Organ Preservation With Durvalumab-based Immunotherapy in Combination With Chemoradiation as Definitive Therapy for Early Stage Esophageal Adenocarcinoma With Indication for Radical Surgery

NCT05713838 | Recruiting Phase 2 DMC

• 1 other identifier: PRESTO
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 22

Brief Summary

The present clinical trial is a prospective, investigator-initiated, single-arm, open-label, multicenter phase II trial investigating whether a definite organ preservation therapy consisting of the combination of durvalumab with chemoradiation is an efficient and safe treatment option for early stage, cT1 and cT2N0, esophageal adenocarcinoma with indication for radical surgery.

Conditions

Esophagus Adenocarcinoma

Keywords

esophageal adenocarcinoma; GEJ adenocarcinoma

Outcome Measures

Primary Outcomes (1)

• Rate of clinical and pathological complete response (cCR/pCR)

  Rate of clinical and pathological complete response rate at time of endoscopic re-evaluation (at the end of the core study treatment) according to Becker criteria and investigator-based RECIST v1.1 assessment as well as endoscopic response criteria similar to the Japanese Gastric Cancer Association Guideline

  8 weeks after completion of core treatment

Secondary Outcomes (6)

• Rate of cCR/pCR (long term follow up)

  1, 2 and 3 years after start of treatment

• Subgroup analysis of cCR/pCR

  8 weeks after completion of core treatment and after 1 year

• Rate of salvage surgery

  up to 48 months

• Mortality

  90 days, 12 months after start of treatment

• Determination of the sites of tumor relapse

  up to 48 months

Study Arms (1)

Durvalumab + Chemoradiotherapy

EXPERIMENTAL

Core Treatment: * D1: Durvalumab (1500 mg, IV) PLUS FLOT (50 mg/m² docetaxel, 85 mg/m² oxaliplatin, 200 mg/m² calcium folinate and 2600 mg/m² 5-FU 24h) * D15: FLOT (50 mg/m² docetaxel, 85 mg/m² oxaliplatin, 200 mg/m² calcium folinate and 2600 mg/m² 5-FU 24h), * D29: Durvalumab (1500 mg, IV) PLUS mFOLFOX (85 mg/m² oxaliplatin, 200 mg/m² calcium folinate, 400 mg/m² 5-FU bolus and 1600 mg/m² 5-FU 48h) PLUS 50 Gy radiotherapy * 5 weeks with 5 days a week radiotherapy (25 daily fractions, 2.0 Gy = ∑50Gy) * D43: mFOLFOX (85 mg/m² oxaliplatin, 200 mg/m² calcium folinate, 400 mg/m² 5-FU bolus, 1600 mg/m² 5-FU 48h) (radiation cont.) * D57: Durvalumab (1500 mg, IV) PLUS mFOLFOX (85 mg/m² oxaliplatin, 200 mg/m² calcium folinate, 400 mg/m² 5-FU bolus and 1600 mg/m² 5-FU 48h) (radiation cont.) Maintenance Phase Durvalumab monotherapy max. 12 cycles à 4 weeks: Durvalumab (1500 mg, IV, Q4W) D1

Drug: Durvalumab; Drug: FLOT; Drug: mFOLFOX-6; Radiation: Radiotherapy

Interventions

Durvalumab DRUG

1500 mg Durvalumab, IV, day 1 Q4W (max. 15 cycles)

Also known as: IMFINZI

Durvalumab + Chemoradiotherapy

FLOT DRUG

50 mg/m² docetaxel, 85 mg/m² oxaliplatin, 200 mg/m² calcium folinate and 2600 mg/m² fluorouracil as 24 h-infusion, 2 cycles

Durvalumab + Chemoradiotherapy

mFOLFOX-6 DRUG

85 mg/m² oxaliplatin, 200 mg/m² calcium folinate, 400 mg/m² fluorouracil as bolus dose and 1600 mg/m² fluorouracil as 48 h-infusion, ² cycles

Durvalumab + Chemoradiotherapy

Radiotherapy RADIATION

5 weeks with 5 days a week radiotherapy (25 daily fractions with 2.0 Gy = ∑50Gy)

Durvalumab + Chemoradiotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has given written informed consent.
• Patient is, in the investigator's judgement, willing and able to comply with the study protocol including the planned surgical treatment.
• Patient is ≥ 18 years of age at time of signing the written informed consent.
• Patient has been diagnosed with histologically confirmed esophageal adenocarcinoma (including gastroesophageal junction (GEJ) (Siewert I-III)) with:
• cT2 N0 M0 stage or T1 N0 M0 stage and a given indication for radical surgical resection to current S3-guidelines (this includes patients with a given indication for radical surgery after endoscopic-resection of a cT1-2 N0 M0 tumor \[poor grading or L1/V1 invasion or basal R1 resection or deep submucosal infiltration\]) (see section 4.2.3 for detailed information).
• tumor is considered medically and technically resectable.
• Tumor is tested (local testing with validated assays is sufficient, e.g., Dako PD-L1 IHC 22C3 or 28-8) for PD-L1 according to combined positive score (CPS) and results must be available prior study enrollment. In addition, tumor should be tested locally for MSI status and PD-L1 according to tumor proportion score (TPS) OR a representative tumor specimen that is suitable for central determination of PD-L1 TPS and MSI status is available. The analysis requires paraffin embedded biopsy samples of the tumor to be provided to the Sponsor.
• NOTE: It is encouraged that CPS, TPS and MSI testing is performed in parallel locally at the trial site prior to enrollment, but at least CPS per local testing has to be available prior to enrollment.
• Patient has not received prior cytotoxic or targeted therapy.
• Patient has not had a prior complete esophagogastric tumor resection.
• Patient has a ECOG ≤ 1.
• Patient must have life expectancy of at least 12 weeks
• Female patients of childbearing potential and male patients with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 6 months after the last study treatment if it is in the core treatment phase or for at least 3 months after last study treatment occurred in the maintenance phase. Male patients must refrain from donating sperm during this same period. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
• Patient has a body weight \> 30 kg
• Patient has adequate hematological, hepatic and renal function as indicated by the following parameters:

You may not qualify if:

• Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein.
• Patient has a known dihydropyrimidine dehydrogenase (DPD) deficiency. Patients with reduced DPD activity (CPIC activity score of 1.0-1.5) might participate in the study and receive a reduced dosage of 5-FU.
• Patient has active or history of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
• NOTE: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone, or controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible based on consultation with the sponsor's medical monitor. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all following conditions are met:
• Rash must cover \< 10% of body surface area.
• Disease is well controlled at baseline and requires only low-potency topical corticosteroids.
• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.
• Patient had a prior allogeneic bone marrow transplantation or prior solid organ transplantation.
• Patient has a history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.
• NOTE: History of radiation pneumonitis within the radiation field (fibrosis) is permitted.
• Patient has active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test prior to enrollment) or hepatitis C infection NOTE: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
• Patient has active tuberculosis.
• Patient has uncontrolled tumor-related pain (Patients requiring pain medication must be on a stable regimen at study entry.)
• Patient received an administration of a live, attenuated vaccine within four weeks prior to start of enrollment, or anticipation that such a live attenuated vaccine will be required during the study or within 30 days after the last dose of durvalumab.
• Patient had a prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibodies.

Sponsors & Collaborators

• Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: lead

Study Sites (22)

Klinikum St. Marien Kommunalunternehmen - Anstalt des öffentlichen Rechts der Stadt Amberg

Amberg, Germany

RECRUITING

HELIOS Klinikum Bad Saarow

Bad Saarow, Germany

RECRUITING

Charite Univeristätsmedizin Berlin

Berlin, 13353, Germany

NOT YET RECRUITING

Universitätsklinikum Brandenburg an der Havel Medizinische Hochschule Brandenburg

Brandenburg, Germany

RECRUITING

Krankenhaus St. Joseph-Stift GmbH

Bremen, 28209, Germany

RECRUITING

Klinikum Darmstadt GmbH

Darmstadt, 64283, Germany

NOT YET RECRUITING

Kliniken Essen Mitte Klinik für Internistische Onkologie und Hämatologie

Essen, Germany

RECRUITING

Institute of Clinical Cancer Research, University Cancer Center (UCT) Frankfurt Krankenhaus Nordwest

Frankfurt, Germany

RECRUITING

Universitätsmedizin Göttingen

Göttingen, 37075, Germany

RECRUITING

Universitätsklinikum Halle (Saale) Universitätsklinik und Poliklinik für Innere Medizin I

Halle, Germany

RECRUITING

Universitätsklinikum Heidelberg, RadioOnkologie & Strahlentherapie

Heidelberg, Germany

RECRUITING

St. Elisabeth Gruppe GmbH, St. Anna Hospital Herne

Herne, Germany

RECRUITING

Klinikverbund Allgäu gGmbH

Kempten, 87439, Germany

RECRUITING

Universitätsklinikum Schleswig-Holstein

Kiel, 24105, Germany

NOT YET RECRUITING

ÜBAG - Medizinisches Versorgungszentrum Dr. Vehling-Kaiser GmbH

Landshut, 84036, Germany

RECRUITING

Klinikum Ludwigshafen gGmbH

Ludwigshafen, 67063, Germany

RECRUITING

Klinikum rechts der Isar der Technischen Universität München

München, Germany

RECRUITING

Gemeinschaftspraxis für Hämatologie und Onkologie GEHO

Münster, Germany

RECRUITING

Kreiskliniken Reutlingen GmbH Klinikum am Steinberg Reutlingen Ermstalklinik, Bad Urach

Reutlingen, Germany

RECRUITING

Leopoldina-Krankenhaus Medizinische Klinik II

Schweinfurt, Germany

RECRUITING

Klinikum Mutterhaus Trier

Trier, Germany

RECRUITING

Klinikum Wolfsburg

Wolfsburg, Germany

RECRUITING

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus

Interventions

durvalumab; Radiotherapy

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Salah-Eddin Al-Batran, Prof. Dr.

  Institut für Klinische Krebsforschung IKF GmbH

  STUDY CHAIR

• Thorsten Götze, Prof. Dr.

  Institute of Clinical Cancer Research, University Cancer Center (UCT) Frankfurt Krankenhaus Nordwest

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Thorsten Götze, Prof. Dr.

CONTACT

+496976014187; goetze.thorsten@khnw.de

Ulas Tenekeci, Dr.

CONTACT

+49 69 589978764; tenekeci.ulas@ikf-khnw.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients eligible for this trial will be enrolled into one of two cohorts: Cohort 1 will consist of participants with PD-L1 combined positive score (CPS) \< 10. Cohort 2 will consist of participants with PD-L1 CPS ≥ 10. Patients in both cohorts will receive immunotherapy with durvalumab in parallel to 2 cycles FLOT chemotherapy induction followed by immunotherapy with durvalumab in parallel with 3 cycles of modified FOLFOX chemotherapy plus concomitant radiation (50 Gy). After initial core treatment and endoscopic re-evaluation patients with complete remission will receive durvalumab monotherapy (1500 mg, IV, Q4W) for a maximum of 12 cycles. Patients in whom a locoregional persistence is confirmed will be offered surgical resection instead of entering the the maintenance period.

Study Record Dates

• First Submitted: January 26, 2023
• First Posted: February 6, 2023
• Study Start: August 28, 2023
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2028
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

DE (22)