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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Neoplasm, Esophageal; Neoplasm, Esophagus; Malignant Esophagus Tumor
• Intervention / Treatment: Combination product: Bintrafusp alfa

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hanneke WM van Laarhoven, M.D, PhD; Phone Number: 31 20 5665955; Email: h.vanlaarhoven@amsterdamumc.nl
• Study Contact Backup: Name: Linde Veen; Phone Number: 31 20 5665955; Email: l.veen1@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081HV
      • Recruiting
      • Amsterdam UMC
      • Contact: Linde Veen; Phone Number: +31612538338; Email: l.veen1@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Immunotherapy; Adding bintrafusp alfa (a combined TGF-β en PDL-1 inhibitor) to definitive chemoradiation with Paclitaxel and Carboplatin

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 β receptor II (TGFβRII or TGFβ 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.; Other Names: M7824

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility bintrafusp alfa	The primary endpoint is feasibility defined as percentage completion of treatment with bintrafusp alfa.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity according to different criteria	• Incidence and severity of toxicity defined according to CTCAE v5 and Radiation Oncology Group (RTOG) criteria.	36 months
Completion of treatment	Percentage completion of chemotherapy and radiation treatment	36 months
Progression free survival	Any progression free survival	36 months
Survival	Overall survival	36 months
QOL	Quality of life, with a special focus on dysphagia	36 months
Local progression free survival	Local in-field progression free survival	36 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker development	Potential biomarker development based on assessment of tumour and duodenal biopsies, blood samples and faecal samples	36 months
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

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Hanneke WM van Laarhoven, M.D., PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2020
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): November 1, 2028

Study Registration Dates

• First Submitted: October 15, 2020
• First Submitted That Met QC Criteria: October 15, 2020
• First Posted (Actual): October 20, 2020

Study Record Updates

• Last Update Posted (Actual): January 19, 2021
• Last Update Submitted That Met QC Criteria: January 15, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: esophageal cancer; PD-L1; TGF-β; definitive chemoradiation; feasability
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Neoplasms; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma
• Other Study ID Numbers: Volgt 2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No