Trial Title:
Organ Preservation With Durvalumab-based Immunotherapy in Combination With Chemoradiation as Definitive Therapy for Early Stage Esophageal Adenocarcinoma With Indication for Radical Surgery
NCT ID:
NCT05713838
Condition:
Esophagus Adenocarcinoma
Conditions: Official terms:
Adenocarcinoma
Durvalumab
Conditions: Keywords:
esophageal adenocarcinoma
GEJ adenocarcinoma
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
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.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Durvalumab
Description:
1500 mg Durvalumab, IV, day 1 Q4W (max. 15 cycles)
Arm group label:
Durvalumab + Chemoradiotherapy
Other name:
IMFINZI
Intervention type:
Drug
Intervention name:
FLOT
Description:
50 mg/m² docetaxel, 85 mg/m² oxaliplatin, 200 mg/m² calcium folinate and 2600 mg/m²
fluorouracil as 24 h-infusion, 2 cycles
Arm group label:
Durvalumab + Chemoradiotherapy
Intervention type:
Drug
Intervention name:
mFOLFOX-6
Description:
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
Arm group label:
Durvalumab + Chemoradiotherapy
Intervention type:
Radiation
Intervention name:
Radiotherapy
Description:
5 weeks with 5 days a week radiotherapy (25 daily fractions with 2.0 Gy = ∑50Gy)
Arm group label:
Durvalumab + Chemoradiotherapy
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.
Detailed description:
Patients with early stage, cT1 and cT2N0 esophageal adenocarcinoma with indication for
radical surgery (esophagectomy or transhiatal extended gastrectomy) will be enrolled in
two cohorts according to their PD-L1 CPS (cohort 1 CPS < 10, cohort 2 CPS ≥ 10). All
patients will receive core treatment consisting of immunotherapy with durvalumab in
parallel to 2 cycles FLOT chemotherapy, followed by immunotherapy with durvalumab in
parallel to 3 cycles of modified FOLFOX plus concomitant radiation (50 Gy). Eight weeks
after this, patients will undergo tumor assessment consisting of
esophagogastroduodenoscopy with extensive biopsies (bite-on-bite biopsies and fine-needle
aspiration), endoscopic ultrasonography with measurement of maximum tumor thickness, and
CT- or MRI-scans for tumor re-evaluation. Surgical resection would be offered only to
those patients in whom a locoregional persistence is confirmed on tumor assessment, in
the absence of any signs of distant dissemination. Patients with complete remission will
enter the maintenance phase receiving durvalumab monotherapy for up to 12 cycles.
The primary objective of this trial is to investigate the treatment efficacy of the
combination of durvalumab and chemoradiation as organ preservative treatment option
avoiding mortality and surgical complications with rate of clinical and pathological
complete response (cCR/pCR) at time of endoscopic re-evaluation defined as primary
efficacy endpoint.
The secondary objectives are the further assessment of the efficacy of the combination of
durvalumab and chemoradiation as organ preservative treatment option 1-/2- and 3-year
cCR/pCR rate, rate of salvage surgery, 90-day and 1-year mortality as secondary endpoints
and to assess the quality of life (QoL).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patient has given written informed consent.
2. Patient is, in the investigator's judgement, willing and able to comply with the
study protocol including the planned surgical treatment.
3. Patient is ≥ 18 years of age at time of signing the written informed consent.
4. Patient has been diagnosed with histologically confirmed esophageal adenocarcinoma
(including gastroesophageal junction (GEJ) (Siewert I-III)) with:
1. 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).
2. tumor is considered medically and technically resectable.
5. 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.
6. Patient has not received prior cytotoxic or targeted therapy.
7. Patient has not had a prior complete esophagogastric tumor resection.
8. Patient has a ECOG ≤ 1.
9. Patient must have life expectancy of at least 12 weeks
10. 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.
11. Patient has a body weight > 30 kg
12. Patient has adequate hematological, hepatic and renal function as indicated by the
following parameters:
1. Leukocytes ≥ 3,000/µL, platelets ≥ 100,000/µL without transfusion, absolute
neutrophil count (ANC) ≥ 1,500/µL without granulocyte colony-stimulating factor
support, hemoglobin ≥ 90 g/L (9 g/dL) - Patients may be transfused to meet this
criterion.
2. Bilirubin ≤ 1.5 x upper limit of normal (ULN), aspartate transaminase and
alanine transaminase ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN
3. Serum creatinine ≤ 1.5 x ULN, or glomerular filtration rate > 45 mL/min
(calculated using the Cockcroft-Gault formula)
4. Serum albumin ≥ 25 g/L (2.5 g/dL)
5. For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x
ULN; for patients receiving therapeutic anticoagulation: stable anticoagulant
regimen
13. Patient has no human immunodeficiency virus (HIV) infection. NOTE: Patient with
infection is eligible if he/she meets all the following criteria:
1. CD4 count is ≥350 cells/µL, viral load is undetectable, and not taking
prohibited cytochrome (CYP)-interacting medications
2. Probable long-term survival with HIV if cancer were not present
3. 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
4. HIV is not multi-drug resistant
5. Taking medication and/or receiving antiretroviral therapy that does not
interact or have overlapping toxicities with the study medication
Exclusion Criteria:
1. 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.
2. 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.
3. 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.
4. 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.
5. Patient had a prior allogeneic bone marrow transplantation or prior solid organ
transplantation.
6. 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.
7. 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).
8. Patient has active tuberculosis.
9. Patient has uncontrolled tumor-related pain (Patients requiring pain medication must
be on a stable regimen at study entry.)
10. 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.
11. 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.
12. 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.
13. Patient 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
1. Intranasal, inhaled, topical steroids or local steroid injections (e.g. intra
articular injection)
2. Systemic corticosteroids at physiologic dose not to exceed 10mg/day of
prednisone or its equivalent
3. Steroids as premedication for hypersensitivity reactions (e.g. CT
premedication)
14. 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.
15. Patient has a clinically significant valvular defect.
16. 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.
17. Patient has peripheral polyneuropathy ≥ NCI CTCAE grade 2.
18. Patient has uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5
mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN).
19. Patient has a serious infection requiring oral or IV antibiotics within 14 days
prior to study enrollment.
20. Patient has chronic inflammatory bowel disease.
21. Patient has clinically significant active gastrointestinal bleeding.
22. Patient underwent major surgical procedure other than for diagnosis within 4 weeks
prior to initiation of study treatment.
23. 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.
24. 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.
25. Patient has taken an investigational drug within 28 days prior to initiation of
study drug.
26. 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Klinikum St. Marien Kommunalunternehmen - Anstalt des öffentlichen Rechts der Stadt Amberg
Address:
City:
Amberg
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Ludwig Fischer von Weikersthal, Dr.
Facility:
Name:
HELIOS Klinikum Bad Saarow
Address:
City:
Bad Saarow
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Daniel Pink, PD Dr.
Facility:
Name:
Charite Univeristätsmedizin Berlin
Address:
City:
Berlin
Zip:
13353
Country:
Germany
Status:
Not yet recruiting
Contact:
Last name:
Annika Kurreck, Dr.
Facility:
Name:
Universitätsklinikum Brandenburg an der Havel Medizinische Hochschule Brandenburg
Address:
City:
Brandenburg an der Havel
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Mark Reinwald, PD Dr.
Facility:
Name:
Krankenhaus St. Joseph-Stift GmbH
Address:
City:
Bremen
Zip:
28209
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Michael Alexander van Geer, Dr.
Facility:
Name:
Klinikum Darmstadt GmbH
Address:
City:
Darmstadt
Zip:
64283
Country:
Germany
Status:
Not yet recruiting
Contact:
Last name:
Carl Schmimanski, Prof. Dr.
Facility:
Name:
Kliniken Essen Mitte Klinik für Internistische Onkologie und Hämatologie
Address:
City:
Essen
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Christian Müller, Dr.
Facility:
Name:
Institute of Clinical Cancer Research, University Cancer Center (UCT) Frankfurt Krankenhaus Nordwest
Address:
City:
Frankfurt
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Thorsten Götze, Prof. Dr.
Phone:
00496976014187
Email:
goetze.thorsten@khnw.de
Facility:
Name:
Universitätsmedizin Göttingen
Address:
City:
Göttingen
Zip:
37075
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Johanna Reinecke, Dr.
Facility:
Name:
Universitätsklinikum Halle (Saale) Universitätsklinik und Poliklinik für Innere Medizin I
Address:
City:
Halle
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Ulrich Ronellenfitsch, Prof. Dr.
Facility:
Name:
Universitätsklinikum Heidelberg, RadioOnkologie & Strahlentherapie
Address:
City:
Heidelberg
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Jürgen Debus, Prof. Dr.
Facility:
Name:
St. Elisabeth Gruppe GmbH, St. Anna Hospital Herne
Address:
City:
Herne
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Vera Heuer, Dr.
Facility:
Name:
Klinikverbund Allgäu gGmbH
Address:
City:
Kempten
Zip:
87439
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Christian Langer, Prof. Dr.
Facility:
Name:
Universitätsklinikum Schleswig-Holstein
Address:
City:
Kiel
Zip:
24105
Country:
Germany
Status:
Not yet recruiting
Contact:
Last name:
Anne Letsch, Prof. Dr.
Facility:
Name:
ÜBAG - Medizinisches Versorgungszentrum Dr. Vehling-Kaiser GmbH
Address:
City:
Landshut
Zip:
84036
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Mike Haberkorn
Facility:
Name:
Klinikum Ludwigshafen gGmbH
Address:
City:
Ludwigshafen
Zip:
67063
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Daniel Janke, Dr.
Facility:
Name:
Klinikum rechts der Isar der Technischen Universität München
Address:
City:
München
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Sylvie Lorenzen, Prof. Dr.
Facility:
Name:
Gemeinschaftspraxis für Hämatologie und Onkologie GEHO
Address:
City:
Münster
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Rüdiger Liersch, PD Dr.
Facility:
Name:
Kreiskliniken Reutlingen GmbH Klinikum am Steinberg Reutlingen Ermstalklinik, Bad Urach
Address:
City:
Reutlingen
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Stefan Kubicka, Prof. Dr.
Facility:
Name:
Leopoldina-Krankenhaus Medizinische Klinik II
Address:
City:
Schweinfurt
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Stephan Kanzler, Prof. Dr.
Facility:
Name:
Klinikum Mutterhaus Trier
Address:
City:
Trier
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Rolf Mahlberg, Dr.
Facility:
Name:
Klinikum Wolfsburg
Address:
City:
Wolfsburg
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Nils Homann, Prof. Dr.
Start date:
August 28, 2023
Completion date:
December 2028
Lead sponsor:
Agency:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Agency class:
Other
Source:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05713838
