Phase II Multicenter Trial of Patritumab Deruxtecan in HER3-Expressing Advanced Breast and Non-Small Cell Lung Cancer with Brain Metastases and Leptomeningeal Carcinomatosis

Trial ID: 2023-503251-10-00
Sponsor: Medica Scientia Innovation Research S.L.

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Diseases & Conditions

Breast cancer metastatic Metastases to central nervous system Non-small cell lung cancer

Objectives

The primary objective of this study is to evaluate the **intracranial objective response rate (ORR-IC)** of **Patritumab deruxtecan (HER3-DXd)** in patients with active brain metastases from metastatic breast cancer (MBC) and advanced non-small cell lung cancer (aNSCLC), as assessed by local investigators using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Additionally, for patients with advanced solid tumors with untreated leptomeningeal disease (LMD), the study aims to analyze the overall survival (OS) rate at 3 months. These objectives are clinically relevant as they focus on the efficacy of HER3-DXd in managing brain metastases and LMD, conditions that significantly impact patient prognosis and quality of life.

Secondary objectives include: - Assessing the efficacy of HER3-DXd through various measures such as overall response rate (ORR), 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 for both intracranial and extracranial lesions. - Evaluating the overall survival (OS) of HER3-DXd. - Determining the safety and toxicity profile of HER3-DXd according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v.5.0). - Evaluating quality of life (QoL) and neurocognitive function using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires. - Assessing neurologic function with the Neurologic Assessment in Neuro-Oncology (NANO) scale. - Exploring correlations between HER3 expression levels and treatment efficacy, as well as evaluating predictive and prognostic factors using imaging and biological samples.

Participants

The clinical trial involves participants diagnosed with **Metastatic Breast Cancer** or **Advanced Non-Small Cell Lung Cancer** with asymptomatic untreated or progressing brain metastases, or solid tumors with leptomeningeal disease. The study population includes both male and female subjects aged 18 years and older. Participants are required to have adequate bone marrow, liver, and renal function, and a life expectancy of at least six weeks. The trial does not include vulnerable populations. Participants must have a Karnofsky Performance Status of 70% or higher and an Eastern Cooperative Oncology Group performance status of 2 or lower. The selection criteria emphasize the need for participants to have measurable disease according to specific neuro-oncology criteria and to have received prior systemic treatment in the advanced setting. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the trial details.

Plans and Procedures

The clinical trial is a **Phase II** study designed to evaluate the efficacy and safety of **Patritumab deruxtecan** in patients with **metastatic breast cancer** or **advanced non-small cell lung cancer** with asymptomatic untreated or progressing brain metastases, as well as in patients with solid tumors with leptomeningeal disease. The trial is structured as a multicenter, single-arm study with three distinct cohorts. The primary objective for cohorts 1 and 2 is to assess the intracranial objective response rate (ORR-IC) using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, while cohort 3 aims to analyze the overall survival rate at 3 months. The trial is expected to conclude by September 2025, with recruitment starting in October 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate bone marrow, liver, and renal function, and prior treatment history. Following the screening, participants will receive **Patritumab deruxtecan** via intravenous infusion, with the maximum treatment period set at 45 days. Follow-up visits will be scheduled to monitor the participants' response to treatment and assess any adverse effects, using criteria such as the NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The end-of-study visit will evaluate the overall outcomes and gather final data on the participants' health status.

Participant involvement is expected to last for the duration of the treatment period and follow-up assessments, with conditions for early termination including significant adverse reactions or disease progression that necessitates alternative treatment. The study will adhere to rigorous ethical standards, requiring informed consent and ensuring participants' safety and well-being throughout the trial. The trial's endpoints include both primary and secondary measures, such as progression-free survival (PFS), clinical benefit rate (CBR), and disease control rate (DCR), to comprehensively evaluate the therapeutic potential of **Patritumab deruxtecan** in the specified patient population.

Treatment

The clinical trial involves the administration of **Patritumab deruxtecan**, a novel therapeutic agent under investigation. Patritumab deruxtecan is provided in the form of a **solution for infusion** and is administered **intravenously**. The dosing regimen for this investigational product is specified as a maximum daily dose of **0.27 mg/kg** and a maximum total dose of **84 mg/kg** over a treatment period not exceeding **45 days**. The active substance, patritumab deruxtecan, is a protein-based compound, specifically categorized under "Protein - Other". This investigational drug is developed by Daiichi Sankyo, Inc. and is also referred to by its sponsor product code, U3-1402 or HER3-DXd.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed as a single-arm study, focusing solely on the effects and outcomes of Patritumab deruxtecan. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the specified regimen. The trial aims to evaluate the efficacy of Patritumab deruxtecan in patients with active brain metastases from HER3-expressing advanced breast cancer and non-small cell lung cancer, as well as in patients with leptomeningeal carcinomatosis from HER3-expressing advanced solid tumors.

Efficacy

The efficacy of Patritumab deruxtecan in this clinical trial will be assessed using several primary and secondary endpoints. For Cohorts 1 and 2, the primary endpoint is the **intracranial objective response rate (ORR-IC)**, which is defined as the rate of patients achieving a complete response (CR) or partial response (PR) as determined by local investigators using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort 3, the primary endpoint is the 3-month overall survival (OS) rate, which measures the rate of patients alive at 3 months post-treatment initiation.

Secondary endpoints include the overall response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), duration of response (DOR), and best percentage change in tumor burden. These will be evaluated using the ESMO-European Association of Neuro-Oncology (EANO) criteria for intracranial lesions in Cohort 3 and RANO-BM criteria for Cohorts 1 and 2, along with RECIST v.1.1 for extracranial and overall lesions. Additional assessments include overall survival (OS), safety and tolerability as per NCI-CTCAE v.5.0, quality of life (QoL) using EORTC QLQ-C30, EORTC QLQ-BN20, and EORTC QLQ-BR45, neurocognitive function, and neurologic function using the NANO scale.

Exploratory endpoints will investigate efficacy according to HER3 expression levels, tumor type, and prior antibody-drug conjugate (ADC) therapy, among other factors. These assessments will be conducted at various timepoints throughout the trial, with specific intervals for data collection and analysis as per the study protocol.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.
Age ≥ 18 years at time of signing ICF.
Life expectancy ≥ 6 weeks.
Karnofsky Performance Status (KPS) ≥70%, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
Patient must be able to tolerate therapy.
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).
No indication for immediate local therapy (neurosurgery, brain radiotherapy).
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).
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.
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.
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.
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.
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.
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.
Patient must be accessible for treatment and follow-up.
Cohort 1 and cohort 2 specific inclusion criteria: Histologically documented BC (cohort 1) or NSCLC of squamous or non-squamous histologic types (cohort 2).
Cohort 1 and cohort 2 specific inclusion criteria: Newly diagnosed BM or BM progressing after local treatment.
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).
Cohort 1 specific inclusion criterion: Known HER2 status, by local assessment.
Cohort 3 specific inclusion criteria: Histologically documented solid tumor of any type.
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.
Cohort 3 specific inclusion criteria: Newly diagnosed LMD or LMD progressing after radiotherapy.

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Exclusion Criteria

Current participation in another therapeutic clinical trial.
Treatment with approved or investigational cancer therapy within 14 days prior to initiation of study drug.
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.
Previous systemic therapy with any anti-HER3 directed drug.
Known allergy or hypersensitivity to HER3-DXd or any of the drug components.
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.
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).
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.
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.
Pregnant or lactating women.
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.
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.
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.
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.
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.
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.
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.
Participants who are unable or unwilling to comply with the requirements of the protocol in the opinion of the investigator.