Trial Title:
HER3-DXd in Breast Cancer and NSCLC Brain Metastases and Solid Tumor Leptomeningeal Disease
NCT ID:
NCT05865990
Condition:
Metastatic Breast Cancer
Advanced Non-Small Cell Squamous Lung Cancer
Solid Tumor, Adult
Conditions: Official terms:
Breast Neoplasms
Lung Neoplasms
Neoplasm Metastasis
Brain Neoplasms
Patritumab deruxtecan
Conditions: Keywords:
Brain Metastasis
Leptomeningeal Disease
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Active, not recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
An international, multicenter, single-arm, three-cohort, two-stage optimal Simon's
design, phase II clinical trial.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Patritumab deruxtecan
Description:
HER3 directed antibody drug conjugate (ADC) that is comprised of a fully human anti-HER3
immunoglobulin gamma-1 (IgG1) monoclonal antibody attached to a topoisomerase I inhibitor
payload (an exatecan derivative, DXd) via a stable tetrapeptide-based cleavable linker.
Arm group label:
Patritumab deruxtecan (HER3-DXd)
Other name:
HER3-DXd
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.
Criteria for eligibility:
Criteria:
- GENERAL INCLUSION CRITERIA (Patients will be included in the study only if they meet
all the following inclusion criteria):
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 the 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.
8. Patient has adequate bone marrow, liver, and renal function:
1. 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).
2. 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); alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in
patients with liver metastases); international normalized ratio (INR) <
1.5.
3. 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.
9. Patients must have received at least 1 prior line of systemic treatment* in the
advanced setting.
- Prior systemic treatments for eligible patients with BC are defined as
follows:
- Patients with triple-negative breast cancer (TNBC) must have received
at least one line of prior systemic therapy for advanced disease.
- Patients with luminal BC must have received at least one line of ET
and one line of CT in the advanced setting.
- Patients with HER2-positive BC must have progressed to at least two
previous treatments with HER2-targeted therapies in the advanced
setting.
- Prior systemic treatments for eligible patients with aNSCLC are 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.
- Patients 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.
10. 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.
11. 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 protocol,
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 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.
12. For male subjects: being surgically sterile or having agreed to true abstinence
(must refrain from heterosexual intercourse) or having female partners 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. Male patients 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.
13. Patient must be accessible for treatment and follow-up.
- SPECIFIC INCLUSION CRITERION FOR COHORT 1 AND COHORT 2 (Cohort 1 and cohort 2
patients will be included in the study only if they meet all the following inclusion
criteria):
1. Histologically documented BC (cohort 1) or NSCLC of squamous or non-squamous
histologic types (cohort 2).
2. Newly diagnosed BM or BM progressing after local treatment.
3. 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 MRI.
- SPECIFIC INCLUSION CRITERION FOR COHORT 1 AND COHORT 2 (Cohort 1 and cohort 2
patients will be included in the study only if they meet all the following inclusion
criteria):
1. Histologically documented BC (cohort 1) or NSCLC of squamous or non-squamous
histologic types (cohort 2).
2. Radiologically documented metastatic disease. 3. Newly diagnosed BM or BM
progressing after local treatment. 4. 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 MRI.
- SPECIFIC INCLUSION CRITERION FOR COHORT 1 (Cohort 1 patients will be included in the
study only if they meet the following inclusion criterion):
1. Locally determined HER2 status.
- SPECIFIC INCLUSION CRITERIA FOR COHORT 3 (Cohort 3 patients will be included in the
study only if they meet all the following inclusion criteria):
1. Histologically documented solid tumor of any type.
2. Type I LMD, defined by positive 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.
3. Newly diagnosed LMD or LMD progressing after radiotherapy.
- EXCLUSION CRITERIA (Patients will be excluded from the study if they meet any of the
following criteria):
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. Patients with an active cardiac disease or a history of cardiac dysfunction or
conduction abnormalities including any of the following:
1. Unstable angina pectoris or documented myocardial infarction within 6
months prior to study entry.
2. Symptomatic pericarditis.
3. Documented congestive heart failure (CHF) (New York Heart Association
[NYHA] Class III-IV).
4. Left ventricular ejection fraction (LVEF) < 50% as determined by
multigated acquisition (MUGA) scan or echocardiogram (ECHO).
5. Ventricular arrhythmias except for benign premature ventricular
contractions.
6. Other cardiac arrhythmias requiring a pacemaker or not controlled with
medication.
7. Long QT syndrome (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. 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-positive cells' 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-positive cells' 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. 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 brain
metastases 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Salzburg Cancer research Institute-Center for Clinical Cancer and Immunology Trials
Address:
City:
Salzburg
Country:
Austria
Facility:
Name:
Medical University of Vienna
Address:
City:
Vienna
Country:
Austria
Facility:
Name:
Hospital Universitari Dexeus
Address:
City:
Barcelona
Country:
Spain
Facility:
Name:
Hospital Universitari Vall D'Hebron
Address:
City:
Barcelona
Country:
Spain
Facility:
Name:
Hospital Beata María Ana
Address:
City:
Madrid
Country:
Spain
Facility:
Name:
Hospital Quirónsalud Sagrado Corazón
Address:
City:
Sevilla
Country:
Spain
Facility:
Name:
Hospital Universitario Virgen del Rocío
Address:
City:
Sevilla
Country:
Spain
Facility:
Name:
Hospital Arnau de Vilanova de Valencia
Address:
City:
Valencia
Country:
Spain
Start date:
November 24, 2023
Completion date:
October 2026
Lead sponsor:
Agency:
MedSIR
Agency class:
Other
Collaborator:
Agency:
Daiichi Sankyo
Agency class:
Industry
Source:
MedSIR
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05865990
