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

Metastatic Pancreatic Cancer Clinical Trial

— GABRINOX2  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05065801
• Other study ID #: PROICM 2021-02 GAB
• Status: Recruiting
• Phase: Phase 2
• Start date: January 30, 2022
• Est. completion date: November 30, 2027

Study information

• Verified date: September 2023
• Source: Institut du Cancer de Montpellier - Val d'Aurelle
• Contact: Aurore MOUSSION, MD
• Phone: 0467612446
• Email: Aurore.Moussion[@]icm.unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 162
• Est. completion date: November 30, 2027
• Est. primary completion date: March 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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)

Related Conditions & MeSH terms

• Metastatic Pancreatic Cancer
• Pancreatic Neoplasms

Intervention

Combination Product:
• GABRINOX
Patients in the experimental arm received sequential treatment: 3 cycles of GEMBRAX followed by 2 cycles of FOLFIRINOX
• FOLFIRINOX
Patients in this arm received reatment: 3 cycles of FOLFIRINOX

Locations

Country	Name	City	State
France	Centre Georges-François Leclerc	Dijon	Côte d'Or
France	CHU Grenoble	Grenoble	Auvergne-Rhône-Alpes
France	CHU St Eloi	Montpellier	Herault
France	Institut régional du Cancer de Montpellier	Montpellier	Hérault
France	Centre Catalan d'Oncologie	Perpignan	Pyrénées-Orientales
France	CH de Perpignan	Perpignan	Pyrénées-Orientales
France	Institut GODINOT	Reims	Grand Est
France	CHU St Etienne	Saint-Étienne	Auvergne-Rhône-Alpes

Sponsors (1)

Lead Sponsor	Collaborator
Institut du Cancer de Montpellier - Val d'Aurelle

Country where clinical trial is conducted

France, 

References & Publications (5)

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. — View 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. — View Citation

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival	To compare progression-free survival between the investigational gabrinox treatment and the standard FOLFIRINOX treatment in patients with metastatic 1st line pancreatic adenocarcinoma.; Progression-free survival defined as the time between randomization and the onset of the 1st documented progression or death from any cause.; Tumor progression is assessed according to the RECIST 1.1 criteria and by the centralized review.	From randomization to disease progression or death, up to 6 month
Secondary	Tolerance of treatments	Adverse events rate assessed according to the NCI-CTC AE classification in application	From randomization to 30 days after end of treatment, up to 19 month
Secondary	Objective response rate	Objective response rate (best response during treatment) defined as the percentage of complete or partial response. The tumor response is evaluated according to the RECIST 1.1 criteria.	From randomization to the best response (complete or partial response) during treatment, up to 6 month
Secondary	Disease control rate	Disease control rate defined as the percentage of complete or partial response or stability.; The tumor response is evaluated according to the RECIST 1.1 criteria.	From randomization to the complete or partial response or stability, up to 6 month
Secondary	Overall survival	Overall survival defined as the time between randomization and the onset of death regardless of the cause.	From randomization to death, up to 2 years
Secondary	Quality of life questionnaire -Core 30 (QLQ-C30)	Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	At inclusion, then every 2 months up to 12 months then at 16 months, 20 months and 24 months (2 years)
Secondary	Quality of life questionnaire -PAN 26	Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life in patients with pancreatic cancer in clinical trials.; The module comprises 26 questions assessing pain, dietary changes, jaundice, altered bowel habit, emotional problems related to pancreatic cancer, and other symptoms (cachexia, indigestion, flatulence, dry mouth, taste changes). The QLQ-PAN26 uses for the question 31 to 56 a 4-point scale. The scale scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit") and 4 ("Very much").	At inclusion, then every 2 months up to 12 months then at 16 months, 20 months and 24 months (2 years)
Secondary	Collection of circulating tumor DNA (ctDNA)	Establish a biological database for the analysis of biological predictive factors	At inclusion and when treatment is stopped (approximately 6 month)

External Links

•   A Cancer Journal for Clinicians.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA: janv 2017;67(1):7-30.
•   Descriptive epidemiology of cancers in metropolitan France: incidence, survival and prevalence. Cowppli-Bony A, Colonna M, Ligier K, Jooste V, Defossez G, Monnereau A, et al.