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JOURNAL ONKOLOGIE – STUDIE
TUXEDO-3

HER3-DXd in Breast Cancer and NSCLC Brain Metastases and Solid Tumor Leptomeningeal Disease

Rekrutierend

NCT-Nummer:
NCT05865990

Studienbeginn:
November 2023

Letztes Update:
09.04.2024

Wirkstoff:
Patritumab Deruxtecan

Indikation (Clinical Trials):
Breast Neoplasms, Lung Neoplasms, Neoplasm Metastasis, Brain Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
MedSIR

Collaborator:
Daiichi Sankyo

Studienleiter

Matthias Preusser, MD
Principal Investigator
Medical Oncologist. Head of Clinical Division of Oncology, Medical University of Vienna
Rupert Bartsch, MD, PhD
Principal Investigator
Consultant Hematology and Medical Oncology, Medical University of Vienna

Kontakt

Studienlocations
(3 von 9)

Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

- 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 paraffin-embedded [FFPE], no cytology/cell block, no

bone/decalcified bone sample) of primary tumor or any metastatic site from biopsy

collected after last round of prior treatment and ≤ 6 months prior to HER3-DXd,

if possible, 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). Collection and/or shipment of

pre-treatment tumor tissue biopsy for retrospective biomarker testing should be

at least initiated treatment at the time of inclusion.

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. 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 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.

Studien-Rationale

Primary outcome:

1. Efficacy: Local determination of intracranial objective response rate (ORR-IC) in cohort 1 and cohort 2. (Time Frame - 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.

2. Efficacy: Overall survival (OS) rate at 3 months in cohort 3. (Time Frame - 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.

Secondary outcome:

1. Efficacy: Central determination of ORR in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

2. Efficacy: progression-free survival (PFS) in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

3. Efficacy: bicompartmental clinical benefit rate (CBR) in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

4. Efficacy: disease control rate (DCR) in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

5. Efficacy: time to response (TTR) in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

6. Efficacy: duration of response (DoR) in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

7. Efficacy: best percentage of change in tumor burden in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

8. Efficacy: overall survival (OS) in cohort 1 and cohort 2. (Time Frame - 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.

9. Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) in cohort 1, cohort 2, and cohort 3. (Time Frame - 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.

10. 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. (Time Frame - 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.

11. 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. (Time Frame - 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.

12. 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. (Time Frame - 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.

13. 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. (Time Frame - 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.

Geprüfte Regime

  • Patritumab deruxtecan (HER3-DXd):
    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.

Quelle: ClinicalTrials.gov


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