Evaluation of Bintrafusp Alfa Combined with Chemoradiation in Esophageal Squamous Cell Carcinoma: A Feasibility Study

Trial ID: 2023-503312-32-00
Protocol: 73750
Sponsor: Amsterdam UMC Stichting

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Diseases & Conditions

Oesophageal squamous cell carcinoma

Objectives

The primary objective of this study is to evaluate the **feasibility** of administering **bintrafusp alfa** in combination with definitive chemoradiation, which includes carboplatin, paclitaxel, and radiation, in patients diagnosed with **esophageal squamous cell carcinoma** or carcinoma of the gastroesophageal junction. This assessment focuses on the completion of treatment with bintrafusp alfa, which is clinically relevant as it may offer a novel therapeutic approach for this patient population.

Secondary objectives include:

Assessing the incidence and severity of toxicity as defined by CTCAE v5 and Radiation Oncology Group (RTOG) criteria.
Evaluating the safety profile of bintrafusp alfa when used in conjunction with definitive chemoradiotherapy.
Determining the percentage of patients completing chemotherapy and radiation treatment.
Calculating the withdrawal rate from chemoradiation due to complications related to bintrafusp alfa.
Measuring infield locoregional progression-free survival and any progression-free survival.
Assessing overall survival rates.
Evaluating quality of life, with a particular focus on dysphagia.
Conducting exploratory biomarker analyses from tumor tissue and blood-derived samples to correlate with safety and clinical outcomes.

These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on patient safety, treatment adherence, and overall clinical outcomes.

Participants

The clinical trial involves participants diagnosed with **esophageal squamous cell carcinoma**. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 2, indicating they are fully active or capable of self-care. Participants are required to have adequate hematological, renal, and hepatic functions. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the inclusion of individuals with surgically irresectable tumors or those with locoregional recurrences without distant metastasis. Participants must be accessible for management and follow-up at the treatment center. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **feasibility** of combining **bintrafusp alfa** with definitive chemoradiation in patients with **esophageal squamous cell carcinoma**. This is a phase 2, randomized, double-blind, controlled trial. The trial aims to assess the completion of treatment with bintrafusp alfa in conjunction with chemoradiation, which includes carboplatin, paclitaxel, and radiation. The study is expected to run until July 31, 2029, with recruitment having commenced on December 30, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven squamous cell carcinoma of the esophagus or gastroesophageal junction, adequate organ function, and an ECOG performance status of 0-2. Following the screening, participants will receive treatment over a maximum period of 43 weeks, with regular follow-up visits to monitor treatment progress and assess any adverse events. The primary endpoint is the percentage of patients completing at least two of the three planned cycles of bintrafusp alfa. Secondary endpoints include the incidence and severity of toxicity, safety, progression-free survival, overall survival, and quality of life.

The expected length of participant involvement is up to 43 weeks, with conditions for early termination including significant adverse events or disease progression. Participants will also attend an end-of-study visit to evaluate the overall outcomes and any long-term effects of the treatment. The trial will adhere to strict protocols to ensure the safety and well-being of participants, with regular assessments and monitoring throughout the study duration.

Treatment

The clinical trial involves the administration of **Bintrafusp alfa**, a novel experimental medication, which is a **concentrate for solution for infusion**. The active substance, **bintrafusp alfa**, is a protein-based therapeutic agent designed to inhibit both PD-L1 and TGF-β pathways. This dual-action mechanism is intended to enhance the immune response against tumor cells. The pharmaceutical form of the medication is a concentrate that requires preparation into a solution for intravenous infusion. The maximum daily dose of bintrafusp alfa is 2400 mg, with the same amount being the maximum total dose per treatment cycle. The treatment period is set to a maximum of 43 days. The administration route is via **IV infusion**, and the dosing schedule is determined by the study protocol to ensure optimal therapeutic efficacy and safety.

In addition to the experimental treatment, participants will receive standard-of-care therapy, which includes definitive chemoradiation. This involves the administration of **carboplatin** and **paclitaxel**, alongside radiation therapy. These non-experimental treatments are well-established in the management of esophageal squamous cell carcinoma and are used in combination with bintrafusp alfa to assess the feasibility and potential enhancement of therapeutic outcomes. The dosing and administration of carboplatin and paclitaxel follow standard clinical guidelines, and their integration into the study protocol is designed to complement the investigational treatment.

Participant compliance with the treatment regimen is monitored through regular assessments and documentation of infusion sessions. The study protocol includes specific guidelines for the preparation and administration of the infusion solution, as well as criteria for dose adjustments based on individual patient responses and tolerability. The trial aims to evaluate the completion of treatment with bintrafusp alfa in combination with chemoradiation, focusing on the feasibility and safety of this therapeutic approach in patients with squamous cell carcinoma of the esophagus or gastroesophageal junction.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the feasibility of treatment, defined as the percentage of patients completing at least two of the three planned cycles of **bintrafusp alfa**. Secondary endpoints include the incidence and severity of toxicity, safety of the combination therapy, percentage completion of chemotherapy and radiation treatment, infield locoregional progression-free survival, any progression-free survival, overall survival, and quality of life with a focus on dysphagia. Additionally, potential biomarker development will be evaluated through the assessment of tumor and duodenal biopsies, feces, and blood samples. The occurrence of treatment-emergent adverse events (TEAEs) and treatment-related adverse events, including laboratory test abnormalities of grade ≥3, will also be monitored. Patient-reported outcomes, such as anxiety, depression, worry of cancer progression, and work productivity, will be collected to provide further insights into the efficacy of the treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically proven squamous cell carcinoma of the esophagus or gastro esophageal junction
Written, voluntary informed consent
Patients must be accessible to management and follow-up in the treatment center
Surgically irresectable (T1-T4a, N0 or N+, M0), as determined by Endoscopic Ultra Sound (EUS), PET scan and diagnostic CT scan of neck, thorax and abdomen. Patients with M1 disease solely on the basis of supraclavicular metastasis are eligible. Patients with resectable tumors refusing radical surgery or inoperable patients due to comorbidity are eligible
Locoregional recurrences without distant metastasis after surgery alone or endoscopical resection
Locoregional recurrences without distant metastasis after neoadjuvant chemoradiation + resection or definitive chemoradiation outside the previously irradiated area, provided that full dose of radiation can safely be delivered
If the tumor extends below the gastroesophageal (GE) junction into the proximal stomach, the bulk of the tumor must involve the esophagus or GE junction
Age ≥ 18
ECOG performance status 0-2
Adequate hematological, renal and hepatic functions
Tumors that cannot be passed with an endoscope for endoscopic ultrasound are eligible if all other criteria are fulfilled.

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Exclusion Criteria

Past or current history of malignancy other than entry diagnosis interfering with prognosis of esophageal cancer
Patient with tracheo-esophageal fistula or extension into the mucosal layer of the trachea, highly at risk to develop fistula. Thus, tumor extension to the trachea is allowed, but not through the trachea
Patient with aortal involvement with high risk of bleeding or developing a fistula
Patients with pathological lymph nodes at both supraclavicular and truncus coeliacus level
Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation
Patient (male or female) in the reproductive age is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment
Previous chemotherapy, radiation and/or treatment with checkpoint inhibitors for the currently present esophageal tumor
Previous chemotherapy and/or treatment with targeted agents and/or checkpoint inhibitors for other forms of cancer within the last six months
Previous radiation to the mediastinum precluding full dose radiation of the currently present esophageal tumor
Presence of an esophageal stent
History of bleeding diathesis or major bleeding event (grade ≥ 2) in the month prior to first dose of trial treatment
Current use of direct oral anticoagulants or coumarins
Clinically significant cardiovascular disease precluding safe treatment with chemoradiation
Evidence of pulmonary fibrosis and/or clinically significant impairment of lung function precluding safe treatment with chemoradiation. In case of doubt about pulmonary function, a lung function test should be performed and, in case of abnormalities, discussed with the principle investigator
Serious underlying medical condition which would impair the ability of the patient to receive the planned treatment, including prior allergic reactions to drugs containing cremophor, such as teniposide or cyclosporine
Mental status that would prohibit the understanding and giving of informed consent
Inadequate caloric- and/or fluid intake despite consultation of a dietician and/or tube feeding
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine for patients with a history of autoimmune-related hypothyroidism, insulin for patients with type 1 diabetes mellitus, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with vitiligo with dermatological manifestations only are eligible to enter the study
Diagnosis of HIV unless stable on antiretroviral therapy for at least 4 weeks, no evidence of multi-drug resistance, viral load of < 400 copies/ml and CD4+ T-cells ≥ 350 cells/μl
Active HBV/HCV. Participants on a stable dose of antiviral therapy with HBV/HCV viral load below the limit of quantification are eligible
A diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10 mg/day prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
Evidence of interstitial lung disease or active, non-infectious pneumonitis
An active infection requiring systemic therapy, which has not resolved 3 days (simple infection such as cystitis) to 7 days (severe infection such as pyelonephritis) prior to the first dose of trial treatment
Administration of a live vaccine within 30 days prior to the first dose of trial treatment. Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved COVID vaccines are permitted
Patients with prior allogeneic stem cell or solid organ transplantation