HER3-DXd in Breast Cancer and NSCLC Brain Metastases and Solid Tumor Leptomeningeal Disease
- Conditions
- Solid Tumor, AdultMetastatic Breast CancerAdvanced Non-Small Cell Squamous Lung Cancer
- Interventions
- Registration Number
- NCT05865990
- Lead Sponsor
- MedSIR
- Brief Summary
The goal of this phase II clinical trial\] is to analyze the efficacy of patritumab deruxtecan (HER3-DXd) in patients with metastatic breast cancer (MBC) or advanced non-small cell lung cancer (aNSCLC) with active brain metastases (BM) who have received at least one line of systemic therapy in the advanced setting, or patients with active leptomeningeal carcinomatosis/disease (LMD) after radiotherapy from an advanced solid tumor who do not need immediate local treatment, and have not received prior treatment with an anti-HER3 targeted drug\].
The main questions it aims to answer are:
* The intracranial objective response rate (ORR-IC) per local investigator as judged by best central nervous system (CNS) response according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria of HER3-DXd in patients with active BM from MBC (Cohort 1) and aNSCLC (Cohort 2).
* The overall survival (OS) rate at 3 months of HER3-DXd in patients with advanced solid tumors with untreated LMD (Cohort 3).
Participants will receive HER3-DXd on day (D1) of each 21-day cycle until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.
Researchers will compare historical groups to see if HER3-DXd positively impacts patient outcomes.
- Detailed Description
In this international, multicenter, single-arm, multicohort, optimal Simon's design phase II clinical trial, patients will be treated with HER3-DXd, which is a new antibody-drug conjugate (ADC) that targets specifically the HER3 protein (which is expressed in the surface of tumor cells) and that is attached to deruxtecan.
Male or female patients ≥ 18 years of age with MBC or aNSCLC with untreated or progressing BM after local treatment, or solid tumor patients with treatment-naive LMD or patients with recurrence of LMD after radiotherapy, and no need for immediate local treatment. All patients except for patients with LMD (cohort 3) must have received one prior line of systemic therapy in the advanced setting.
Note I: prior systemic treatments for breast cancer (BC) eligible patients would be defined as follows:
* triple negative breast cancer (TNBC) patients must have received at least one line of prior systemic therapy for advanced disease.
* luminal BC patients must have received at least one line of endocrine therapy (ET) and one line of chemotherapy (CT) in the advanced setting.
* HER2-positive (HER2\[+\]) BC patients must have progressed on at least two previous treatments with HER2-targeted therapies in the advanced setting.
Note II: prior systemic treatments for NSCLC eligible patients would be defined as follows:
* Patients without and with epidermal growth factor receptor (EGFR) (and other) activating driver alterations are allowed.
* Patients with activating driver alterations must have received at least one prior line of an approved genotype directed therapy.
* Patients with EGFR T790M mutation following first-line treatment with erlotinib, gefitinib, afatinib, or dacomitinib must have received second-line osimertinib, and have documentation of radiological disease progression on treatment.
After confirmed eligibility, patients will be assigned to one of three study cohorts as follows:
* Cohort 1 (N=20): 10 patients in the stage I and 10 patients in the stage II. MBC with untreated or progressing BM after local treatment.
* Cohort 2 (N=20): 10 patients in the stage I and 10 patients in the stage II. aNSCLC with untreated or progressing BM after local treatment.
* Cohort 3 (N=20): 10 patients in the stage I and 10 patients in the stage II. Advanced solid tumor with treatment-naive LMD or LMD progressing after radiotherapy.
Upon meeting all selection criteria, patients enrolled in the study will receive patritumab deruxtecan (HER3-DXd), which will be dosed at 5.6 mg/kg body weight as an intravenous (IV) infusion administered on day 1 (D1) of each 21-day cycle.
Patients will receive treatment disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.
Patients discontinuing the study treatment period prematurely, will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected, until end of study (EoS) or study termination, whichever occurs first.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 60
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Patritumab deruxtecan (HER3-DXd) Patritumab deruxtecan HER3-DXd will be dosed at 5.6 mg/kg body weight as an intravenous (IV) infusion administered on day 1 (D1) of each 21-day cycle for patients from all cohorts until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. * Cohort 1: MBC with untreated or progressing BM after local treatment. * Cohort 2: aNSCLC with untreated or progressing BM after local treatment. * Cohort 3: advanced solid tumor with treatment-naive LMD or LMD progressing after radiotherapy.
- Primary Outcome Measures
Name Time Method Efficacy: Overall survival (OS) rate at 3 months in cohort 3. From baseline up to 3 months 3-month OS, defined as the rate of patients alive at 3 months after treatment initiation in cohort 3.
Efficacy: Local determination of intracranial objective response rate (ORR-IC) in cohort 1 and cohort 2. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months Rate of patients with complete response (CR) or partial response (PR) determined locally by investigator, using Response Assessment in Neuro-Oncology Brain Metastases (RANO)-BM criteria in cohort 1 and cohort 2.
- Secondary Outcome Measures
Name Time Method Efficacy: disease control rate (DCR) in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months DCR, defined as the rate of patients with objective response (CR or PR), or stable disease (SD), determined by central review as per RANO-BM in cohort 1 and cohort 2 and ESMO-EANO in cohort 3 for intracranial lesions, and RECIST v.1.1 for extracranial and overall lesions (bicompartmental DCR) in all cohorts.
Efficacy: time to response (TTR) in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months TTR, defined as the period from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, centrally reviewed as per RANO-BM in cohort 1 and cohort 2 and ESMO-EANO in cohort 3 for intracranial lesions, and RECIST v.1.1 for extracranial and overall lesions in all cohorts.
Efficacy: duration of response (DoR) in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months DOR, defined as the period from the first occurrence of a documented objective response to disease progression or death from any cause, observed for patients who achieved a CR or PR. It will be centrally reviewed as per RANO-BM in cohort 1 and cohort 2 and ESMO-EANO in cohort 3 for intracranial lesions, and RECIST v.1.1 for extracranial and overall lesions in all cohorts.
Efficacy: best percentage of change in tumor burden in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months Best percentage of change in tumor burden centrally reviewed as per RANO-BM in cohort 1 and cohort 2 and ESMO-EANO in cohort 3 for intracranial lesions, and RECIST v.1.1 for extracranial and overall measurable lesions in all cohorts.
Efficacy: bicompartmental clinical benefit rate (CBR) in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months CBR, defined as the rate of patients with objective response (CR or PR), or stable disease for at least 24 weeks, centrally reviewed as per RANO-BM in cohort 1 and cohort 2 and ESMO-EANO in cohort 3 for intracranial lesions, and RECIST v.1.1 for extracranial and overall lesions (bicompartmental CBR) in all cohorts.
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months Safety and tolerability of HER3-DXd as per National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) Version 5.0 (NCI-CTCAE v.5.0) in all cohorts.
Efficacy: Central determination of ORR in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months ORR, defined as the rate of patients with CR or PR determined by central review as per RANO-BM in cohort 1 and cohort 2 and per ESMO-EANO in cohort 3 for intracranial lesions, and per RECIST v.1.1 for extracranial and overall lesions (bicompartmental ORR) in all cohorts.
Efficacy: progression-free survival (PFS) in cohort 1, cohort 2, and cohort 3. From baseline up to 12 months PFS, defined as the period from treatment initiation to the first occurrence of disease progression or death from any cause or treatment discontinuation from any other reason, whichever occurs first, that will be centrally reviewed as per RANO-BM for intracranial lesions in cohort 3 and RECIST v.1.1 for extracranial and overall lesions in all cohorts.
Efficacy: overall survival (OS) in cohort 1 and cohort 2. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months OS, defined as the period from treatment initiation to death from any cause or last available follow-up in cohort 1 and cohort 2.
Patient reported outcomes (PROs) with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) of patients in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months Assessment of overall change from baseline in QoL with the EORTC QLQ-C30 scale to measure cancer patients' physical, psychological and social functions in all cohorts. All scales and single items are transformed into scores ranging from 0 to 100. A high score for a functional scale represents a high level of functioning, whereas a high score for a symptom scale/single item represents a high level of symptomatology.
Effects of the tumor and its function using the European Organization for Research and Treatment of Cancer breast cancer-specific Quality of Life Questionnaire (EORTC QoL-BR45) of breast cancer patients in cohort 1. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months Assessment of overall change from baseline of the effects in QoL of breast cancer patients in cohort 1 with the breast specific tool EORTC QLQ-BR45 scale to measure physical, psychological and social functions. All scales and single items are transformed into scores ranging from 0 to 100. A high score for a functional scale represents a high level of functioning, whereas a high score for a symptom scale/single item represents a high level of symptomatology.
Assessment of overall change from baseline of the effects of the tumor in and its treatment in neurologic function using the Neurologic Assessment in Neuro-Oncology (NANO) scale in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months Differences in neurologic assessment in NANO scale in all cohorts. High-scale values represent impaired neurological performances. NANO scale differences (values before and after treatment) below or equal to 0 represent a stable or improved neurological performance and vice versa.
Effects of the tumor and its function with the European Organization for Research and Treatment of Cancer brain cancer-specific Quality of Life Questionnaire (EORTC QLQ-BN20) of patients in cohort 1, cohort 2, and cohort 3. From baseline to the date of first documented progression, death from any cause, or treatment discontinuation from any reason, whichever came first, assessed up to 12 months Assessment of overall change from baseline of the effects of brain tumors and its treatment on symptoms, functions and health-related quality of life with the brain specific tool (EORTC QLQ-BN20) in all cohorts. All scales and single items are transformed into scores ranging from 0 to 100. A high score for a functional scale represents a high level of functioning, whereas a high score for a symptom scale/single item represents a high level of symptomatology.
Trial Locations
- Locations (8)
Salzburg Cancer research Institute-Center for Clinical Cancer and Immunology Trials
🇦🇹Salzburg, Austria
Medical University of Vienna
🇦🇹Vienna, Austria
Hospital Universitari Dexeus
🇪🇸Barcelona, Spain
Hospital Universitari Vall D'Hebron
🇪🇸Barcelona, Spain
Hospital Beata María Ana
🇪🇸Madrid, Spain
Hospital Quirónsalud Sagrado Corazón
🇪🇸Sevilla, Spain
Hospital Universitario Virgen del Rocío
🇪🇸Sevilla, Spain
Hospital Arnau de Vilanova de Valencia
🇪🇸Valencia, Spain
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