Durvalumab-Based Immunotherapy with Chemoradiation for Organ Preservation in Early-Stage cT1-cT2N0 Esophageal Adenocarcinoma
- Trial ID
- 2024-512980-29-00
- Protocol
- PRESTO
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the PRESTO Trial is the **assessment** of the treatment efficacy of the combination of durvalumab and chemoradiation as an organ-preservative treatment option for early-stage, cT1 and cT2N0, esophageal adenocarcinoma, including gastroesophageal junction (GEJ), with an indication for radical surgery. This study aims to evaluate the potential of this combination therapy to avoid mortality and surgical complications by achieving a clinical and pathological complete response (cCR/pCR) at the time of endoscopic re-evaluation. The clinical relevance of this objective lies in its potential to offer a less invasive treatment alternative that could preserve organ function and improve patient outcomes.
Secondary objectives include:
- Assessment of the 1-, 2-, and 3-year cCR/pCR rate.
- Evaluation of the rate of salvage surgery.
- Assessment of the 90-day and 1-year mortality.
- Evaluation of the quality of life (QoL).
- Assessment of the safety and tolerability of the treatment regimen.
Participants
The clinical trial involves participants diagnosed with **esophageal adenocarcinoma**, including gastroesophageal junction (GEJ) tumors, specifically at stages T1-T2N0, with an indication for radical surgery. The study population includes both male and female subjects, aged 18 years and older, who are considered medically and technically resectable. Participants are required to have adequate hematological, hepatic, and renal function, and must not have received prior cytotoxic or targeted therapy. The trial population was selected based on specific inclusion criteria, including a histologically confirmed diagnosis and a life expectancy of at least 12 weeks. Participants must also have a body weight greater than 30 kg and an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. The sponsor has not provided information regarding the total number of participants. The trial includes individuals who are part of a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria emphasize the need for participants to have no prior complete esophagogastric tumor resection and to be willing and able to comply with the study protocol, including planned surgical treatment.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **durvalumab** and chemoradiation as a definitive organ preservation treatment for patients with early-stage T1-T2N0 esophageal adenocarcinoma, including gastroesophageal junction (GEJ) tumors, who have an indication for radical surgery. This is a randomized, double-blind, controlled trial with an estimated duration extending until April 2028. The trial aims to assess the rate of clinical and pathological complete response (cCR/pCR) at the time of endoscopic re-evaluation, as well as long-term outcomes at 1, 2, and 3 years post-treatment initiation.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate hematological, hepatic, and renal function, and a confirmed diagnosis of esophageal adenocarcinoma. Following the screening, participants will be randomized to receive the investigational treatment. The treatment phase will involve regular follow-up visits to monitor response and adverse events, with assessments conducted according to Becker criteria and RECIST v1.1 guidelines. The end-of-study visit will include a comprehensive evaluation of treatment outcomes and any long-term effects.
The expected length of participant involvement in the trial is up to 60 months, depending on individual response and treatment tolerability. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their safety and well-being are prioritized throughout the study.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Fluorouracil**, marketed as "5-FU medac 50 mg/ml, Injektionslösung," is provided as a **solution for injection**. It is administered via **intravenous infusion** with a maximum daily dose of 2600 mg/m² and a total maximum dose of 11200 mg/m² over a treatment period of up to 9 weeks. The active substance is of chemical origin, and the product is manufactured by MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH (WEDEL).
**Calcium folinate pentahydrate**, available as "Leucovorin 10 mg/ml Lösung zur Injektion/Infusion," is also a **solution for injection/infusion**. It is administered through **intravenous infusion** with a maximum daily dose of 200 mg/m² and a total maximum dose of 1000 mg/m² over a 9-week period. This chemical substance is produced by PFIZER PHARMA GMBH.
**Docetaxel**, under the brand name "TAXOTERE 20 mg/1 ml concentrate for solution for infusion," is provided as a **concentrate for solution for infusion**. It is delivered via **intravenous infusion** with a maximum daily dose of 50 mg/m² and a total maximum dose of 100 mg/m² over a 9-week treatment period. The chemical origin of the active substance is noted, and the product is manufactured by SANOFI WINTHROP INDUSTRIE.
**Oxaliplatin**, marketed as "medoxa 5 mg/ml Konzentrat zur Herstellung einer Infusionslösung," is a **solution for infusion**. It is administered through **intravenous infusion** with a maximum daily dose of 85 mg/m² and a total maximum dose of 425 mg/m² over a 9-week period. The chemical substance is produced by MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH (WEDEL).
**Durvalumab**, available as "IMFINZI 50 mg/mL concentrate for solution for infusion," is a **solution for infusion**. It is administered via **intravenous infusion** with a maximum daily dose of 1500 mg and a total maximum dose of 22500 mg over a treatment period of up to 60 weeks. The active substance is of protein origin, and the product is manufactured by ASTRAZENECA AB.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment regimen. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of the experimental medications in combination with chemoradiation for the treatment of early-stage esophageal adenocarcinoma.
Efficacy
The efficacy of the treatment in the clinical trial will be assessed primarily through the rate of clinical and pathological complete response (**cCR/pCR**) at the time of endoscopic re-evaluation. This evaluation will occur at the end of the core study treatment and will be conducted 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. Secondary endpoints include the rate of cCR/pCR at 1, 2, and 3 years after the start of treatment, with a long-term follow-up planned. Subgroup analyses will be performed based on characteristics such as MSI high, PD-L1 CPS>1, PD-L1 CPS>5, and particularly CPS ≥10 or <10.
Additional secondary endpoints include the rate of salvage surgery, 90-day and 1-year mortality rates after the start of treatment in both non-surgery and salvage surgery populations, and the determination of tumor relapse sites. The incidence and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will be monitored, with severity graded according to CTCAE v5.0. The relationship of adverse events to durvalumab, chemotherapy, and/or radiation will also be evaluated. The frequency of clinically significant abnormal laboratory parameters will be assessed, and quality of life (QoL) data will be collected from patients using the EORTC QLQ-C30 and the esophageal module OES18.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 IIII)) with: a. 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 cT1-2N0 M0 tumor [poor grading or L1/V1 invasion or basal R1 resection or deep submucosal infiltration]). b. 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: a. Leukocytes ≥ 3,000/μL, platelets ≥ 100,000/μL without transfusion, absolute neutrophil count (ANC) ≥ 1,500/μL without granulocyte colonystimulating factor support, hemoglobin ≥ 90 g/L (9 g/dL) - Patients may be transfused to meet this criterion. b. Bilirubin ≤ 1.5 x upper limit of normal (ULN), aspartate transaminase and alanine transaminase ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN c. Serum creatinine ≤ 1.5 x ULN, or glomerular filtration rate > 45 mL/min (calculated using the Cockcroft-Gault formula) d. Serum albumin ≥ 25 g/L (2.5 g/dL) e. For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN; for patients receiving therapeutic anticoagulation: stable anticoagulant regimen
- Patient has no human immunodeficiency virus (HIV) infection. NOTE: Patient with infection is eligible if he/she meets all the following criteria: a. CD4 count is ≥350 cells/μL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications b. Probable long-term survival with HIV if cancer were not present c. Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study d. HIV is not multi-drug resistant e. Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication
Exclusion Criteria
- 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 any known contraindication (including hypersensitivity) to docetaxel, 5-FU, leucovorin (calcium folinate), or oxaliplatin. In cases of pernicious anemia or other anemias due to vitamin B 12 deficiency, folinic acid (Leucovorin) is contraindicated and trial inclusion is not possible or only possible after compensation the anaemic status.
- 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: o Rash must cover < 10% of body surface area. o Disease is well controlled at baseline and requires only low-potency topical corticosteroids. o 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.
- 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.
- Patient had a treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is longer, prior to study enrollment.
- atient had a treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed a.Intranasal, inhaled, topical steroids or local steroid injections b.Systemic corticosteroids at physiologic dose not to exceed 10mg/day of prednisone or its equivalent c.Steroids as premedication for hypersensitivity reactions
- Patient has a significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina.
- Patient has a clinically significant valvular defect.
- Patient has a history of malignancy other than EGA within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g. 5-year OS rate >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
- Patient has peripheral polyneuropathy ≥ NCI CTCAE grade 2.
- Patient has uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN).
- Patient has a serious infection requiring oral or IV antibiotics within 14 days prior to study enrollment.
- Patient has chronic inflammatory bowel disease.
- Patient has clinically significant active gastrointestinal bleeding.
- Patient underwent major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment.
- Patient has evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the study medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results.
- Patient participated in another interventional clinical study ≤ 30 days prior to study enrollment or participation in such a study at the same time as this study.
- Patient has taken an investigational drug within 28 days prior to initiation of study drug.
- Female patients, who are pregnant or breast feeding or planning to become pregnant within and 6 months after the end of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 28 Aug 2023 | 32 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Leucovorin 10 mg/ml Lösung zur Injektion/ Infusion | Test | LÖSUNG ZUR INJEKTION/ INFUSION | INTRAVENOUS INFUSION | 200 | 9 | PRD4259228 |
TAXOTERE 20 mg/1 ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 50 | 9 | PRD479192 |
medoxa 5 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENIOUS INFUSION | 85 | 9 | PRD870678 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1500 | 60 | PRD6651398 |
5-FU medac 50 mg/ml, Injektionslösung | Test | INJEKTIONSLÖSUNG | INTRAVENIOUS INFUSION | 2600 | 9 | PRD536079 |