Anti-PD-1, Capecitabine, and Oxaliplatin for the first-line treatment of dMMR esophagogastric cancer (AuspiCiOus-dMMR): a proof-of-principle study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amsterdam UMC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Nov 2021 → ongoing

Decision date (initial)

2024-04-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509380-24-00

EudraCT number

2021-001181-38

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

To assess changes in Interferon gamma (IFN-ϒ) expression signature and infiltration of cytotoxic T cells in the
tumor immune microenvironment at baseline, after two courses of CapOx and after 8 weeks of PD-1
inhibition maintenance using retifanlimab in DMMR patients.

Conditions and MedDRA coding

Metastatic upper gastrointestinal cancer, cancer of esophagus and stomach

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1.  Patients must provide written informed consent according to ICH/GCP, and national/local regulations prior to any screening procedures.  dMMR identified by IHC of mismatch repair proteins MLH1, PMS2, MSH2 en MSH6  Primary tumor or metastasis accessible for repeat fresh histological biopsies  Male or female adult patients (> 18 years).  Patients with histologically confirmed diagnosis of metastatic or irresectable HER2 negative adenocarcinoma of the stomach or oesophagus, patients with HER2 positive disease are eligible when treatment with trastuzumab is contraindicated.  Patients with metastatic or irresectable adenocarcinoma of the stomach or oesophageal junction (Siewert II or III) not pre-treated with chemotherapy or radiotherapy for irresectable or metastatic disease. Palliative radiotherapy on the primary tumor or a metastatic lesion is allowed if other untreated lesions for RECIST evaluation are present. Chemoradiation with carboplatin area under the curve (AUC) 2 and paclitaxel 50 mg/m2 for irresectable disease is allowed if subsequent disease progression is proven on radiological imaging.  Measurable/evaluable disease as assessed by RECIST 1.1  ECOG (WHO) performance status 0-2  Adequate hepatic, renal and hematological function

Exclusion criteria 1

1.  Severe renal impairment (CLcr ≤ 30 ml/min)  Any clinically significant disorder impacting the risk-benefit balance negatively per physician’s judgment.  Presence of additional malignancy that is progressing or has required active treatment in the last 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded.  Active autoimmune disease that has required systemic treatment in past 2 years, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.  Any clinically significant gastrointestinal disorder, including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 2.  Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6 months.  NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure. Or known abnormal ECG with clinically significant abnormal findings.  Active infection or an unexplained fever >38.5°C (excluding tumor fever), which in the physician’s opinion might compromise the patient’s health.  Current use or any use in last two weeks of strong CYP3A-enzyme, CYP2C8, and/or strong UGT1A inhibitors/inducers.  Known hypersensitivity or contraindications to any of the components of capecitabine or oxaliplatin.  History of severe and unexpected reactions to fluoropyrimidine therapy.  Known complete dihydropyrimidine dehydrogenase (DPD) deficiency.  Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of cytotoxic agents.  Treatment within 4 weeks with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine.  Pre-existing motor or sensory neurotoxicity greater than WHO grade 1.  History of organ transplant, including allogeneic stem cell transplantation.  Receiving probiotics as of the first dose of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Interferon gamma (IFN-ϒ) expression and number of infiltrating cytotoxic T-cells

Secondary endpoints 1

1.  Overall survival  Progression-free survival  Response rate according to RECIST 1.1 or iRECIST  Adverse events according to NCI CTCAE version 5.0.  Quality of life  Percentage of patients proceeding to subsequent lines of treatment after progression and describe the types of subsequent treatments  Reasons for forgoing subsequent treatment after progression

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amsterdam UMC

Sponsor organisation

Amsterdam UMC

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Amsterdam UMC

Contact name

Prof. Dr. H.W.M. van Laarhoven

Public contact point

Organisation

Amsterdam UMC

Contact name

Prof. Dr. H.W.M. van Laarhoven

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications