyrosine kinase receptors for signaling. There is limited clinical evidence of the activity of drugs targeting HER2 in cancers harboring ERBB3 mutations, but few patients with breast cancer have been evaluated. Furthermore, the distribution of ERBB3 mutations seems to differ in breast carcinoma when compared to other cancer types. A few patients with a HER2 non-amplified metastatic breast cancer were treated at Institut Curie with the combination of a HER2-directed antibody and of a HER2 tyrosine kinase inhibitor (TKI) and all responded, warranting further explorations in this setting.
The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody, with a Bayesian design in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation.
To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles, until cancer progression, inacceptable toxicity or patient's withdrawal from the trial.
Tumor radiological assessments will be performed every 6 weeks during the 6 first months (first 8 cycles), then every 9 weeks until disease progression. In addition, Quality of Life will be evaluated throughout the treatment.
Blood samples (at baseline, cycles 1, 2 and 3, and at end of treatment) and tissue samples (at baseline and optionally at progression) will be collected as part as exploratory objective analyses on biomarkers (ctDNA monitoring and next-generation sequencing (NGS)).
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 2024-519624-24-00 | CTIS | None | View |