Trial Title:
Evaluating Pembrolizumab, Trastuzumab and FLOT as Perioperative Treatment of HER2-positive, Localized Esophagogastric Adenocarcinoma
NCT ID:
NCT05504720
Condition:
Esophagogastric Adenocarcinoma
Conditions: Official terms:
Adenocarcinoma
Pembrolizumab
Trastuzumab
Conditions: Keywords:
gastric adenocarcinoma
GEJ adenocarcinoma
Her-2 positive esophagogastric adenocarcinoma
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Active, not recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
All eligible patients will receive pembrolizumab at a dosage of 200 mg flat dose in
combination with trastuzumab (6 mg/kg after loading dose of 8 mg/kg) every 3 weeks and
5-FU 2600 mg/m2 for 24 h, folinic acid 200 mg/m2, oxaliplatin 85 mg/m2 and docetaxel 50
mg/m2 (FLOT regimen) every 2 weeks for 8 weeks, followed by surgical resection 4 weeks
after last preoperative treatment at the earliest, followed (within 4-10 weeks) by
further 8 weeks of the same regime, followed by pembrolizumab 200 mg and trastuzumab 6
mg/kg alone for up to 11 cycles. In total 1 year of systemic treatment (17 pembrolizumab/
trastuzumab administrations max. per patient incl. pre- and postoperative
chemo-immunotherapy).
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
200 mg flat dose, IV, over 30 minutes; day 1, 22, 43 (8 weeks) pre- and post-surgery,
followed by post chemotherapy phase day 1 q3w for 11 cycles; max. 17 applications
Arm group label:
Pembrolizumab Trastuzumab
Other name:
Keytruda
Intervention type:
Drug
Intervention name:
Trastuzumab
Description:
loading dose 8 mg/kg IV over 90 min: day 1 pre- and post-surgery; maintenance dose 6
mg/kg IV over 30 min: Day 22, 43 pre- and post-surgery; followed by 6 mg/kg post
chemotherapy phase, day 1 q3w for 11 cycles; max. 17 applications
Arm group label:
Pembrolizumab Trastuzumab
Other name:
Ontruzant
Intervention type:
Drug
Intervention name:
FLOT
Description:
Docetaxel 50 mg/m² IV over 1 hour plus Oxaliplatin 85 mg/m² IV over 2 hours plus Folinic
Acid 200 mg/m² IV over 1 hour plus 5-FU 2600 mg/m² IV over 24 hours every 2 weeks (day 1,
15, 29, 43) for 8 weeks pre- and 8 weeks post-surgery
Arm group label:
Pembrolizumab Trastuzumab
Summary:
The study is an open-label, single arm, multicenter phase II trial investigating the
clinical activity of a perioperative therapy consisting of a combination of
pembrolizumab, trastuzumab and FLOT, followed by pembrolizumab plus trastuzumab alone for
a maximum systemic treatment duration of one year in patients with Her-2 positive
localized esophagogastric adenocarcinoma.
Detailed description:
Her-2 positive patients suffering from localized esophagogastric adenocarcinoma (≥ T2 any
N+ or any T N+) without evidence of metastatic disease will be included in the study.
Eligible subjects will receive a combination of pembrolizumab and trastuzumab with FLOT 8
weeks pre- as well as post-surgery, followed by pembrolizumab and trastuzumab treatment
for up to one year (maximum of 17 administrations of systemic treatment with
pembrolizumab and trastuzumab incl. pre- and postoperative chemo-immunotherapy) or until
tumor relapse/progression or occurrence of limiting toxicity.
The primary objective of this phase II study is to demonstrate the efficacy of the
FLOT/trastuzumab/pembrolizumab regimen in terms of an improvement in disease free
survival (DFS) according to RECIST v1.1 and an increase in the pathological complete
response (pCR) rate compared to historical controls (interim read out after surgery of
last patient in study with 18 months recruitment after 24 months). Secondary objectives
are further efficacy and tolerability parameters, including overall response rate
according to RECIST v1.1, R0 resection rate, overall survival, safety, and tolerability
(including perioperative morbidity).
The exploratory objective is to assess whether clinical efficacy correlates with
molecularly-defined subgroups (PD-L1 expression, MSI subtypes, and others).
30 patients will be enrolled in this trial.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. The participant provides written informed consent for the trial.
2. Male/female* participants who are at least 18 years of age on the day of signing
informed consent.
*There are no data that indicate special gender distribution. Therefore, patients
will be enrolled in the study gender-independently.
3. In the investigator's judgement, participant is willing and able to comply with the
study protocol including the planned surgical treatment
4. Histologically confirmed adenocarcinoma of the GEJ (Type I-III according to
Sievert´s classification) or the stomach (cT2, cT3, cT4, any N category, M0), or
(any T, N+, M0) that:
- is not infiltrating any adjacent organs or structures by CT or MRI evaluation
- does not involve peritoneal carcinomatosis
- is considered medically and technically resectable Note: the absence of distant
metastases must be confirmed by CT or MRI of the thorax and abdomen, and, if
there is clinical suspicion of osseous lesions, a bone scan. If peritoneal
carcinomatosis is suspected clinically, its absence must be confirmed by
laparoscopy. Diagnostic laparoscopy is mandatory in patients with T3 or T4
tumors of the diffuse type histology in the stomach.
5. Participants must have HER2-positive disease defined as either IHC 3+ or IHC 2+, the
latter in combination with ISH+, as assessed locally by a certified test on primary
tumor (see Appendix 4)
6. Participants must be candidates for potential curative resection as determined by
the treating surgeon
7. No prior systemic-anti cancer therapy (e.g. cytotoxic or targeted agents or
radiotherapy)
8. No prior partial or complete esophagogastric tumor resection
9. ECOG (Eastern Cooperative Oncology Group) performance status score of 0 or 1
10. Male participants: A male participant must agree to use a contraception as detailed
in Appendix 2 of this protocol during the treatment period and for at least 6 months
after the last dose of study intervention and refrain from donating sperm during
this period.
Female participants: A female participant is eligible to participate if she is not
pregnant (see Appendix 2), not breastfeeding, and at least one of the following
conditions applies:
- Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR
- A WOCBP who agrees to follow the contraceptive guidance as given in Appendix 2
during the treatment period and for at least 7 months after the last dose of
study intervention.
11. Participants have adequate organ function as defined in the following table (Table
2). Specimens must be collected within 14 days prior to enrolment (also to be
repeated if older than 14 days at day of first treatment).
Hematological:
- Absolute neutrophil count (ANC) ≥ 1500/μL
- leucocytes ≥ 3000/μL
- Thrombocytes ≥ 100 000/μL
- Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without erythropoietin
dependency and without packed red blood cell (pRBC) transfusion within the last 2
weeks)
Renal:
• Measured or calculated (b) creatinine clearance≥ 50 mL/min
Hepatic:
- Total bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total
bilirubin levels > 1.5 × ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN Coagulation
- International normalized ratio (INR) OR prothrombin time (PT) and
- Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
intended use of anticoagulants ALT (SGPT)=alanine aminotransferase (serum glutamic
pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic
oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of
normal.
Exclusion Criteria:
1. Participants with involved retroperitoneal (e.g. para-aortal, paracaval or
interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastasis!)
2. A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of
study intervention (see Appendix 2). If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required.
3. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX-40, CD137).
4. Participant received colony-stimulating factors (e.g. granulocyte colony-stimulating
factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or
recombinant erythropoietin) within 28 days prior to the first dose of study
intervention.
5. Major surgery within 2 weeks of starting study intervention and patients must have
recovered from any effects of any major surgery.
6. Concomitant use of drugs inhibiting (dihydropyrimidine dehydrogenase) DPD activity
(including sorivudine, brivudine), the required wash out phase is 4 weeks before
start of the study intervention.
7. Inadequate cardiac function (LVEF value < 55 %) as determined by echocardiography
8. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic
arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte
disturbances, etc.), or patients with congenital long QT syndrome.
9. Participant has received a live vaccine or live-attenuated vaccine within 30 days
prior to the first dose of study drug. Administration of killed vaccines is allowed.
10. Participant is currently participating in or has participated in a study of an
investigational agent or has used an investigational device within 4 weeks prior to
the first dose of study intervention.
11. Participant has a diagnosis of immunodeficiency or is receiving chronic systemic
steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any
other form of immunosuppressive therapy within 7 days prior to the first dose of
study drug.
12. Participant has a known additional malignancy that is progressing or has required
active treatment within the past 2 years. Participants with basal cell carcinoma of
the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
are not excluded.
13. Participant has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with
features suggestive of MDS/AML.
14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion protein; known hypersensitivity to
Chinese hamster ovary cell products or to any component of the pembrolizumab or
trastuzumab formulation
15. Any known contraindication (including hypersensitivity) to docetaxel, 5-FU, folinic
acid/leucovorin, or oxaliplatin.
16. Known DPD deficiency. Patients with a reduced DPD activity (CPIC activity score of
1.0-1.5) might participate in the study and receive a reduced dosage of 5-FU after
discussion with the coordinating investigator and sponsor
[https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/]
17. Participant has active autoimmune disease that has required systemic treatment in
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
18. Participant has a history of (non-infectious) pneumonitis/interstitial lung disease
that required steroids or has current pneumonitis/interstitial lung disease.
19. Participant has an active infection requiring systemic therapy.
20. Participant has a known history of Human Immunodeficiency Virus (HIV) infection
21. Participant has a known history of Hepatitis B (defined as Hepatitis B surface
antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is
detected) infection.
22. Participant is considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within
3 months) myocardial infarction, uncontrolled major seizure disorder, unstable
spinal cord compression, superior vena cava syndrome, extensive interstitial
bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, previous
allogenic bone marrow/blood transplantation or any psychiatric disorder or substance
abuse that prohibits obtaining informed consent.
23. Participant is pregnant or breastfeeding or expecting to conceive or father children
within the projected duration of the study, starting with the screening visit
through 6 months after the last dose of study intervention.
24. Participant has had an allogenic tissue/solid organ transplant.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Charité - Universitätsmedizin Berlin / Campus Virchow Klinikum (CVK)
Address:
City:
Berlin
Zip:
13353
Country:
Germany
Facility:
Name:
MVZ Onkologischer Schwerpunkt
Address:
City:
Berlin
Zip:
14195
Country:
Germany
Facility:
Name:
KEM | Klinik für Internistische Onkologie gGmbH
Address:
City:
Essen
Zip:
45136
Country:
Germany
Facility:
Name:
Institut für Klinisch-Onkologische Forschung am Krankenhaus Nordwest
Address:
City:
Frankfurt/main
Zip:
60488
Country:
Germany
Facility:
Name:
Hämatologisch-Onkologische Praxis Eppendorf
Address:
City:
Hamburg
Zip:
20249
Country:
Germany
Facility:
Name:
Nationales Centrum für Tumorerkrankungen
Address:
City:
Heidelberg
Zip:
69120
Country:
Germany
Facility:
Name:
St. Anna Hospital Herne
Address:
City:
Herne
Zip:
44649
Country:
Germany
Facility:
Name:
Tagestherapiezentrum (TTZ) am Interdisziplinären Tumorzentrum (ITM)
Address:
City:
Mannheim
Zip:
68167
Country:
Germany
Facility:
Name:
Klinikum rechts der Isar der TU München
Address:
City:
München
Zip:
81675
Country:
Germany
Facility:
Name:
Klinikum Nürnberg
Address:
City:
Nürnberg
Zip:
90419
Country:
Germany
Facility:
Name:
Krankenhaus Barmherzige Brüder
Address:
City:
Regensburg
Zip:
93049
Country:
Germany
Facility:
Name:
Universitätsklinikum Ulm
Address:
City:
Ulm
Zip:
89070
Country:
Germany
Facility:
Name:
Klinikum Wolfsburg
Address:
City:
Wolfsburg
Zip:
38440
Country:
Germany
Start date:
February 13, 2023
Completion date:
December 2027
Lead sponsor:
Agency:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Agency class:
Other
Collaborator:
Agency:
Merck Sharp & Dohme LLC
Agency class:
Industry
Collaborator:
Agency:
Organon Healthcare GmbH
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/NCT05504720