This study has been transitioned to CTIS with ID 2024-519075-26-00 check the CTIS register for the current data. Primary objective: To explore the safety and feasibility of neoadjuvant capecitabine, oxaliplatin, docetaxel, and atezolizumab in GE-…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety will be measured by SAEs and treatment related complications leading to
delays in systemic treatment and/or surgery. Pre-operative treatment-related
complications include all immune-related adverse events, attributable to the
study medication, that lead to delays in systemic treatment or surgery.
Logistical reasons or non-study-medication related complications (i.e.
bacterial infections) leading to delays will not be considered dose-limiting
toxicity.
Post-operative complications, including, but not limited to anastomotic
dehiscence/leakage, wound dehiscence, abcess, perforation, bleeding and
infection will be recorded. Clinical and/or radiological anastomotic leakage
rate of > 10% after (sub)total gastrectomy and > 40% after esophagectomy with
cervical anastomosis would be reason to consider the study treatment as unsafe.
Feasibility will be measured by adherence to the timelines of the study
protocol.
All patients will be discussed in our multidisciplinary team meeting prior to
start of treatment, at the time of evaluation and prior to the operation. In
case of immune related complications, patients will be discussed in our
immunotherapy team meeting.
Secondary outcome
- Pathological tumor regression grade and the rate of complete response
- Effect of therapy on intratumoral T-cell infiltration, CD4/CD8 ratio and
immune checkpoints upregulation in the time interval post-atezolizumab
monotherapy, post combination treatment with chemotherapy and at surgery
- Radiological tumor regression, and when possible the immune recist criteria,
will be assessed prior to cycle 4 of combination treatment
- Immunogenic mutational load will be determined by tumor tissue DNA WES.
Peripheral blood DNA WES will also be performed and used as a control for
somatic mutation sorting (only genes relating to gastric cancer and/or
immune-related genes, deemed informational for this study, will be assessed )
- Immune suppressive pathways and IFN-y induced gene expression will be
analyzed by use of RNA sequencing on pre- and post-therapy tissue;
- Date of relapse, as determined by disease recurrence or disease-related death
during follow-up after surgery. Follow-up will be performed according to the
assessment table.
- Organoids
Background summary
Gastric cancer (GC) is one of the most common types of cancer and remains a
major cause of death. Esophagogastric junction (GEJ) and gastric cardia
represent sites with a rapidly increasing incidence of adenocarcinoma.
Peri-operative chemotherapy and chemoradiation therapy have been shown to
improve survival, but despite these treatment regimens, the 5-year overall
survival for stage II disease and beyond is a mere 35%.1 The standard treatment
for gastric cancer often consists of neoadjuvant chemotherapy with an
anthracycline, platinum and 5-FU based regimen.
In this study, we aim to explore novel combinations of immunomodulating
chemotherapy with immunotherapy in the neoadjuvant setting, which could lead to
both improved pathological responses, but also translate in improved
disease-free and overall survival as compared to chemoradiotherapy or
chemotherapy alone.
Study objective
This study has been transitioned to CTIS with ID 2024-519075-26-00 check the CTIS register for the current data.
Primary objective: To explore the safety and feasibility of neoadjuvant
capecitabine, oxaliplatin, docetaxel, and atezolizumab in GE-junction and
gastric adenocarcinoma
Secondary objectives:
• To assess pathological tumor regression and rates of complete response
• To explore the immune activating capacity of atezolizumab in combination with
chemotherapy using changes in CD8 T-cell infiltration and immune checkpoints
upregulation
• To assess disease-free survival
• To assess overall survival
Study design
In this exploratory study, patients with resectable GE junction or gastric
cancer will receive neoadjuvant treatment. The first cycle of therapy will
consist of atezolizumab monotherapy, followed by four cycles of capecitabine,
oxaliplatin, docetaxel and atezolizumab.
Intervention
All patients will be treated with a single cycle of atezolizumab monotherapy,
followed by four cycles of capecitabine, oxaliplatin, docetaxel and
atezolizumab. All treatment cycles will be given pre-operatively and patients
will not receive adjuvant treatment.
Prior to start of treatment, a minimum of 12 tumor and 3 normal tissue biopsies
will be taken through endoscopy.
Patients will be treated with one cycle of atezolizumab 1200mg monotherapy on
day 1 (week1), followed by four cycles of atezolizumab 1200mg, docetaxel
50mg/m2, oxaliplatin 100mg/m2 and capecitabine 825mg/m2 in week 3, 6, 9 and 12.
A CT-scan will be performed prior to cycle 4. The operation will take place
approximately 7 weeks after the last treatment cycle .
Endoscopy with biopsies will be performed at baseline, after the first cycle of
atezolizumab monotherapy and after prior to cycle 4 of combination treatment.
Blood draws (incl. PBMC, serum and plasma collection) will be required at
baseline, before every cycle of therapy, peri- and post-operatively.
During follow-up, CT-scans will be performed 6, 12, 24 and 36 months after
surgery.
Study burden and risks
Patients will undergo an endoscopy for determination of the required resection
margins and for acquisition of study-related biopsies. Repeat endoscopy for
this patient category is common practice at our institute prior to start of
treatment. At baseline and before each treatment, blood samples will be drawn,
for both follow-up of treatment effects and for research purposes.
Participation will mean 2 additional endoscopies, one after monotherapy
atezolizumab and one prior to cycle 4 of combination treatment. Site visits for
the treatment with chemo- and immunotherapy is comparable to that of patients
not being treated within the study.
Additional risks of the investigational treatment includes immune related side
effects associated with atezolizumab (see paragpraph*).
Also, in this protocol we have adapted the dexamethasone dose given prior to
and following docetaxel.
In this study, we expect the rate of edema to be low since the cumulative dose
of docetaxel will be 200mg/m2. Dexamethasone will thus be given mainly for
prevention of allergic reactions.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
- Primary resectable, gastro-oesophageal junction adenocarcinoma or gastric
adenocarcinoma
- WHO performance status of 0 or 1
- No distant metastases
- CT-scan < 4 weeks to registration
- Patients must be willing to undergo esophagogastroscopy and biopsies prior to
start of treatment and during treatment at set timepoints
Exclusion criteria
- Clinical symptoms or radiological suspicion of perforation
- Active auto-immune disease or documented history of autoimmune disease, or
other medical conditions requiring systemic steroid or immunosuppressive
medications, except for subjects with vitiligo, diabetes mellitus type 1,
residual hypothyroidism due to autommune condition only requiring hormone
replacement, psoriasis or resolved childhood asthma/atopy not requiring
systemic treatment
- Conditions requiring systemic treatment with either corticosteroids (>10mg
daily prednisone equivalents or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal
replacement doses > 10 mg daily prednisone equivalents are permitted in the
absence of active autoimmune disease;
- Previous treatment with immune checkpoint inhibitors
- History of allergy to study drug components, hypersensitivity reaction to any
monoclonal antibody
- Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus
ribonucleic acid (HCV antibody) indicating acute or chronic infection;
- History of testing positive human immunodeficiency virus or known acquired
immunodeficiency syndrome (AIDS)
- Malignancies other than disease under study within 3 years prior to
inclusion, requiring systemic treatment or judged by the investigators to be
incompatible with the study, except for non-melanoma skin cancer.
Design
Recruitment
Medical products/devices used
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 | CTIS2024-519075-26-00 |
| EudraCT | EUCTR2017-003854-17-NL |
| CCMO | NL63069.031.17 |