Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03959293
Recruitment Status : Not yet recruiting
First Posted : May 22, 2019
Last Update Posted : May 24, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Federation Francophone de Cancerologie Digestive

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.


Condition or disease Intervention/treatment Phase
Gastric Adenocarcinoma Gastric Cancer Drug: Durvalumab Drug: Tremelimumab Drug: FOLFIRI Protocol Phase 2

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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".
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : July 15, 2019
Estimated Primary Completion Date : November 15, 2023
Estimated Study Completion Date : July 31, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: FOLFIRI plus durvalumab
  • 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
1500 mg by 1-hour IV infusion - Every 4 weeks

Drug: FOLFIRI Protocol
  • 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

Experimental: FOLFIRI plus durvalumab plus tremelimumab
  • 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: Tremelimumab
75 mg by 1-hour IV infusion - Every 4 weeks

Drug: FOLFIRI Protocol
  • 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




Primary Outcome Measures :
  1. Percentage of patients alive and without progression at 4 months [ Time Frame: 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.


Secondary Outcome Measures :
  1. Percentage of patients alive and without progression at 4 months according to centralized review [ Time Frame: 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.

  2. Overall survival (OS) [ Time Frame: 2 years ]
    OS is defined as the time between the date of randomization and the date of death (whatever the cause). Alive patients will be censured at date of last news.

  3. Time to strategy failure [ Time Frame: An average of 6 months ]

    Is defined as the time between randomization date and date of death (from any cause) or the date of first radiological progression in the FOLFIRI + durvalumab arm or date of the second radiological progression after re-introduction of tremelimumab in the FOLFIRI plus durvalumab plus tremelimumab arm or date of definitive discontinuation.

    In case a treatment is stopped for toxicity reason but re-introduced later for progression, then this progression will not be considered for this endpoint.


  4. Adverse event frequency estimation according to NCI-CTCAE v4.0 classifications [ Time Frame: An average of 6 months ]
    Toxicities will be graded according to the NCI-CTCAE v4.0 classifications.

  5. Incidence of treatment upon the quality of life (QoL) of patients in order to assess that treatment do not impact significantly the QoL [ Time Frame: An average of 6 months ]
    Quality of life (QoL) is evaluated using the EORTC QLQ - STO22 questionnaires.

  6. Incidence of treatment upon the quality of life (QoL) of patients [ Time Frame: An average of 6 months ]
    Quality of life (QoL) is evaluated using the EORTC QLQ-C30

  7. Time to progression (TTP) (according to iRECIST) [ Time Frame: An average of 1 year ]
    TTP : Time to progression (TTP): Is defined as the time between date of randomization and the date of first radiological progression (according to iRECIST). Patients without progression will be censored at date of last news or date of death. The death will not be considered as an event.

  8. Progression-free survival (median PFS) (according to iRECIST) [ Time Frame: An average of 1 year ]
    Progression free survival (PFS) median: Is defined as the time between date of randomization and date of the first radiological progression (according to iRECIST) or death (from any cause), whichever occurs first. Patients alive without progression will be censored at date of last news.

  9. Best objective response rate (BRR) (according to iRECIST) [ Time Frame: An average of 1 year ]
    Best Objective Response rate (BRR): Is defined as complete or partial response at the best response evaluation during the treatment according to iRECIST.

  10. Disease control rate (DCR) (according to iRECIST) [ Time Frame: An average of 1 year ]
    Disease control rate (DCR) at each timepoint: Is defined as complete or partial response or stable disease at the best response evaluation according to iRECIST.

  11. Time to progression (TTP) (according to RECIST V1.1) [ Time Frame: An average of 1 year ]
    TTP : Time to progression (TTP): Is defined as the time between date of randomization and the date of first radiological progression (according to RECIST v1.1). Patients without progression will be censored at date of last news or date of death. The death will not be considered as an event.

  12. Progression-free survival (median PFS) (according to RECIST V1.1) [ Time Frame: An average of 1 year ]
    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.

  13. Best objective response rate (BRR) (according to RECIST V1.1) [ Time Frame: An average of 1 year ]
    Best Objective Response rate (BRR): Is defined as complete or partial response at the best response evaluation during the treatment according to RECIST v1.1.

  14. Disease control rate (DCR) (according to RECIST V1.1) [ Time Frame: An average of 1 year ]
    Disease control rate (DCR) at each timepoint: Is defined as complete or partial response or stable disease at the best response evaluation according to RECIST v1.1.

  15. OS according to the expression of PD-L1 [ Time Frame: 2 years ]
    Efficacy endpoints will be evaluated according to the expression of PD-L1.

  16. PFS according to the expression of PD-L1 [ Time Frame: 2 years ]
    Efficacy endpoints will be evaluated according to the expression of PD-L1.

  17. TTP according to the expression of PD-L1. [ Time Frame: 2 years ]
    Efficacy endpoints will be evaluated according to the expression of PD-L1.

  18. BRR according to the expression of PD-L1. [ Time Frame: 2 years ]
    Efficacy endpoints will be evaluated according to the expression of PD-L1.

  19. DCR according to the expression of PD-L1. [ Time Frame: 2 years ]
    Efficacy endpoints will be evaluated according to the expression of PD-L1.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Exclusion Criteria:

  • - 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03959293


Contacts
Layout table for location contacts
Contact: Daniel GONZALEZ +33 (0)3 80 39 34 04 daniel.gonzalez@u-bourgogne.fr
Contact: David TOUGERON, PhD, MD +33 (0)5 49 44 37 51 david.tougeron@chu-poitiers.fr

Sponsors and Collaborators
Federation Francophone de Cancerologie Digestive
AstraZeneca

Layout table for additonal information
Responsible Party: Federation Francophone de Cancerologie Digestive
ClinicalTrials.gov Identifier: NCT03959293     History of Changes
Other Study ID Numbers: PRODIGE 59 - DURIGAST
FFCD 1707 ( Other Identifier: FFCD Number )
2018-002014-13 ( EudraCT Number )
First Posted: May 22, 2019    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Irinotecan
Durvalumab
Tremelimumab
Antibodies, Monoclonal
Leucovorin
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances