This study has been transitioned to CTIS with ID 2023-509380-24-00 check the CTIS register for the current data. The purpose of this study is to investigate the effect of treatment with two courses of chemotherapy followed by immunotherapy. Immune…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess changes in Interferon gamma (IFN-*) expression signature and
infiltration of cytotoxic T cells in the tumor immune microenvironment at
baseline, after two courses of CapOx and after 6 weeks of PD-1 inhibition
maintenance using the anti PD-1 monoclonal antibody retifanlimab in dMMR
patients.
Secondary outcome
Secondary study parameters:
1. To determine overall survival and compare data with a propensity score
matched cohort from the Dutch randomized phase 2 LyRICX study and from the
Dutch Cancer Registry.
2. To assess the progression free survival and compare data with a propensity
score matched cohort from the Dutch randomized phase 2 LyRICX study and from
the Dutch Cancer Registry.
3. To determine response rate.
4. To determine adverse events.
5. To determine patient reported quality of life.
6. To determine the percentage of patients proceeding to subsequent lines of
treatment after progression and describe the types of treatment.
7. To determine the reasons for forgoing subsequent treatment after progression.
Exploratory translational research objectives:
1. To explore the impact of cytotoxic therapy (capecitabin and oxaliplatin) on
the tumor immune microenvironment in dMMR cancers.
2. To identify candidate markers of response to PD-1 pathway inhibitors and
potential aetiologies of de novo or acquired resistance in patients with dMMR
cancers.
3. To explore whether (1) and (2) are related to response to treatment and
survival.
4. To establish patient derived tumor organoids and autologous immune cell
co-culturing experiments to assess markers of response to treatment and
identify resistance pathways.
Background summary
Chemotherapy with cell-killing agents is still the cornerstone of treatment for
esophageal and gastric cancer. Previous research has shown that immunotherapy
may also be effective in some patients, especially when the tumors are
characterized by specific features. A non-functioning DNA repair mechanism,
also called mismatch repair deficiency (MMR), is one of them. Research has
shown that immunotherapy only works after several months. Therefore, treatment
with chemotherapy is needed in the first months of treatment.
In this study, we want to study this effect in more detail. We determine what
influence a short period of chemotherapy (2 courses) followed by immunotherapy
has on the immune response directed against the tumor. To this end, we examine
an immune stimulating characteristic, also called a marker, and the number of
immune cells of a certain type that are located in and around the tumor. In
addition, we look at whether the tumor gets smaller, the patient's quality of
life, what the experienced side effects are, and how this compares to patients
receiving standard treatment.
Study objective
This study has been transitioned to CTIS with ID 2023-509380-24-00 check the CTIS register for the current data.
The purpose of this study is to investigate the effect of treatment with two
courses of chemotherapy followed by immunotherapy. Immune therapy stimulates
the body's immune response directed against the tumor. In addition, the goal is
to determine if the combination of chemotherapy followed by immunotherapy works
better than chemotherapy alone, both in terms of tumor response and side
effects.
Study design
Prospective multi-center, open label, proof-of-principle phase 2 trial
Intervention
Patients will be prospectively included and treated with: two three-weekly
cycles of capecitabine and oxaliplatin followed by retifanlimab intravenous
every four weeks up to progression or unacceptable toxicity, with a maximum of
two years.
Study burden and risks
Extra VENA punction: baseline, week 6, week 7, week 14 and at progression: 45ml
and 7ml blood (translational research)
Extra QUESTIONNAIRE: every 3 weeks, neurotoxicity 5-10 min, up to 3 times
Extra QUESTIONNAIRE: every 12 weeks, 20-30 min
Extra FECES collection and diet diary using 3 days: baseline, week 6, week 14
Extra BIOPT: baseline, week 6, week 14, biopsies primary gastroesophageal tumor
and/or emtastases
In regular treatment, a biopsy will be taken to diagnose metastatic cancer.
Also every 3 weeks, a phyiscal examination and a venapunction will take place
to assure that the next cycle can be administered. The blood and tumor tissue
for biomarkers, feces collection and questionnaires are extra.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
- Male or female adult patients (> 18 years)
- Primaire tumor or metastasis accessible for repeat fresh histological biopsies
- dMMR identified by IHC of mismatch repair proteins MLH1, PMS2, MSH2, and MSH6
- Patients with histologically confirmed diagnosis of metastatic or
irresectable HER2 negative adenocarcinoma of the stomach or oesophagus;
patients with HER2 positive disease are eligble 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 eligble for evaluation
are present
- Measurable disease as assessed by RECIST 1.1
- ECOG (WHO) performace status 0-2
- Patient has adequate hepatic, renal and hematological function
Exclusion criteria
- Severe renal impairment (CLcr <= 30 ml/min)
- 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.)
- 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 esophagogastric cancer.
- Complete dihydropyrimidine dehydrogenase deficiency.
- 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.
- 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.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-509380-24-00 |
| EudraCT | EUCTR2021-001181-38-NL |
| CCMO | NL77094.018.21 |