Informations générales (source: ClinicalTrials.gov)
A Randomized Phase II Study Evaluating FOLFIRI + Durvalumab vs FOLFIRI + Durvalumab and Tremelimumab in Second-line Treatment of Patients With Advanced Gastric or Gastro-oesophageal Junction Adenocarcinoma
Interventional
Phase 2
Federation Francophone de Cancerologie Digestive (Voir sur ClinicalTrials)
juillet 2019
novembre 2024
09 juillet 2024
Gastric adenocarcinoma is the 4th most frequent cancer and the 2nd leading cause of
cancer mortality. Most of the patients have metastatic, locally advanced or recurrent
unresectable disease. So, systemic treatment remains an important issue especially since
chemotherapy improves survival and quality of life (compared to best supportive care
alone).
Second-line chemotherapy-based treatment improves overall survival (OS) as compared to
best supportive care alone in patients with an acceptable general condition (performance
status 0-2). Indeed, with docetaxel monotherapy there was a significant difference in
overall survival for the chemotherapy arm with a median of 5.2 versus 3.6 months in best
supportive care alone arm (HR=0.67, p=0.01). Irinotecan monotherapy also significantly
improves overall survival compared to supportive care alone in a phase III study (4.0
versus 2.4 months; HR=0.48, 95%CI 0.25-0.92; p=0.012).
Based on a phase III trial FOLFIRI (5-FU plus irinotecan) is one most used regimen in
second-line in European countries, especially in France. FFCD 0307 trial, a phase III
comparing FOLFIRI-ECX (epirubicin-cisplatin-capecitabine) to the reverse sequence
(ECX-FOLFIRI), showed that both sequences are possible.
Preliminary results in metastatic gastric cancer with anti-PD1 mAbs are highly promising.
In a trial with pembrolizumab, only PD-L1 positive tumors were eligible to the treatment
with a cut off at 1%. Thirty-nine patients were enrolled and 67% had received at least
two prior chemotherapy regimens. The overall response rate was 22%. The median PFS and OS
were 1.9 months and 11.4 months, respectively. KEYNOTE-059 Phase 2 multicohort study with
pembrolizumab monotherapy in advanced gastric cancer treatment has been presented at ASCO
2017 meeting. Among 259 patients included in the trial response rate was 11.6%. OS was
5.6 months. Response rates were 15.5% in PDL1+ tumors versus 6.4% in PDL1- tumors and
57.1% in MSI tumors versus 9% in MSS tumors. Up until now, overlap between microsatellite
instability and PD-L1 expression is unknown in gastric cancer. An anti-PD-L1 mAb
(avelumab) was evaluated in a phase Ib expansion study (n=20, Japanese patients), with
15% of objective response rate and 11.9 weeks for progression-free survival. A second
cohort with avelumab included 55 patients for maintenance therapy after first-line
chemotherapy, with 7.3% of objective response rate and 14 weeks of PFS. Phase I/II
CheckMate-032 evaluated nivolumab (anti-PD-1) ± ipilimumab (anti-CTLA4) at different
doses in advanced gastric cancer (17). The overall response rate was between 8% to 24%
and the median OS between 4.8 to 6.9 months according to treatment arm.
Others anti-PD1/anti-PD-L1/anti-CTLA4 mAbs are also currently under investigation in
gastric cancer alone or in combination with chemotherapy. Nevertheless, up until now
there is no published data concerning ICI plus chemotherapy in gastric cancer. The
present randomized multicentric non-comparative phase II study aimed to assess the rate
of patients alive and without progression at 4 months with advanced gastric or
gastro-oesophageal junction (GEJ) adenocarcinoma, pre-treated with fluoropyrimidine +
platinum +/- taxane, with two arms Folfiri plus durvalumab versus Folfiri plus durvalumab
plus tremelimumab. Indeed, most patients in the French multicentric first-line GASTFOX
trial (506 patients planned between 2017 and 2020) can be included in the second-line
setting in the DURIGAST trial. Due to the lack of data concerning Folfiri plus durvalumab
plus tremelimumab combination, a safety run-in phase will be performed at the beginning
of the DURIGAST trial.
Etablissements
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| HOPITAL FOCH | jeudi 19 juin 2025 | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Ch - Centre Hospitalier - Abbeville - France | Contact (sur clinicalTrials) | ||||
| Ch - Centre Hospitalier de Bézier - Béziers - France | Contact (sur clinicalTrials) | ||||
| Ch - Centre Hospitalier de Carcassonne - Carcassonne - France | Contact (sur clinicalTrials) | ||||
| Ch - Centre Hospitalier de Cholet - Cholet - France | Contact (sur clinicalTrials) | ||||
| Ch - Chp Du Cotentin - Cherbourg-en-Cotentin - France | Contact (sur clinicalTrials) | ||||
| Ch - Hôpital Claude Bernard - Albi - France | Contact (sur clinicalTrials) | ||||
| Ch - Hôpital Côte Basque - Bayonne - France | Contact (sur clinicalTrials) | ||||
| Ch - Hôpital Duchenne - Boulogne-sur-Mer - France | Contact (sur clinicalTrials) | ||||
| Ch - Hôpital Germon Et Gauthier - Béthune - France | Contact (sur clinicalTrials) | ||||
| Ch - Hôpital Henri Duffaut - Avignon - France | Contact (sur clinicalTrials) | ||||
| Ch - Hôpital Victor Dupouy - Argenteuil - France | Contact (sur clinicalTrials) | ||||
| Ch - Hopitaux Civils de Colmar - Colmar - France | Contact (sur clinicalTrials) | ||||
| Chu - Aphp - Hôpital Saint Louis - 75475 - Paris - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital Côte de Nacre - Caen - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital Estaing - Clermont-Ferrand - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital Hôtel Dieu - Angers - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital Jean Minjoz - Besançon - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital La Miletrie - Poitiers - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital Morvan - Brest - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital Robert Debré - 51092 - Reims - France | Contact (sur clinicalTrials) | ||||
| Chu - Hôpital Sud - Amiens - France | Contact (sur clinicalTrials) | ||||
| Privé - Clinique Capio Belharra - Bayonne - France | Contact (sur clinicalTrials) | ||||
| Privé - Clinique de L'Europe - Amiens - France | Contact (sur clinicalTrials) | ||||
| Privé - Clinique Des Cèdres - Cornebarrieu - France | Contact (sur clinicalTrials) | ||||
| Prive - Clinique Jean Mermoz - Lyon - France | Contact (sur clinicalTrials) | ||||
| Privé - Clinique Maurice Tubiana - Caen - France | Contact (sur clinicalTrials) | ||||
| Privé - Clinique Saint Côme - Compiègne - France | Contact (sur clinicalTrials) | ||||
| Privé - Clinique Sainte Catherine - Avignon - France | Contact (sur clinicalTrials) | ||||
| Privé - Clinique Tivoli - Bordeaux - France | Contact (sur clinicalTrials) | ||||
| Privé - Hôpital Privé D'Antony - Antony - France | Contact (sur clinicalTrials) | ||||
| Privé - Hôpital Privé Paul D'Egine - Champigny-sur-Marne - France | Contact (sur clinicalTrials) | ||||
| Privé - Infirmerie Protestante - Caluire-et-Cuire - France | Contact (sur clinicalTrials) | ||||
| Prive - Institut Montsouris - Paris - France | Contact (sur clinicalTrials) | ||||
| Privé - Pôle Santé Léonard de Vinci - Chambray-lès-Tours - France | Contact (sur clinicalTrials) | ||||
| Privé - Polyclinique Bordeaux Nord - Bordeaux - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
Inclusion Criteria:
- Age ≥ 18 years.
- Body weight > 30kg.
- Histologically proven advanced-stage unresectable adenocarcinoma of the stomach or
the GEJ (Siewert II or III).
- Known MSS/MSI status or tumor tissue available (frozen or paraffin-embedded, primary
tumors or metastases) in order to allow determination of MSS/MSI status. The
investigator needs to ensure that tumor tissues will be sent after patient
randomization.
- Failure to platinium-based 1st line therapy with or without trastuzumab, or early
recurrent disease after surgery with neo-adjuvant and/or adjuvant platinium-based
chemotherapy (within 6 months of the end of chemotherapy) or progression during
neo-adjuvant and/or adjuvant platinium-based chemotherapy.
- Eligible for a second-line treatment with irinotecan and 5-FU.
- Measurable or non-measurable lesion according to the Response Evaluation Criteria in
Solid Tumors (RECIST 1.1).
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Adequate organ function: ANC ≥ 1.5 x 109/L, haemoglobin ≥ 9 g/dL, platelets ≥ 100 x
109/L, AST/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastase(s)), GGT ≤ 3 x ULN (≤
5 x ULN in case of liver metastase(s)), bilirubin ≤ 1.5 x ULN, creatinin clearance >
40 mL/min (MDRD).
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients.
- Man and woman who childbearing potential agrees to use two methods (one for the
patient and one for the partner) of medically acceptable forms of contraception
during the study and for 6 months after the last treatment intake.
- Patient is able to understand, sign, and date the written informed consent form at
the screening visit prior to any protocol-specific procedures performed.
- Age ≥ 18 years.
- Body weight > 30kg.
- Histologically proven advanced-stage unresectable adenocarcinoma of the stomach or
the GEJ (Siewert II or III).
- Known MSS/MSI status or tumor tissue available (frozen or paraffin-embedded, primary
tumors or metastases) in order to allow determination of MSS/MSI status. The
investigator needs to ensure that tumor tissues will be sent after patient
randomization.
- Failure to platinium-based 1st line therapy with or without trastuzumab, or early
recurrent disease after surgery with neo-adjuvant and/or adjuvant platinium-based
chemotherapy (within 6 months of the end of chemotherapy) or progression during
neo-adjuvant and/or adjuvant platinium-based chemotherapy.
- Eligible for a second-line treatment with irinotecan and 5-FU.
- Measurable or non-measurable lesion according to the Response Evaluation Criteria in
Solid Tumors (RECIST 1.1).
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Adequate organ function: ANC ≥ 1.5 x 109/L, haemoglobin ≥ 9 g/dL, platelets ≥ 100 x
109/L, AST/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastase(s)), GGT ≤ 3 x ULN (≤
5 x ULN in case of liver metastase(s)), bilirubin ≤ 1.5 x ULN, creatinin clearance >
40 mL/min (MDRD).
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients.
- Man and woman who childbearing potential agrees to use two methods (one for the
patient and one for the partner) of medically acceptable forms of contraception
during the study and for 6 months after the last treatment intake.
- Patient is able to understand, sign, and date the written informed consent form at
the screening visit prior to any protocol-specific procedures performed.
-
- Concurrent enrolment in another clinical study - unless it is an observational
study or during the follow-up period of an interventional study.
- Receipt of the last dose of anticancer therapy ≤ 2 weeks prior to the first dose of
study drug.
- Radiotherapy within 4 weeks prior to the first dose of treatment.
- History of chronic inflammatory bowel disease (IBD).
- Current or prior bowel obstruction within 28 days before the first dose of study
drugs.
- Any unresolved significant toxicity NCI CTCAE v4.0 ≥ grade 2 from previous
anticancer therapy.
- Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable
- Major surgical procedure (e.g. exploratory laparoscopy is not considered as a major
surgical procedure) within 28 days prior to the first dose of treatment.
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
- Active or prior documented autoimmune or inflammatory disorders (patients with
alopecia, vitiligo, controlled hypo or hyperthyroidism, any chronic skin condition
not requiring immunosuppressant therapy are eligible). Patients without active
disease in the last 5 years may be included.
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially
increase risk of incurring AEs or compromise the ability of the patient to give
written informed consent.
- Severe cardiac disorders within 6 months.
- Severe liver dysfunction
- History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing
pneumonia, or evidence of active pneumonitis on screening chest CT-scan.
- History of leptomeningeal carcinomatosis. Patients whose brain metastases have been
treated may participate provided they show radiographic stability. In addition, any
neurologic symptoms that developed either as a result of the brain metastases or
their treatment must have resolved or be stable either, without the use of steroids,
or are stable on a steroid dose of ≤10mg/day of prednisone or its equivalent for at
least 14 days prior to the start of treatment
- Positive test for HIV, active hepatitis B or hepatitis C, active tuberculosis.
- History of active primary immunodeficiency
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of study drugs (excepted: intranasal, inhaled, topical steroids or local
steroid injection -at physiologic dose does not exceed 10 mg/day of prednisone or
its equivalent - steroids as premedication for hypersensitivity reactions).
- Receipt of live attenuated vaccine within 30 days prior to the first dose of
treatment
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients. In order to check all the contraindications of each drugs, please refer
to the updated versions of the SmPCs presented in Appendix 9.
- Current or prior use of St. John's Wort within 14 days before the first dose of
study drugs (St. John's Wort is not allowed during participation in the trial).
- Treatment with sorivudine or analogs (brivudine).
- Treatment with phenytoin or analogs.
- Prior treatment with irinotecan, anti-PD1, anti PD-L1, anti-CLTA4 or other
immunotherapy for cancer treatment
- Known Uridine Diphosphate Glucuronyltransferase (UGT1A1) or Dihydropyrimidine
Dehydrogenase (DPD) enzyme deficiencies.
- Active infection requiring intravenous antibiotics at the time of Day 1 of Cycle 1.
- Other malignancy within 5 years prior to study enrolment, except for localized
cancer in situ, basal or squamous cell skin cancer.
- Pregnant or breastfeeding female patient.