Clinical Trial Evaluating FOLFIRI + Durvalumab vs FOLFIRI + Durvalumab and Tremelimumab in Second-line Treatment of Patients With Advanced Gastric or Gastro-oesophageal Junction Adenocarcinoma

NCT03959293 | Active Not Recruiting Phase 2

• 3 other identifiers: PRODIGE 59 - DURIGASTFFCD 17072018-002014-13
• Study Type: interventional
• Target: 107
• Locations: 1 country
• Sites: 35

Brief Summary

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.

Conditions

Gastric Adenocarcinoma; Gastric Cancer

Outcome Measures

Primary Outcomes (1)

• Percentage of patients alive and without progression at 4 months

  Progression free survival (PFS) median is defined as the time between date of randomization and date of the first radiological progression (according to RECIST 1.1) or death (from any cause), whichever occurs first. Patients alive without progression will be censored at date of last news.

  4 months

Secondary Outcomes (3)

• Percentage of patients alive and without progression at 4 months according to centralized review

  4 months

• Overall survival (OS)

  2 years

• Progression-free survival (median PFS) (according to iRECIST)

  An average of 1 year

Study Arms (2)

FOLFIRI plus durvalumab

EXPERIMENTAL

* Durvalumab: 1500 mg by 1-hour IV infusion. Every 4 weeks until progression * FOLFIRI (1 course every 2 weeks, until progression): * Irinotecan: 180 mg/m² by 2-hour IV infusion, * Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) by 2-hours IV infusion, * 5-FU bolus: 400 mg/m² by 10-minutes IV bolus, * Continuous 5-FU: 2400 mg/m² by 46-hour IV infusion

Drug: Durvalumab; Drug: FOLFIRI Protocol

FOLFIRI plus durvalumab plus tremelimumab

EXPERIMENTAL

* Durvalumab: 1500 mg by 1-hour IV infusion - Every 4 weeks. * Tremelimumab: 75 mg by 1-hour IV infusion - Every 4 weeks (for only 4 cycles). * FOLFIRI (1 course every 2 weeks, until progression): * Irinotecan: 180 mg/m² by 2-hour IV infusion * Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) by 2-hours IV infusion * 5-FU bolus: 400 mg/m² by 10-minutes IV bolus * Continuous 5-FU: 2400 mg/m² by 46-hour IV infusion

Drug: Durvalumab; Drug: Tremelimumab; Drug: FOLFIRI Protocol

Interventions

Durvalumab DRUG

1500 mg by 1-hour IV infusion - Every 4 weeks

FOLFIRI plus durvalumab; FOLFIRI plus durvalumab plus tremelimumab

Tremelimumab DRUG

75 mg by 1-hour IV infusion - Every 4 weeks

FOLFIRI plus durvalumab plus tremelimumab

FOLFIRI Protocol DRUG

* Irinotecan: 180 mg/m² by 2-hour IV infusion, * Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) by 2-hours IV infusion, * 5-FU bolus: 400 mg/m² by 10-minutes IV bolus, * Continuous 5-FU: 2400 mg/m² by 46-hour IV infusion

FOLFIRI plus durvalumab; FOLFIRI plus durvalumab plus tremelimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• \- 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

Sponsors & Collaborators

• Federation Francophone de Cancerologie Digestive: lead
• AstraZeneca: collaborator

Study Sites (35)

Ch - Centre Hospitalier

Abbeville, France

Location

Ch - Hôpital Claude Bernard

Albi, France

Location

Chu - Hôpital Sud

Amiens, France

Location

Privé - Clinique de L'Europe

Amiens, France

Location

Chu - Hôpital Hôtel Dieu

Angers, France

Location

Privé - Hôpital Privé D'Antony

Antony, France

Location

Ch - Hôpital Victor Dupouy

Argenteuil, France

Location

Ch - Hôpital Henri Duffaut

Avignon, France

Location

Privé - Clinique Sainte Catherine

Avignon, France

Location

Ch - Hôpital Côte Basque

Bayonne, France

Location

Privé - Clinique Capio Belharra

Bayonne, France

Location

Chu - Hôpital Jean Minjoz

Besançon, France

Location

Ch - Hôpital Germon Et Gauthier

Béthune, France

Location

Ch - Centre Hospitalier de Bézier

Béziers, France

Location

Privé - Clinique Tivoli

Bordeaux, France

Location

Privé - Polyclinique Bordeaux Nord

Bordeaux, France

Location

Ch - Hôpital Duchenne

Boulogne-sur-Mer, France

Location

Chu - Hôpital Morvan

Brest, France

Location

Chu - Hôpital Côte de Nacre

Caen, France

Location

Privé - Clinique Maurice Tubiana

Caen, France

Location

Privé - Infirmerie Protestante

Caluire-et-Cuire, France

Location

Ch - Centre Hospitalier de Carcassonne

Carcassonne, France

Location

Privé - Pôle Santé Léonard de Vinci

Chambray-lès-Tours, France

Location

Privé - Hôpital Privé Paul D'Egine

Champigny-sur-Marne, France

Location

Ch - Chp Du Cotentin

Cherbourg, France

Location

Ch - Centre Hospitalier de Cholet

Cholet, France

Location

Chu - Hôpital Estaing

Clermont-Ferrand, France

Location

Ch - Hopitaux Civils de Colmar

Colmar, France

Location

Privé - Clinique Saint Côme

Compiègne, France

Location

Privé - Clinique Des Cèdres

Cornebarrieu, France

Location

Prive - Clinique Jean Mermoz

Lyon, France

Location

Chu - Aphp - Hôpital Saint Louis

Paris, 75475, France

Location

Prive - Institut Montsouris

Paris, France

Location

Chu - Hôpital La Miletrie

Poitiers, France

Location

Chu - Hôpital Robert Debré

Reims, 51092, France

Location

Related Publications (2)

• Tougeron D, Louvet C, Desrame J, Evesque L, Angelergues A, Carnot A, Breysacher G, Zaanan A, Etchepare N, Mabro M, Kaluzinski L, Petorin C, Chibaudel B, Aparicio T, Bodere A, Rinaldi Y, Le Malicot K, Emile JF, Lepage C, Baures A, Djamai H, Taly V, Laurent-Puig P. Circulating tumor DNA strongly predicts efficacy of chemotherapy plus immune checkpoint inhibitors in patients with advanced gastro-esophageal adenocarcinoma. Commun Med (Lond). 2025 Apr 24;5(1):136. doi: 10.1038/s43856-025-00867-x.

  PMID: 40275077 DERIVED

• Tougeron D, Dahan L, Evesque L, Le Malicot K, El Hajbi F, Aparicio T, Bouche O, Bonichon Lamichhane N, Chibaudel B, Angelergues A, Bodere A, Phelip JM, Mabro M, Kaluzinski L, Petorin C, Breysacher G, Rinaldi Y, Zaanan A, Smith D, Gouttebel MC, Perret C, Etchepare N, Emile JF, Sanfourche I, Di Fiore F, Lepage C, Artru P, Louvet C; PRODIGE 59-FFCD 1707-DURIGAST Investigators/Collaborators. FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: The PRODIGE 59-FFCD 1707-DURIGAST Randomized Clinical Trial. JAMA Oncol. 2024 Jun 1;10(6):709-717. doi: 10.1001/jamaoncol.2024.0207.

  PMID: 38573643 DERIVED

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

durvalumab; tremelimumab; IFL protocol

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A safety analysis will be performed on 11 patients to ensure that treatment is well tolerated. This is not a "phase 1/phase 2" study but a phase 2 with "stop and go".

Study Record Dates

• First Submitted: May 9, 2019
• First Posted: May 22, 2019
• Study Start: July 17, 2019
• Primary Completion: March 15, 2022
• Study Completion: November 27, 2024
• Last Updated: July 8, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

FR (35)