Anti-PD-1 and CapOx for the First-line Treatment of dMMR Esophagogastric Cancer (AuspiCiOus) (AuspiCiOus)

September 15, 2022 updated by: H.W.M. van Laarhoven, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Anti-PD-1, Capecitabine, and Oxaliplatin for the First-line Treatment of dMMR Esophagogastric Cancer (AuspiCiOus-dMMR): a Proof-of-principle Study

To investigate the effects of the combination of two chemotherapies followed by immunostimulants on the interferon gamma expression and infiltration of cytotoxic T cells in the tumour microenvironment in patients with previously untreated metastatic or locally advanced esophagogastric cancer.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a multi-center, open label, proof-of-principle study for patients with previously untreated metastatic or locally advanced esophagogastric cancer. Patients are sequentially treated with standard of care capecitabine and oxaliplatin, and retifanlimab. Patients are treated with 2 cycles of CapOx (1 cycle is 3 weeks) and sequentially with 4-weekly cycles of retifanlimab up to 2 years. The investigators will include 25 patients in this study.

Biopsies, blood and faeces will be collected during treatment for assessment of infiltrating immune cells and IFNy expression, as well as for other translational research purposes. CT scans are made for evaluation of tumor response before and after chemotherapy, and after 2-3 cycles of immunotherapy.

Study Type

Interventional

Enrollment (Anticipated)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients must provide written informed consent according to ICH/GCP, and national/local regulations prior to any screening procedures.
  • Male or female adult patients (≥ 18 years).
  • Patients with histologically confirmed diagnosis of metastatic or irresectable HER2 negative adenocarcinoma of the stomach or gastroesophageal junction (Siewert II and III); patients with HER2 positive disease are eligible when treatment with trastuzumab is contraindicated. If histology cannot be obtained, cytology is acceptable to prove metastatic disease.
  • Patients with metastatic or irresectable adenocarcinoma of the stomach or oesophagus 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 eligible for evaluation are present.
  • Measurable disease as assessed by RECIST 1.1
  • dMMR identified by IHC of mismatch repair proteins MLH1, PMS2, MSH2 en MSH6
  • Primary tumor or metastasis accessible for repeat fresh histological biopsies
  • ECOG (WHO) performance status 0-2

  • Patient has adequate bone marrow and organ function as defined by the following laboratory values:

    • Absolute Neutrophil Count (ANC) > 1.5 x 109 /L
    • Hemoglobin (Hgb) > 5.6 mmol/L
    • Platelets > 100 x 109 /L
  • Serum total bilirubin within ≤ 1.5 x ULN (upper limit of normal); or total bilirubin < 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert's syndrome; biliary drainage is allowed for biliary obstruction
  • Serum creatinine < 1.5 x ULN or creatinine clearance >30 mL/min/1.73 m2
  • Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) < 2.5x ULN within normal range or < 5.0 x ULN if liver metastases are present
  • If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative pregnancy test (urine or serum; beta-human chorionic gonadotropin (β-hCG)) documented prior to the first administration of study drug. If sexually active, the patient must agree to use contraception considered adequate and appropriate by the Investigator during the period of administration of study drug and after the end of treatment as recommended.
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion Criteria:

  • Severe renal impairment (CLcr ≤ 30 ml/min)
  • Any clinically significant disorder impacting the risk-benefit balance negatively per physician's judgment.
  • Any prior anti-cancer chemotherapy, biologic or investigational therapy for metastatic or irresectable stomach or oesophageal cancer
  • Disease progression within six months after completion of (neo)adjuvant chemotherapy containing a fluoropyrimidine and/or platinum compound. (Disease progression within 6 months after completion of neoadjuvant chemoradiation carboplatin AUC 2 and paclitaxel 50 mg/m2 is allowed.)
  • All target lesions in a radiation field without documented disease progression.
  • Patient has known brain metastases, unless previously treated and well-controlled for at least 3 months (defined as clinically stable, no edema, no steroids and stable in 2 scans at least 4 weeks apart).
  • Past or current malignancy other than entry diagnosis interfering with prognosis of metastatic gastroesophageal cancer.
  • Known uncontrollable hypersensitivity or contraindications to any of the components of retifanlimab, fluoropyrimidines, leucovorin, oxaliplatin. Patients with previous dose reductions or delays are eligible.
  • Complete dihydropyrimidine dehydrogenase deficiency.
  • Patient has active, uncontrolled bacterial, viral or fungal infection(s) requiring systemic therapy.
  • Patient has known past or active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
  • Signs of interstitial lung disease (ILD)
  • Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment contraindicate patient participation in the clinical study.
  • Use of other investigational drugs within 30 days of enrollment.
  • Patient is enrolled in any other clinical protocol or investigational trial that will interfere with the primary endpoint of the current study.
  • Patients who in the investigators' opinion may be unwilling, unable or unlikely to comply with requirements of the study protocol.
  • 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 study treatment.
  • 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 CTCAE grade 1.
  • History of organ transplant, including allogeneic stem cell transplantation.
  • Receiving probiotics as of the first dose of study treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Capecitabine, oxaliplatin and retifanlimab
IV and PO Capecitabine 1000 mg/m2, oxaliplatin 130 mg/m2, every three weeks (up to 2 cycles) IV retifanlimab 500mg, every four weeks
Drug: Capecitabine
PO Capecitabine
Other Names:
  • Xeloda
Drug: Oxaliplatin
IV Oxaliplatin
Other Names:
  • Oxaliplatin Accord
Drug: Retifanlimab
IV retifanlimab
Other Names:
  • INCMGA00012

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect of chemo- and immunotherapy on the interferon gamma expression signature in the tumor microenviornment
Time Frame: 40 months
RNA expression analysis (Nanostring) to determine changes in Interferon gamma expression signature before and during treatment
40 months
Effect of chemo- and immunotherapy on the immune infiltrate in the tumor microenvironment
Time Frame: 40 months
Flow cytometry to determine changes in immune infiltrate in the tumor before and during treatment
40 months
Effect of chemo- and immunotherapy on the immune infiltrate on the tumor microenvironment
Time Frame: 40 months
Multicolor immunohistochemstry to determine changes in immune infiltrate in the tumor before and during treatment
40 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 60 months
Determine overall survival of patients within the study
60 months
Overall survival
Time Frame: 60 months
Compare overall survival with a propensity score matched cohort
60 months
Progression free survival (PFS)
Time Frame: 60 months
Assess the PFS of patients within the study
60 months
Progression free survival (PFS)
Time Frame: 60 months
Compare PFS with a propensity score matched cohort
60 months
Response rate
Time Frame: 60 months
Determine response rate by comparing RECIST evaluation of CT scans before and during treatment
60 months
Adverse events
Time Frame: 60 months
To determine adverse events of CapOx and retifanlimab
60 months
Measure PROMs via established PROFILES
Time Frame: 60 months
Patient reported outcome measures (PROMs) are measured with the established PROFILES infrastructure (Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship). PROMs will be assessed and compared at baseline and throughout treatment
60 months
Percentage subsequent treatment lines
Time Frame: 60 months
The percentage of patients proceeding to subsequent lines of treatment after progression
60 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Impact of cytotoxic therapy and PD-1 inhibition on the anti-tumor immune respons
Time Frame: 40 months
Assess changes in RNA expression (Nanostring) in peripheral blood mononuclear cells (PBMCs) before and during treatment
40 months
Impact of cytotoxic therapy and PD-1 inhibition on the anti-tumor immune respons
Time Frame: 40 months
Percentage tumor and immune cells in tumor tissue
40 months
Phenotype of PBMCs
Time Frame: 40 months
Determine change in phenotype of PBMCs with flow cytometry, before and after chemotherapy
40 months
Immunohistochemistry
Time Frame: 40 months
Perform immunohistochemistry on tumor tissue to determine relative increase of infiltrating immune cells
40 months
Stromal markers in tumor
Time Frame: 40 months
Assess changes in expression level of ADAM12 in tumor tissue
40 months
ctDNA
Time Frame: 40 months
Assess changes in concentration of circulating tumor (ct)DNA in blood
40 months
Fecal microbiome
Time Frame: 40 months
Change in composition of the fecal microbiome by DNA sequencing as a potential biomarker for response to treatment
40 months
Cytokine and chemokine release profile
Time Frame: 40 months
Assess changes in cytokine and chemokine profile in blood with Luminex bead fluorescence assay before and during treatment
40 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

Incyte Corporation

Investigators

  • Study Director: Jan M Prins, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  • Principal Investigator: Sarah Derks, VU Medisch Centrum - Vrije Universiteit

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

November 5, 2021

Primary Completion (ANTICIPATED)

May 1, 2025

Study Completion (ANTICIPATED)

November 4, 2029

Study Registration Dates

First Submitted

September 7, 2021

First Submitted That Met QC Criteria

December 15, 2021

First Posted (ACTUAL)

January 4, 2022

Study Record Updates

Last Update Posted (ACTUAL)

September 16, 2022

Last Update Submitted That Met QC Criteria

September 15, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL77094.018.21

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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