DAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer (epNEC) to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard Chemotherapy

Official title

A Phase III, Multi-center, Open-label, Randomised, Controlled Trial of Intravenous Obrixtamig in Combination With Carboplatin and Etoposide vs. Carboplatin and Etoposide as First-line Therapy in DLL3-positive Patients With Unresectable Locally Advanced or Metastatic Extrapulmonary Neuroendocrine Carcinomas

Overview

This study is open to adults with advanced extrapulmonary neuroendocrine cancer. The purpose of this study is to find out if a study medicine called obrixtamig plus standard chemotherapy (carboplatin and etoposide) improves survival when compared to standard chemotherapy (carboplatin and etoposide) alone. Obrixtamig is an antibody-like molecule that may help the immune system fight cancer. Another purpose of the study is to test a medical device being developed to measure levels of the tumour marker delta-like ligand 3 (DLL3). Participants are put into 2 groups randomly, which means by chance. One group (treatment arm) receives obrixtamig and standard chemotherapy followed by obrixtamig alone for up to 3 years. The other group (control arm) receives standard chemotherapy without obrixtamig for about 4 months. All treatments are given as infusions into a vein. During the study, participants in both groups visit the study site regularly. Participants in the treatment arm stay overnight at the study site following the first 2 obrixtamig treatments. The doctors regularly check participants' health and take note of any unwanted effects. At some of the visits, doctors check the size of the tumour(s). The results are compared between the 2 groups to see whether the treatment works.

Interventions

• Drug Obrixtamig
  Obrixtamig
• Drug Carboplatin
  Carboplatin
• Drug Etoposide
  Etoposide
• Device Ventana DLL3 RxDx assay
  Ventana DLL3 RxDx assay

Primary outcome measures

• Overall survival (OS) [Time frame: Up to 38 months]

Secondary outcome measures (9)

• Progression-free survival (PFS) [Time frame: Up to 38 months]
• Change from baseline to Week 19 in the physical functioning domain of the EORTC QLQ-C30 [Time frame: At baseline, up to week 19]
• Objective response (OR) [Time frame: Up to 38 months]
• Duration of response (DoR) [Time frame: Up to 38 months]
• Disease control (DC) [Time frame: Up to 38 months]
• Occurrence of treatment-emergent Grade 3 or greater Cytokine release syndrome (CRS) [Time frame: Up to 38 months]
• Occurrence of treatment-emergent Grade 3 or greater Immune cell associated neurotoxicity syndrome (ICANS) [Time frame: Up to 38 months]
• Occurrence of treatment-emergent adverse events (AEs) leading to permanent discontinuation of trial medication during the on-treatment period [Time frame: Up to 38 months]
• Occurrence of treatment-emergent AEs leading to dose modification of trial medication (i.e. dose interruption, dose delay, dose reduction) [Time frame: Up to 38 months]

Eligibility criteria

Inclusion criteria

• Patients with poorly differentiated unresectable locally advanced or metastatic extrapulmonary neuroendocrine carcinoma (epNEC) with Ki-67 >20% or mitotic rate mitotic rate with number of mitoses >20 per 2 mm2, regardless of primary site (including site of unknown origin)
• Patients with tumours with mixed histologies are eligible only if neuroendocrine carcinoma component is predominant and represents more than 70% of the overall tumour tissue
• No prior systemic treatment for unresectable locally advanced or metastatic epNEC (except for the completed one cycle of standard platinum + etoposide). Prior peri-operative chemotherapy or -radiation for curative intention is allowed if at least 6 months have elapsed between completion of this therapy and diagnosis of unresectable locally advanced or metastatic disease
• Patients who have finished one cycle of standard platinum + etoposide regimen as first-line treatment (Cycle 0: etoposide with carboplatin or cisplatin, administered at a minimum dose of cisplatin 75 mg/m2 or carboplatin area under the curve (AUC) 5 and etoposide 80 mg/m2) prior to randomisation
• Patients must comply with criteria for receiving further chemotherapy treatment as first-line standard of care (SoC) treatment within 28 days after the start of the initial chemotherapy (Cycle 0)
• Adequate archival Formalin-Fixed Paraffin-Embedded (FFPE) tumour tissue, as specified in the Laboratory Manual, must be available for central laboratory analysis of Delta-like ligand 3 (DLL3) expression status. Tumours must be positive (as defined in the diagnostic study protocol) for DLL3 expression status assessed by investigational VENTANA DLL3 (SP347) RxDx Assay
• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
• Male or female participants ≥18 years old and at least at the legal age of consent in countries where it is greater than 18 years at the time of signature of the informed consent form (ICF) Further inclusion criteria apply.

Exclusion criteria

• Presence of leptomeningeal disease and/or carcinomatous meningitis
• Patients with diagnosis of Merkel cell carcinoma or medullary thyroid carcinoma
• Patients with neuroendocrine prostate cancer
• Patients with well-differentiated neuroendocrine tumours of any grade according to the world health organization (WHO) classification, 5th edition
• Patients with a history of well differentiated Neuroendocrine tumour (NET) tumour that transformed into poorly differentiated Neuroendocrine carcinoma (NEC)
• Previous treatment with obrixtamig or other DLL3-targeting therapies (e.g. T-cell engager (TcEs), cell therapies, antibody-drug conjugates, or radiopharmaceuticals)
• Previous treatment with anti-PD-1 or programmed death ligand 1 (PD-L1) therapies during the one cycle of standard platinum + etoposide first-line chemotherapy (Cycle 0)
• Toxicity from previous treatments that has not resolved to ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or grade prior to Cycle 0. Participants with alopecia any grade, CTCAE ≤Grade 2 asthenia/fatigue, amenorrhea/menstrual disorders any grade, CTCAE ≤Grade 2 peripheral neuropathy, and/or CTCAE ≤Grade 2 endocrinopathies controlled by replacement therapy, and toxicities, which are considered irreversible but stable for at least 4 weeks, per Investigator judgement may be eligible Further exclusion criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 23 centers

• Beijing Cancer Hospital — Beijing
• Beijing GoBroad Hospital — Beijing
• The First Hospital of Jilin University — Changchun
• Xiangya Hospital, Central South University — Changsha
• Hunan Province Tumor Hospital — Changsha
• Sichuan Cancer Hospital — Chengdu
• West China Hospital, Sichuan University — Chengdu
• Chongqing University Affiliated Cancer Hospital — Chongqing
• … and 15 more centers

United States · 20 centers

• Mayo Clinic — Scottsdale
• City of Hope-Duarte-56419 — Duarte
• University of California San Francisco — San Francisco
• University of California Los Angeles — Santa Monica
• Mayo Clinic - Florida — Jacksonville
• Emory University — Atlanta
• The Skip Viragh Outpatient Cancer Research Building — Baltimore
• Dana-Farber Cancer Institute — Boston
• … and 12 more centers

Germany · 13 centers

Center list to be confirmed — check the primary protocol.

Japan · 13 centers

Center list to be confirmed — check the primary protocol.

Spain · 10 centers

Center list to be confirmed — check the primary protocol.

France · 8 centers

• Hôpital Beaujon — Clichy
• HOP François Mitterrand — Dijon
• Hôpital Edouard Herriot — Lyon
• INS Paoli-Calmettes — Marseille
• HOP Haut-Lévêque — Pessac
• … and 3 more centers

Italy · 8 centers

Center list to be confirmed — check the primary protocol.

Brazil · 5 centers

• Hospital de Amor — Barretos
• Instituto D'Or de Pesquisa E Ensino - Pe — Recife
• Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto — São José do Rio Preto
• ICESP - Instituto do Cancer do Estado de Sao Paulo — São Paulo
• A.C. Camargo — São Paulo

Portugal · 5 centers

Center list to be confirmed — check the primary protocol.

Argentina · 4 centers

• Centro Medico Reumatologico - OMI — CABA
• Hospital Britanico de Buenos Aires — CABA
• Clinica Privada Independencia — Munro
• Sanatorio Parque S.A. — Rosario

Australia · 4 centers

• Royal North Shore Hospital — St Leonards
• Flinders Medical Centre — Bedford Park
• Peter MacCallum Cancer Centre — Melbourne
• Fiona Stanley Hospital — Murdoch

Belgium · 4 centers

• Cliniques Universitaires Saint-Luc — Brussels
• Universitair Ziekenhuis Antwerpen — Edegem
• UZ Leuven — Leuven
• Centre Hospitalier Universitaire de Liège — Liège

Finland · 4 centers

• Helsinki University Hospital — Helsinki
• KYS Sädesairaala — Kuopio
• Tampere University Hospital — Tampere
• Turku University Hospital / TYKS — Turku

Israel · 4 centers

Center list to be confirmed — check the primary protocol.

Netherlands · 4 centers

Center list to be confirmed — check the primary protocol.

Norway · 4 centers

Center list to be confirmed — check the primary protocol.

South Korea · 4 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 4 centers

Center list to be confirmed — check the primary protocol.

Chile · 3 centers

• Instituto Oncológico FALP — Providencia
• Bradford Hill- Centro de Investigación Clínica — Recoleta
• Clínica Alemana de Santiago S.A. — Santiago

Denmark · 3 centers

• Aarhus University Hospital — Aarhus N
• Rigshospitalet — Copenhagen
• Odense University Hospital — Odense C

Sweden · 3 centers

Center list to be confirmed — check the primary protocol.

Taiwan · 3 centers

Center list to be confirmed — check the primary protocol.

Austria · 2 centers

• Medical University of Graz — Graz
• AKH - Medical University of Vienna — Vienna

Czechia · 2 centers

• Masaryk Memorial Cancer Institute — Brno
• University Hospital Hradec Kralove (FNHK) — Hradec Králové

Hong Kong · 2 centers

Center list to be confirmed — check the primary protocol.

Poland · 2 centers

Center list to be confirmed — check the primary protocol.

Canada · 1 center

• Sunnybrook Health Sciences Centre — Toronto

Mexico · 1 center

Center list to be confirmed — check the primary protocol.

New Zealand · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07544654 · 1438-0011 · 2025-523869-22-00 · U1111-1328-6623

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗