Tapestry: Addition of TGF-β and PDL-1 Inhibition to Definitive Chemoradiation in Esophageal Squamous Cell Carcinoma

Neoplasm, Esophageal Clinical Trial

— TAPESTRY  

Official title:

TGF-β And PDL-1 Inhibition in Esophageal Squamous Cell Carcinoma Combined With Chemoradiation TheRapY

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04595149
• Other study ID #: Volgt 2
• Status: Recruiting
• Phase: Phase 2
• Start date: November 30, 2020
• Est. completion date: November 1, 2028

Study information

• Verified date: January 2021
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Hanneke WM van Laarhoven, M.D, PhD
• Phone: 31 20 5665955
• Email: h.vanlaarhoven[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The outcome of irresectable oesophaguscancer is poor, despite the fact that curative treatment with definitive chemoradiation is possible. The outcome of treatment can possibly be improved by combining chemoradiation with immunotherapy such as bintrafusp alfa, a combined TGF-β and PD-L1 inhibitor. In this study investigators investigate the feasibility of combining bintrafusp alfa with definitive chemoradiation in patients with irresectable squamous cell carcinoma of the esophagus.

Description:

This is a non-randomized feasibility study in which patients with esophageal squamous cell carcinoma receive bintrafusp alfa (B), combined with paclitaxel (P), carboplatin (C), and radiation (RT). For safety reasons the first ten patients will be treated in a maximum of four selected hospitals. If no unexpected safety signals occur, the study will start in all participating centers.

Paclitaxel 50 mg/m2 and Carboplatin AUC = 2 will be given by intravenous infusion on days 1, 8, 15, 22, 29, and 36. External beam radiotherapy will be delivered to a total dose of 50.4 Gy in 28 fractions of 1.8 Gy, 5 fractions per week, starting the first day of the first cycle of chemotherapy (see below for details on radiation technique).

Bintrafusp alfa will be given iv every three weeks on day 1, 22, and 43 at a dose of 2400 mg.

Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Wk 7 Day 1 Day 8 Day 15 Day 22 Day 29 Day 36 Day 43 __________________________________________________

P P P P P P C C C C C C B B B RTx5 RTx5 RTx5 RTx5 RTx5 RTx3

__________________________________________________ P = paclitaxel; C = carboplatin, B = bintrafusp alfa RT = radiotherapy

Feasibility of this treatment strategy is the main focus of this study. In this study feasibility is defined as ≥80% of patients completing two cycles (of in total three) cycles of bintrafusp alpha. In the ART-DECO study, which included a similar patient population, more than 80% of patients was able to receive five cycles of carboplatin and paclitaxel (i.e. up to week 5) (personal communication dr. Hulshof). Therefore, the investigators will regard treatment with Bintrafusp alfa during chemoradiation feasible if ≥80% of patients complete two cycles of bintrafusp alfa, while with a completion rate ≤62% the treatment will be regarded unfeasible.

The primary end point of this feasibility study is the percentage of patients completing bintrafusp alfa treatment. This study requires 41 subjects to decide whether the proportion completing at least two cycles of bintrafusp alfa, P, is less than or equal to 0.62 or greater than or equal to 0.80. If the number of patients completing two or more cycles of Bintrafusp alfa is 31 or more, the hypothesis that P ≤ 0.62 is rejected with a target error rate of 0.05 and an actual error rate of 0.048. If the number of patients completing two or more cycles of bintrafusp alfa is 30 or less, the hypothesis that P ≥ 0,80 is rejected with a target error rate of 0.20 and an actual error rate of 0.182. The test statistic used is the one-sided one-sample test for binomial proportion, testing against the fixed reference proportion of 0.62. Taking into account 20% drop-out, 52 patients need to be included in the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 52
• Est. completion date: November 1, 2028
• Est. primary completion date: November 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven squamous cell carcinoma of the esophagus or gastro esophageal junction.

• 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.

• Tumors that cannot be passed with an endoscope for endoscopic ultrasound are eligible if all other criteria are fulfilled.

• 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 (cf. Appendix A).

• Adequate hematological, renal and hepatic functions defined as:

• Neutrophils = 1.5 x 109/L

• Platelets = 100 x 109/L

• Hemoglobin = 5.6 mmol

• Total bilirubin = 1.5 x upper normal limit

• Creatinine clearance (Cockroft) > 60 ml/min

• Written, voluntary informed consent

• Patients must be accessible to management and follow-up in the treatment center

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.

• 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.

• 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.

• Patients with prior allogeneic stem cell or solid organ transplantation.

Related Conditions & MeSH terms

• Carcinoma, Squamous Cell
• Esophageal Neoplasms
• Esophageal Squamous Cell Carcinoma
• Malignant Esophagus Tumor
• Neoplasm, Esophageal
• Neoplasm, Esophagus
• Neoplasms

Intervention

Combination Product:
• Bintrafusp alfa
Bintrafusp alfa (M7824, MSB0011359C) is an innovative first-in-class, bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor ß receptor II (TGFßRII or TGFß Trap) covalently linked via a flexible linker to the C-terminus of each heavy chain of an immunoglobulin G1 (IgG1) antibody blocking programmed death ligand 1 (anti-PD-L1). Bintrafusp alfa is the international nonproprietary name for M7824.

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC	Amsterdam	Noord-Holland

Sponsors (1)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarker development	Potential biomarker development based on assessment of tumour and duodenal biopsies, blood samples and faecal samples	36 months
Other	Patient reported outcomes	Patient reported outcomes other than quality of life, including but not limited to anxiety and depression, worry of cancer progression and work productivity.	36 months
Primary	Feasibility bintrafusp alfa	The primary endpoint is feasibility defined as percentage completion of treatment with bintrafusp alfa.	36 months
Secondary	Toxicity according to different criteria	• Incidence and severity of toxicity defined according to CTCAE v5 and Radiation Oncology Group (RTOG) criteria.	36 months
Secondary	Completion of treatment	Percentage completion of chemotherapy and radiation treatment	36 months
Secondary	Progression free survival	Any progression free survival	36 months
Secondary	Survival	Overall survival	36 months
Secondary	QOL	Quality of life, with a special focus on dysphagia	36 months
Secondary	Local progression free survival	Local in-field progression free survival	36 months