A Clinical Study of the Anti-cancer Effects of an Investigational Therapy or Chemotherapy in Patients With Recurring Uterine Cancer

Official title

A Phase III, Randomized, Multi-site, Open-label Trial of BNT323/DB-1303 Versus Investigator's Choice of Chemotherapy in Previously Treated Patients With HER2- Expressing Recurrent Endometrial Cancer

Overview

The study is divided into two cohorts (Cohort 1 and Cohort 2), to which participants will be enrolled based on the amount of human epidermal growth factor receptor 2 (HER2) in their tumor sample. In Cohort 1, the main goal is to assess how well BNT323 (also known as DB-1303) or chemotherapy (doxorubicin or paclitaxel \[or docetaxel, if participants cannot take paclitaxel\]) works by determining the progression-free survival (PFS) of participants who have been previously treated with immune checkpoint inhibitors (ICIs). In Cohort 2, the main goal is to assess how well BNT323 works by determining the objective response rate (ORR), that is, the percentage of participants whose tumor shrinks (partial response) or disappears (complete response) after treatment. The safety of BNT323 will also be assessed by following the occurrence of unfavorable/adverse effects that are seen after treatment. Other measures include the pharmacokinetics of BNT323 (or how BNT323 moves through and out of the body), the body's immune response, and the impact on quality of life.

Detailed description

This is an open-label, randomized, multi-site, Phase III, interventional clinical study designed to determine the efficacy and safety of BNT323 compared with investigator's choice of single agent chemotherapy in previously treated participants with recurrent endometrial cancer (including HER2 1+ or 2+ score as determined using a centralized immunohistochemistry \[IHC\] analysis method), whose disease has progressed on at least one line of platinum-based therapy and ICI (Cohort 1). In addition, participants with recurrent endometrial cancer with HER2 IHC 3+ score will be enrolled in a BNT323 monotherapy arm (Cohort 2) to further investigate the efficacy and safety of BNT323.

In Cohort 1, participants will be randomized 2:1 to receive either BNT323/DB-1303 or investigator's choice of single agent chemotherapy, preferably doxorubicin or paclitaxel (or docetaxel if contraindicated to paclitaxel and available at the site) until Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) defined progressive disease (PD) unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.

In Cohort 2, participants will receive BNT323 monotherapy until RECIST v1.1 defined PD unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.

The study consists of a screening period, a treatment period, a safety follow-up period, an efficacy follow-up period, and a long-term survival follow-up. The expected treatment duration per participant is \~6 months, followed by an anticipated long-term survival follow-up period of up to 53 months.

Interventions

• Drug BNT323/DB-1303
  intravenous (IV) infusion
• Drug Doxorubicin
  IV bolus or infusion
• Drug Paclitaxel
  IV infusion
• Drug Docetaxel
  IV infusion

Primary outcome measures

• Cohort 1: PFS assessed by blinded independent central review (BICR) in participants with HER2 IHC 1+/2+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 2: ORR assessed by BICR in participants with HER2 IHC 3+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]

Secondary outcome measures (12)

• Cohort 1: Overall survival (OS) in participants with HER2 IHC 1+/2+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 1: PFS assessed by the investigator in participants with HER2 IHC 1+/2+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 1: ORR assessed by BICR in participants with HER2 IHC 1+/2+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 1: ORR assessed by the investigator in participants with HER2 IHC 1+/2+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 1: Duration of response (DoR) assessed by BICR in participants with HER2 IHC 1+/2+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 1: DoR assessed by the investigator in participants with HER2 IHC 1+/2+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 1: Percentage of participants with HER2 IHC 1+/2+ recurrent endometrial cancer with occurrence of treatment-emergent adverse events (TEAEs) [Time frame: Up to 35 days after the last dose of study treatment]
• Cohort 1: Percentage of participants with HER2 IHC 1+/2+ recurrent endometrial cancer with occurrence of TEAEs leading to drug interruption, dose reduction, or discontinuation of study treatment. [Time frame: Up to 35 days after the last dose of study treatment]
• Cohort 2: ORR assessed by the investigator participants with HER2 IHC 3+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 2: DoR assessed by BICR in participants with HER2 IHC 3+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 2: DoR assessed by the investigator in participants with HER2 IHC 3+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]
• Cohort 2: PFS assessed by BICR in participants with HER2 IHC 3+ recurrent endometrial cancer [Time frame: Up to approximately 53 months]

Eligibility criteria

Inclusion criteria

• Are female adults (defined as ≥18 years of age or acceptable age according to local regulations at the time of voluntarily giving informed consent).
• Have histologically confirmed endometrial cancer that:

• Is recurrent,
• Has a HER2 IHC score of 1+, 2+ (Cohort 1), or 3+ (Cohort 2) as determined by central laboratory testing for HER2 expression, and
• Is not defined as a true sarcoma (i.e., leiomyosarcoma or endometrial stromal sarcoma). Note: Uterine carcinosarcoma is allowed.
• Have measurable disease defined by RECIST v1.1.
• Have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2.
• Have recurrent endometrial cancer and meet any of the following:

• developed recurrence <12 months from completing platinum-based chemotherapy given as adjuvant therapy for Stage I to III disease, or
• developed recurrence after platinum-based chemotherapy in the recurrent/metastatic setting.
• Have received prior ICI treatment (i.e., anti-programmed death 1/anti-programmed death-ligand 1)
• Have a life expectancy of ≥12 weeks at screening.

Exclusion criteria

• Are ineligible for all options in the investigator's choice of chemotherapy arm, per local prescribing information and institutional guidelines (applicable to Cohort 1 only).
• Have a history of small bowel obstruction requiring hospitalization within the past 3 months prior the first dose of study treatment.
• Have an uncontrolled intercurrent illness that would limit compliance with study requirement or substantially increase risk of incurring adverse events.
• Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, or peritoneal shunt within 2 weeks prior to the first dose of study treatment.
• Have a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Participants with prior use of immunosuppressive medication within 14 days prior to the first dose of study treatment, except for intranasal and inhaled corticosteroids or systemic corticosteroids at doses of less than 10 mg/day of prednisone or equivalent, and topical corticosteroids. Participants receiving corticosteroids may continue if the dose is stable upon giving main informed consent.
• Have a lung-specific intercurrent clinically significant illness including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months prior to the first dose of study treatment, severe asthma, chronic obstructive pulmonary disorder with moderate acute exacerbations, restrictive lung disease, pulmonary fibrosis, radiation pneumonitis, significant pleural effusion etc.), or any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), and/or prior pneumonectomy (complete).
• Have uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to the first dose of study treatment.
• Have unresolved toxicities from previous anti-cancer therapy, defined as toxicities (other than alopecia, fatigue, or endocrinopathies that are well controlled) not yet resolved to Grade ≤1 or baseline.
• Are pregnant or breastfeeding or are planning pregnancy during the study or within 7 months after the last dose of study treatment.
• Have a history of allergies, hypersensitivities, or intolerance to study treatments (investigational medicinal products and auxiliary medicinal product) including any excipients thereof or to other monoclonal antibodies. Participants who have successfully undergone a desensitization process and are able to tolerate the drug are eligible.
• Had prior treatment with topoisomerase I inhibitors, including ADCs.
• Have left ventricular ejection fraction <55% by either echocardiography or multiple-gated acquisition within 28 days prior to the first dose of study treatment. This includes participants with tissue doppler E/e' ratio >15.

NOTE: Other protocol defined Inclusion/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 · 27 centers

• Anhui Provincial Hospital — Hefei
• Beijing Cancer Hospital — Beijing
• The Second Affiliated Hospital of Chongqing Medical University — Chongqing
• Fujian Provincial Cancer Hospital — Fuzhou
• First Affiliated Hospital of Xiamen University — Xiamen
• Gansu Provincial Maternity and Child-care Hospital — Lanzhou
• The First Affiliated Hospital of Sun Yat-sen University — Guangzhou
• Cancer Hospital of Shantou University Medical College — Shantou
• … and 19 more centers

South Korea · 13 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 13 centers

Center list to be confirmed — check the primary protocol.

Italy · 11 centers

Center list to be confirmed — check the primary protocol.

United States · 10 centers

• Yale University School of Medicine — New Haven
• MedStar Washington Hospital Center — Washington D.C.
• Broward Health Medical Center — Fort Lauderdale
• OSF Saint Francis Medical Center — Peoria
• The Center of Hope Reno — Reno
• NYU Langone Hospital - Long Island — Mineola
• NYU Langone Health — New York
• Miami Valley Hospital South — Centerville
• … and 2 more centers

Australia · 10 centers

• Adelaide Oncology & Haematology — Adelaide
• Cancer Research SA — Adelaide
• Monash Health Clinical Trial Center — Clayton
• Gosford Hospital — Gosford
• Peter MacCallum Cancer Centre — Melbourne
• Frankston Hospital — Melbourne
• Shoalhaven Cancer Care Centre — Nowra
• Sunshine Hospital — Saint Albans
• … and 2 more centers

Brazil · 9 centers

• Fundação Sao Francisco Xavier — Ipatinga
• Hospital de Clínicas de Passo Fundo — Passo Fundo
• Instituto de Pesquisa Clínica - Hospital Moinhos de Vento — Porto Alegre
• Hospital de Clínicas de Porto Alegre — Porto Alegre
• Irmandade da Santa Casa de Misericórdia de Porto Alegre — Porto Alegre
• HPT São Lucas da PUCRS - UBEA — Porto Alegre
• Fundação Faculdade Regional de Medicina de São José do Rio Petro — São José do Rio Preto
• Hospital Sirio Libanês — São Paulo
• … and 1 more center

Spain · 9 centers

Center list to be confirmed — check the primary protocol.

France · 8 centers

Center list to be confirmed — check the primary protocol.

Belgium · 6 centers

• Institut Jules Bordet — Brussels
• Cliniques Universitaires Saint-Luc — Brussels
• Universitair Ziekenhuis Gent — Ghent
• AZ Groeninge VZW — Kortrijk
• UZ Leuven — Leuven
• CHU UCL Namur-Sainte-Elisabeth — Namur

Czechia · 6 centers

• Gynekologicko-porodnická klinika, Fakultni nemocnice Brno — Brno
• University Hospital Olomouc - Onkologická klinika- Fakultni — Olomouc
• Fakultní nemocnice Ostrava — Ostrava
• Vseobecna fakultni nemocnice v Praze — Prague
• Fakultní nemocnice Motol a Homolka — Prague
• Fakultní nemocnice Bulovka — Prague

Taiwan · 6 centers

Center list to be confirmed — check the primary protocol.

Turkey (Türkiye) · 6 centers

Center list to be confirmed — check the primary protocol.

Greece · 5 centers

Center list to be confirmed — check the primary protocol.

Israel · 5 centers

Center list to be confirmed — check the primary protocol.

Argentina · 4 centers

• Hospital Británico de Buenos Aires — Buenos Aires
• Investigaciones CORI S.R.L. — La Rioja
• Hospital Provincial del Centenario — Rosario
• Centro Oncológico de Excelencia — San Juan

Denmark · 4 centers

• Aalborg Universit Hospital — Aalborg
• Rigshospitalet — Copenhagen
• Herlev og Gentofte Hospital — Herlev
• Odense University Hospital — Odense

Canada · 3 centers

• Jewish General Hospital — Montreal
• Health Sciences Centre — St. John's
• Princess Margaret Cancer C — Toronto

Finland · 3 centers

• Kuopio University HPT — Kuopio
• … and 2 more centers

Hungary · 3 centers

Center list to be confirmed — check the primary protocol.

Sweden · 3 centers

Center list to be confirmed — check the primary protocol.

Netherlands · 2 centers

Center list to be confirmed — check the primary protocol.

Norway · 2 centers

Center list to be confirmed — check the primary protocol.

Poland · 2 centers

Center list to be confirmed — check the primary protocol.

Singapore · 1 center

Center list to be confirmed — check the primary protocol.

Publications

• Secord AA, Powell MA, McAlpine J. Molecular Characterization and Clinical Implications of Endometrial Cancer. Obstet Gynecol. 2025 Nov 1;146(5):660-671. doi: 10.1097/AOG.0000000000006080. Epub 2025 Sep 18. PMID 40966692

Identifiers

NCT: NCT06340568 · BNT323-01 · GOG-3105 · 2023-507525-42-00 · ENGOT- EN25/NSGO-CTU

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗