Clinical trial NCT05065801: Efficacy of Gembrax Followed by Folfirinox Versus Folfirinox Alone in First Metastatic Line Pancreatic Cancer Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metastatic Pancreatic Cancer
Keywords: pancreatic
cancer
Lead sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
Sponsor class: OTHER
First posted: 2021-10-04
Enrollment: 162
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Male or female aged 18 to 75 on the date the consent is signed.
2. 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.
3. 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).
4. Previous treatment (including radiochemotherapy) for the non-metastatic disease authorized if a delay ≥ 6 months between the last treatment and the recurrence is respected.
5. WHO performance status ≤ 1 6. Uracilemia \<16 ng / ml

7. 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.

8. 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 MCDK-EPI formula).

9. Calcemia AND magnesemia AND kalaemia ≥ LIN and ≤ 1.2 x ULN 10. 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 9 months after discontinuation of treatment. for women and 6 months for men.

11. Signature of consent before any procedure specific to the study. 12. Affiliated with the French national social security.

Exclusion Criteria:

1. Known brain metastasis.
2. Previous treatment with radiotherapy, surgery, chemotherapy or experimental therapy for the treatment of metastatic disease.
3. 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.
4. Known Gilbert's syndrome or homozygous for know UGT1A1 \* 28
5. 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.
6. Patients with high cardiovascular risk, including, but not limited to, coronary stent or myocardial infarction within the past 6 months.
7. Peripheral sensory neuropathy ≥ grade 2 at the time of inclusion.
8. ECG with a QTc interval greater than 450 ms for men and greater than 470 ms for women
9. History of chronic inflammatory disease of the colon or rectum
10. 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)
11. Intolerance or allergy to one of the study drugs (gemcitabine, nab-paclitaxel, oxaliplatin, irinotecan, 5-FU) or to an excipient of one of the drugs (example: fructose) described in the sections Against SPC indications or Special Warnings and Precautions or Prescribing Information
12. Legal incapacity (patient under guardianship or guardianship)

Primary outcomes:
measure: Progression-free survival
timeFrame: From randomization to disease progression or death, up to 6 month
Secondary outcomes:
measure: Tolerance of treatments
timeFrame: From randomization to 30 days after end of treatment, up to 19 month
measure: Objective response rate
timeFrame: From randomization to the best response (complete or partial response) during treatment, up to 6 month
measure: Disease control rate
timeFrame: From randomization to the complete or partial response or stability, up to 6 month
measure: Overall survival
timeFrame: From randomization to death, up to 2 years
measure: Quality of life questionnaire -Core 30 (QLQ-C30)
timeFrame: At inclusion, then every 2 months up to 12 months then at 16 months, 20 months and 24 months (2 years)
measure: Quality of life questionnaire -PAN 26
timeFrame: At inclusion, then every 2 months up to 12 months then at 16 months, 20 months and 24 months (2 years)
measure: Collection of circulating tumor DNA (ctDNA)
timeFrame: At inclusion and when treatment is stopped (approximately 6 month)
Other outcomes:
Locations:
city: Grenoble
country: France
facility: CHU Grenoble
state: Auvergne-Rhône-Alpes
city: Saint-Étienne
country: France
facility: CHU St Etienne
state: Auvergne-Rhône-Alpes
city: Reims
country: France
facility: Institut GODINOT
state: Grand Est
city: Montpellier
country: France
facility: CHU St Eloi
state: Herault
city: Montpellier
country: France
facility: Institut régional du Cancer de Montpellier
state: Hérault
city: Perpignan
country: France
facility: Centre Catalan d'Oncologie
state: Pyrénées-Orientales
city: Perpignan
country: France
facility: CH de Perpignan
state: Pyrénées-Orientales
city: Dijon
country: France
facility: Centre Georges-François Leclerc
Study officials:
affiliation: Institut de Cancérologie de Montpellier (ICM)
name: Fabienne PORTALES, MD
role: STUDY_CHAIR
References:
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citation: 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.
citation: 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.
citation: 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. 2011 May 12;364(19):1817-25. doi: 10.1056/NEJMoa1011923.
citation: 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. Epub 2013 Oct 16.
citation: 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.