A Multicenter, Single-Arm, Three Cohort, Phase Ii Trial of Patritumab Deruxtecan (HER3-DXD) in Patients with Active Brain Metastases From HER3-EXPRESSING Advanced Breast Cancer and Non–Small Cell Lung Cancer, and in Patients with Leptomeningeal Carcinomatosis From HER3-EXPRESSING Advanced Solid Tumors (The TUXEDO-3 Study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medica Scientia Innovation Research S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Oct 2023 → 3 Apr 2026

Decision date (initial)

2023-10-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-503251-10-00

ClinicalTrials.gov

NCT05865990

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

Cohorts 1 and 2: To assess the intracranial objective response rate (ORR-IC) per local investigator as judged by best CNS response according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria of HER3-DXd in patients with active brain metastases from MBC and aNSCLC.  

Cohort 3: To analyze the overall survival (OS) rate at 3 months of HER3-DXd in patients with advanced solid tumors with untreated LMD.​

Secondary objectives 12

1. To assess the efficacy – defined as ORR (only for extracranial and overall lesions in cohorts 1 and 2), investigator-assessed progression-free survival (PFS) –, clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), duration of response (DoR), and best percentage of change in tumor burden as per RANO-BM for intracranial lesions and Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 for extracranial and overall measurable lesions of HER3-DXd.
2. To assess the efficacy – defined as OS – of HER3-DXd.
3. To determine the safety and toxicity profile according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v.5.0) of HER3-DXd.
4. To evaluate the quality of life (QoL) and neurocognitive function with the European Organization For Research And Treatment Of Cancer (EORTC) quality of life questionnaire (QLQ-C30), the brain cancer specific questionnaire (QLQ-BN20), and the BC specific questionnaire (QLQ-BR45) of HER3-DXd.
5. To evaluate the neurologic function with the Neurologic Assessment in Neuro-Oncology (NANO) scale of HER3-DXd.
6. Exploratory objectives All cohorts (cohorts 1, 2 and 3): To assess the correlation between HER3 expression levels and efficacy of HER3-DXd treatment.
7. Exploratory objectives All cohorts (cohorts 1, 2 and 3): To evaluate predictive and/or prognostic factors on MR images, CT images, and blood/tumor samples.
8. Exploratory objectives All cohorts (cohorts 1, 2 and 3): To evaluate the efficacy of HER3-DXd in patients with and without prior ADC therapy.
9. Exploratory objectives Cohorts 1 and 2: To determine the relationship between TROP2 expression levels and the efficacy of HER3-DXd treatment.
10. Exploratory objectives Cohort 1: To determine the estrogen receptor (ER)/progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) expression status on baseline tissue samples and its relationship with efficacy endpoints.
11. Exploratory objectives Cohort 1: To evaluate the efficacy of HER3-DXd in HER2[+] breast cancer patients with and without prior tucatinib treatment.
12. Exploratory objectives Cohort 3: To evaluate predictive and/or prognostic factors on CSF samples (only if collected as per local guidelines and clinical routine).

Conditions and MedDRA coding

Metastatic Breast Cancer or Advanced Non-Small Cell Lung Cancer with asymptomatic untreated or progressing Brain Metastases, or solid tumors with Leptomeningeal disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
2. Age ≥ 18 years at time of signing ICF.
3. Life expectancy ≥ 6 weeks.
4. Karnofsky Performance Status (KPS) ≥70%, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
5. Patient must be able to tolerate therapy.
6. Availability and willingness to provide the most recently available tumor tissue sample (formalin-fixed and paraffin-embedded [FFPE], no cytology/cell block, no bone/decalcified bone sample) of primary tumor or any metastatic site from biopsy preferably collected after last round of prior treatment and ≤ 6 months prior to HER3-DXd treatment, if possible, at the time of inclusion for retrospective exploratory biomarker testing. If archival tissue is not available, a newly obtained baseline biopsy of an accessible tumor lesion is required prior to start of study treatment (unless not possible because of inaccessible tumor location or safety concerns).
7. No indication for immediate local therapy (neurosurgery, brain radiotherapy).
8. Patient has adequate bone marrow, liver, and renal function: Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 7 days before first study treatment dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
9. Patient has adequate bone marrow, liver, and renal function: Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert’s disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) < 1.5.
10. Patient has adequate bone marrow, liver, and renal function: Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 based on Cockcroft−Gault glomerular filtration rate estimation for patients with creatinine levels above institutional normal.
11. Participants in cohort 1 and cohort 2 must have received at least one prior line of systemic treatment in the advanced setting. Note I: prior systemic treatments for BC eligible patients would be defined as follows: 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 ET and one line of CT in the advanced setting. 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 aNSCLC eligible patients would be defined as follows: Patients without activating driver alterations must have received at least one prior line of standard of care systemic therapy for locally advanced or metastatic disease. Patients with activating driver alterations must have received at least one prior line of an approved genotype-directed therapy. Participants with EGFR T790M mutation who received first-line treatment with erlotinib, gefitinib, afatinib, or dacomitinib must have received second-line treatment with osimertinib and have documentation of radiological disease progression.
12. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0). Note: Except for alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion.
13. For women of childbearing potential: agreement to remain abstinent (must refrain from heterosexual intercourse) or use highly effective contraceptive methods, or two effective contraceptive methods, as defined in the CSP, during the treatment period and for at least 7 months after the last dose of study treatment, whichever is longer. Women of childbearing potential must have a negative serum pregnancy test within 14 days before study treatment initiation (with result available prior to dosing) and must agree to refrain from donating eggs during the entire study treatment period and for 7 months after the last administration of the study drug.
14. Being male subjects, surgically sterile or having agreed with true abstinence (must refrain from heterosexual intercourse), or whose female partners are willing to agree with true abstinence or use barrier contraceptive measures mentioned above during the entire study treatment period and for 4 months after the last administration of the study drug. Males must agree to refrain from donating sperm during the entire study treatment period and for 4 months after the last administration of the study drug.
15. Patient must be accessible for treatment and follow-up.
16. Cohort 1 and cohort 2 specific inclusion criteria: Histologically documented BC (cohort 1) or NSCLC of squamous or non-squamous histologic types (cohort 2).
17. Cohort 1 and cohort 2 specific inclusion criteria: Newly diagnosed BM or BM progressing after local treatment.
18. Cohort 1 and cohort 2 specific inclusion criteria: Measurable disease according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, with at least one measurable brain lesion of ≥10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging (MRI).
19. Cohort 1 specific inclusion criterion: Known HER2 status, by local assessment.
20. Cohort 3 specific inclusion criteria: Histologically documented solid tumor of any type.
21. Cohort 3 specific inclusion criteria: Type I LMD, defined by positive cerebrospinal fluid (CSF) cytology or leptomeningeal biopsy, or type II LMD, defined by clinical findings and neuroimaging only, according to European Society for Molecular Oncology (ESMO) Standard Operating Procedures (SOPs) for Clinical Practice Guideline (CPG) 2017.
22. Cohort 3 specific inclusion criteria: Newly diagnosed LMD or LMD progressing after radiotherapy.

Exclusion criteria 18

1. Current participation in another therapeutic clinical trial.
2. Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drug.
3. Patients have a concurrent malignancy or malignancy within five years of study enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
4. Previous systemic therapy with any anti-HER3 directed drug.
5. Known allergy or hypersensitivity to HER3-DXd or any of the drug components.
6. Radiotherapy or limited-field palliative radiotherapy within seven days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously irradiated.
7. Patient with an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities including any of the following: Unstable angina pectoris or documented myocardial infarction within 6 months prior to study entry. Symptomatic pericarditis. Documented congestive heart failure (CHF) (New York Heart Association [NYHA] Class III-IVI). Left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO). Ventricular arrhythmias except for benign premature ventricular contractions. Other cardiac arrhythmias requiring a pacemaker or not controlled with medication. Long QT syndrome (corrected QT interval by Fredericia (QTcF) interval > 450 ms).
8. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), or prior pneumonectomy.
9. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
10. Pregnant or lactating women.
11. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study.
12. Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
13. Known human immunodeficiency virus (HIV) infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥350, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended.
14. History of a major surgical procedure (defined as requiring general anesthesia) or significant traumatic injury within 21 days prior to randomization, or patients who have not recovered from the side effects of any major surgery.
15. A history of uncontrolled seizures, CNS disorders or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs or interfering with subject safety.
16. Patients requiring concomitant use of chronic systemic (intravenously [IV] or oral) corticosteroids at doses higher than 8 mg dexamethasone per day or other immunosuppressive medications except for managing adverse events (AEs), including immune-related adverse events (irAEs) for patients that received immunotherapy in a previous line; (inhaled steroids or intra articular steroid injections are permitted in this study). Note: The use of stable corticosteroid therapy in patients with BM can be discussed with the Medical Monitor.
17. Patients with known substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
18. Participants who are unable or unwilling to comply with the requirements of the protocol in the opinion of the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Cohorts 1 and 2:  ORR-IC, defined as the rate of patients with complete response (CR) or partial response (PR) determined locally by investigator, using RANO-BM criteria.
2. Cohort 3:  3-month OS rate, defined as the rate of patients alive at 3 months after treatment start.

Secondary endpoints 19

1. ORR, defined as the rate of patients with CR or PR centrally reviewed as per ESMO-European Association of Neuro-Oncology (EANO) for intracranial lesions in cohort 3 and RECIST v.1.1 for extracranial and overall lesions (bicompartmental ORR) in all cohorts.
2. PFS, defined as the period from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. It will be determined locally by investigator as per ESMO-EANO (cohort 3) and RANO-BM (cohort 1 and 2) for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions.
3. CBR, defined as the rate of patients with objective response (CR or PR), or stable disease for at least 24 weeks, as per ESMO-EANO (cohort 3) and RANO-BM (cohort 1 and 2) for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions (bicompartmental CBR).
4. DCR, defined as the rate of patients with objective response (CR or PR), or stable disease (SD), as per ESMO-EANO (cohort 3) and RANO-BM (cohort 1 and 2) for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions (bicompartmental DCR).
5. 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, as per ESMO-EANO (cohort 3) and RANO-BM (cohort 1 and 2) for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions.
6. 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, as per ESMO-EANO (cohort 3) and RANO-BM (cohort 1 and 2) for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions.
7. Best percentage of change in tumor burden as per ESMO-EANO (cohort 3) and RANO-BM (cohort 1 and 2) for intracranial lesions and RECIST v.1.1 for extracranial and overall measurable lesions.
8. OS, defined as the period from treatment initiation to death from any cause or last available follow-up.
9. Safety and tolerability as per NCI-CTCAE v.5.0.
10. Assessment of QoL with EORTC QLQ-C30, the brain specific tool (EORTC QLQ-BN20), and the breast specific tool EORTC QLQ-BR45.
11. Neurocognitive function as per EORTC QLQ-C30, the brain specific tool (EORTC QLQ-BN20), and the breast specific tool EORTC QLQ-BR45.
12. Neurologic function as per NANO scale.
13. Exploratory endpoints: Efficacy endpoints according to HER3 expression levels and tumor type.
14. Exploratory endpoints: Predictive and/or prognostic factors on blood/tumor samples.
15. Exploratory endpoints: Efficacy endpoints for patients with and without prior ADC therapy.
16. Exploratory endpoints Cohorts 1 and 2: Efficacy endpoints according to TROP2 expression levels.
17. Exploratory endpoints Cohorts 1: The ER, PgR, and HER2 expression on baseline tissue samples and efficacy endpoints.
18. Exploratory endpoints Cohorts 1: Efficacy endpoints for HER2+ breast cancer patients with and without prior tucatinib treatment.
19. Exploratory endpoints Cohort 3: Predictive and/or prognostic factors on CSF (only if collected as per local guidelines and clinical routine).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Rambla De Catalunya 2 Planta 2 D

City

Barcelona

Postcode

08007

Country

Spain

Scientific contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia Garcia

Public contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia Garcia

Third parties 1

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications