Efficacy of Gembrax Followed by Folfirinox Versus Folfirinox Alone in First Metastatic Line Pancreatic Cancer Patients

Официальное название

Randomized Phase II Trial Evaluating the Efficacy of a Sequential Treatment Gemcitabine Plus Nab-paclitaxel (Gembrax) Followed by Folfirinox Versus Folfirinox Alone in Patients Treated in First Metastatic Line Pancreatic Cancer

Обзор

The aim of this study is to evaluate the efficacy of sequential treatment (Gabrinox) comprising Gembrax regimen (Gemcitabine -Abraxane) followed by the Folfirinox regimen (5FU, Oxaliplatin and Irinotecan) compared to folfirinox alone in patients treated in first metastatic line pancreatic cancer

Подробное описание

Pancreatic cancer is the third leading cause of cancer death in 2016, surpassing breast cancer. It is estimated that by 2030 pancreatic cancer will become the second leading cause of cancer death after lung cancer.

Its prognosis is very poor, with a 5-year overall survival rate (OS) at all stages of 5.5%.

In France, its incidence doubled in men and tripled in women between 1982 and 2012. The World Standardized Rate (MSR) for men and women respectively was 4.9% and 2% in 1980 and 10.2% and 6.9% in 2012. This means an annual rate of change of 2.3 for men to 3.9 for women.

Its diagnosis is often late, carried out in 50% of cases at stage 4, with limited treatment options, explaining its low survival rate at 5 years.

Until 2011, gemcitabine remained the only validated standard with a median survival of 6 months.

Many combinations with gemcitabine have been evaluated but have shown no significant survival advantage over Gemzar alone.

The most promising results reported to date remain the combination of oxaliplatin, irinotecan and 5 fluoro-uracil (FOLFIRINOX), which became the standard metastatic first-line treatment thanks to the results of the phase III study, ACCORD11, randomizing gemcitabine to FFX with for the first time, a significant gain in median survival, progression-free survival and response rate in favor of the experimental arm of 6.8 months vs. 11.1 months respectively (\[HR 0.57, 95 % IC, 0.45-0.7 3\];p\<0.001), 3.3vs6.4 (\[HR 0.47, 95 % IC, 0.37- 0.59\];p\<0.001) et de 9.4 % vs 31.6 % ; p\>0.001.

In 2013, the combination gemcitabine nab-paclitaxel (GEMBRAX) showed, in a randomized phase III study, compared to gemcitabine, a significant gain in terms, median survival, survival without progression and response rate in favor of the experimental arm, respectively for gemcitabine vs GEMBRAX, 6.7 months vs 8.5 months (\[HR 0.72, 95 % IC, 0.62-0.83\];p\<0.001) ; 3.7vs 5.5. (\[HR 0.69, 95 % IC, 0.58- 0.82\];p\<0.001) et de 7 % vs 23% ; p\>0.001.

FOLFIRINOX and GEMBRAX, two chemotherapy protocols which have shown their effectiveness in the 1st metastatic line with a gain in terms of response rate, progression-free survival and median survival but with increased grade 3/4 toxicities, compared to treatment with gemcitabine.

For FOLFIRINOX: a neutropenia rate of 45.7% vs 21% including 5.4% of febrile neutropenia vs 1.2, a rate of diarrhea of 12.7% vs 1.8% and peripheral neuropathies of 9% vs 0

For GEMBRAX neutropenia 38% VS 27% including 3% febrile neutropenia VS 1%, 6% diarrhea vs 1% and peripheral neuropathy 17% vs 1%:

Given the high toxicities, only patients with favorable performance status are eligible to receive these regimens.

The sponsor therefore considered a new concept of sequential GABRINOX treatment combining GEMBRAX followed by FOLFIRINOX, which should make it possible, by reducing toxicities, to increase the response rate and at the same time progression-free survival and median survival.

The sponsor performed a phase 1/2 study evaluating this GABRINOX protocol with the main objective of determining the maximum tolerated dose and increasing the response rate. Phase 2 is encouraging with a disease control rate and an objective response rate of 84.2% and 64.9% respectively, progression-free survival at 10.5 months and overall survival at 15.1 months as well as a more favorable safety profile compared to non-sequential treatments (less neutropenia 34.5%, febrile neutropenia 3.5% and neurotoxicity 5.2%).

These encouraging results led the investigator to propose a phase 2 study comparing the standard first-line treatment regimen FOLFIRINOX with the sequential regimen GABRINOX with the main objective of comparing efficacy in terms of objective response rate.

Вмешательства

• Комбинированный продукт GEMBRAX/FOLFIRINOX Arm A
  Patients in the experimental arm received sequential treatment: A maximum of 6 cycles (12 months) of chemotherapy; One cycle = 3 administrations of GEMBRAX followed by 2 administrations of FOLFIRINOX
• Комбинированный продукт FOLFIRINOX Arm B
  Patients in this arm received : A maximum of 3 cycles (6 months) of chemotherapy. One cycle = 4 administrations of FOLFIRINOX

Первичные конечные точки

• Progression-free survival [Срок оценки: From randomization to disease progression or death, up to 6 month]

Вторичные конечные точки (7)

• Tolerability of treatments [Срок оценки: From randomization to 30 days after end of treatment, up to 13 month for Arm A and 7 month for Arm B]
• Objective response rate [Срок оценки: From randomization to the best response (complete or partial response) during treatment, up to 6 month]
• Disease control rate [Срок оценки: From randomization to the complete or partial response or stability, up to 6 month]
• Overall survival [Срок оценки: From randomization to death, up to 2 years]
• Quality of life questionnaire -Core 30 (QLQ-C30) [Срок оценки: At inclusion, then every 2 months up to 12 months then at 16 months, 20 months and 24 months (2 years)]
• Quality of life questionnaire -PAN 26 [Срок оценки: At inclusion, then every 2 months up to 12 months then at 16 months, 20 months and 24 months (2 years)]
• Collection of circulating tumor DNA (ctDNA) [Срок оценки: At inclusion and when treatment is stopped (approximately 6 month)]

Критерии участия

Критерии включения

• Male or female aged 18 to 75 on the date the consent is signed.
• Histologically or cytologically proven metastatic pancreatic adenocarcinoma. The definitive diagnosis of pancreatic adenocarcinoma metastases will be made by integrating the histopathological data in the context of the radiological data.
• One or more metastatic lesion (s) measurable (Recist 1.1) by Thoraco-Abdomino-Pelvic scanner (or hepatic MRI and Thoraco-Abdomino-Pelvic scanner not injected, if the patient is allergic to the product of contrast).
• Previous treatment (including radiochemotherapy) for the non-metastatic disease authorized if a delay ≥ 6 months between the last treatment and the recurrence is respected.
• WHO performance status ≤ 1
• Uracilemia <16 ng / ml
• Acceptable hematological assessment at inclusion (obtained within 14 days before the start of treatment) defined by: • Neutrophils ≥ 2 × 109 / L; • Platelets ≥ 100,000 / mm3 (100 × 109 / L); • Hemoglobin ≥ 9 g / dl.
• Acceptable renal and hepatic function at inclusion (obtained within 14 days before the start of treatment) defined by: • AST and ALT ≤ 2.5 x upper limit of the norm (ULN), unless liver metastases are present in this case AST and ALT ≤ 5 × ULN is allowed; • Total bilirubin ≤ 1.5 x ULN; • Serum creatinine within the norm limits or calculated clearance ≥ 50ml / min for patients with a serum creatinine value above or below the norm values (clearance calculated by the CKD-EPI formula).
• Calcemia AND magnesemia AND kalaemia ≥ LLN and ≤ 1.2 x ULN
• If the patient is sexually active, he must agree to use contraception deemed adequate and appropriate by the investigator throughout the period of administration of the study drug and up to 6 months after discontinuation of treatment for women and for men.
• Signature of consent before any procedure specific to the study.
• Affiliated with the French national social security.

Критерии исключения

• Known brain metastasis.
• Previous treatment with radiotherapy, surgery, chemotherapy or experimental therapy for the treatment of metastatic disease.
• Major surgery, other than diagnostic surgery (that is, surgery done to obtain a diagnostic biopsy without organ harvesting), within 4 weeks of day 1 of study treatment.
• Known Gilbert's syndrome or homozygous for know UGT1A1 \* 28
• Other concomitant cancer or history of cancer, except cervical cancer in situ treated, skin basal or squamous cell carcinoma, superficial bladder tumor (Ta, Tis, and T1) or a tumor with a good prognosis treated curatively without chemotherapy and without any sign of disease in the 3 years preceding inclusion.
• Patients with high cardiovascular risk, including, but not limited to, coronary stent or myocardial infarction within the past 6 months.
• Peripheral sensory neuropathy ≥ grade 2 at the time of inclusion.
• ECG with a QTc interval greater than 450 ms for men and greater than 470 ms for women
• Any other concomitant and unbalanced disease or serious disturbance that may interfere with the patient's participation in the study and his safety during the study (eg severe hepatic, renal, pulmonary, metabolic, or psychiatric disorders)
• Allergy or intolerance to any study drug (gemcitabine, nab-paclitaxel, oxaliplatin, irinotecan, 5-FU) or any excipient (e.g., fructose) as described in the sections " contraindication or special warnings and precautions" or "prescribing information" of the summary of product characteristics indications.
• Pregnant or breastfeeding women. Women of childbearing potential must have a negative pregnancy test (serum β-hCG) within 72 hours prior to inclusion.
• Patients on vitamin K antagonists (e.g., Coumadin) (modifications to treatment may be required prior to inclusion).
• Treatment with brivudine within 4 weeks before or after treatment with 5-fluorouracil (due to a potentially fatal interaction).
• Active and uncontrolled bacterial, viral, or fungal infections requiring systemic treatment.
• Active HIV infection, known hepatitis B or C infection.
• History of peripheral arterial disease (e.g., claudication, Buerger's disease), chronic inflammatory bowel disease or rectal disease, pulmonary fibrosis or interstitial pneumonia.
• Administration of a live attenuated vaccine within 10 days before inclusion and up to 6 months post-treatment.
• Patient refusal or inability to comply with study procedures.
• Inability to undergo follow-up for geographical, social, or psychological reasons.
• Participation in another clinical trial involving an investigational product within the 30 days prior to inclusion.
• Legal incapacity (patient under guardianship or guardianship).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 8 центров

• CHU Grenoble — Grenoble
• CHU St Etienne — Saint-Etienne
• Institut GODINOT — Reims
• CHU St Eloi — Montpellier
• Institut régional du Cancer de Montpellier — Montpellier
• Centre Catalan d'Oncologie — Perpignan
• CH de Perpignan — Perpignan
• Centre Georges-François Leclerc — Dijon

Публикации

• Portales F, Gourgou S, Fiess C, Salasc F, Assenat E, Ychou M. GABRINOX-2 protocol: a French, prospective, multicentre, randomised phase II trial evaluating gemcitabine/nab-paclitaxel followed by FOLFIRINOX versus FOLFIRINOX alone as first-line treatment for metastatic pancreatic cancer. BMJ Open. 2025 Aug 16;15(8):e104228. doi: 10.1136/bmjopen-2025-104228. PMID 40819868
• Ferlay J, Partensky C, Bray F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 2016 Sep-Oct;55(9-10):1158-1160. doi: 10.1080/0284186X.2016.1197419. Epub 2016 Aug 23. PMID 27551890
• Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13. doi: 10.1200/JCO.1997.15.6.2403. PMID 9196156
• Sultana A, Smith CT, Cunningham D, Starling N, Neoptolemos JP, Ghaneh P. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol. 2007 Jun 20;25(18):2607-15. doi: 10.1200/JCO.2006.09.2551. PMID 17577041
• Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 201 PMID 21561347
• Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. doi: 10.1056/NEJMoa1304369. PMID 24131140
• Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5. PMID 28055103

Идентификаторы

NCT: NCT05065801 · PROICM 2021-02 GAB

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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