Ignite Creation Date:
2024-05-06 @ 12:10 PM
Last Modification Date:
2024-10-26 @ 12:55 PM
Study NCT ID:
NCT03693677
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-07-08
First Post:
2018-10-01
Brief Title:
First Line Metastatic Pancreatic Cancer 5FULVNal-IRI GemcitabineNab-paclitaxel or a Sequential Regimen of 2 Months 5FULVNal-IRI
Sponsor:
Federation Francophone de Cancerologie Digestive
Organization:
Federation Francophone de Cancerologie Digestive
Study Overview
Official Title:
Randomized Phase II Study Comparing 5FULVNal-IRI GemcitabineNab-paclitaxel or a Sequential Regimen of 2 Months 5FULVNal-IRI Followed by Two Months of GemcitabineNab-paclitaxel in Metastatic Pancreatic Cancer
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
FUNGEMAX
Brief Summary:
In Europe pancreatic cancer PC is the 7th most common cancer and the 5th leading cause of cancer death in Europe Each year the number of deaths due to prostate cancer is almost as high as the number of new cases diagnosed reflecting the poor prognosis associated with this disease PC is insidious and is often diagnosed late Despite advances in the management of other more common gastrointestinal cancers the treatment of PC has had few benefits inherent in recent advances in digestive oncology Gemcitabine has thus remained the reference treatment for more than 10 years
Recent studies have shown that gemcitabineNab-paclitaxel combination therapy is more effective in PC than gemcitabine-based therapy alone In addition multidrug therapy approaches Irinotecan-5FULV have also emerged to avoid the emergence of resistance to treatments while limiting toxicities The recently developed Nal-IRI has also shown interesting efficacy in patients with metastatic PC previously treated with gemcitabine with improved overall survival median and limited toxicity Based on this information the NAPOLI trial was conducted in patients with second line PC comparing the efficacy of Nal-IRI5FULV or Nal-IRI and 5FULV alone in this key study the combination Nal-IRI5FULV treatment was more effective than monotherapies Nal-IRI or 5FULV alone
Based on all these data a Phase II trial testing the standard of care gemcitabinenab-paclitaxel vs Nal-IRI5FULV vs Nal-IRI5FULV 2-months sequential regimen followed by gemcitabinenab-paclitaxel will be performed This will allow us to i know the tolerance and efficacy of Nal-IRI5FULV in the first line of treatment ii test a new sequential strategy with Nal-IRI but also iii compare our results in the experimental arms with one of the two world standard therapeutic regimens gemcitabine nab-Paclitaxel All this in order to improve the management of patients with PC from the first line of treatment
Recent studies have shown that gemcitabineNab-paclitaxel combination therapy is more effective in PC than gemcitabine-based therapy alone In addition multidrug therapy approaches Irinotecan-5FULV have also emerged to avoid the emergence of resistance to treatments while limiting toxicities The recently developed Nal-IRI has also shown interesting efficacy in patients with metastatic PC previously treated with gemcitabine with improved overall survival median and limited toxicity Based on this information the NAPOLI trial was conducted in patients with second line PC comparing the efficacy of Nal-IRI5FULV or Nal-IRI and 5FULV alone in this key study the combination Nal-IRI5FULV treatment was more effective than monotherapies Nal-IRI or 5FULV alone
Based on all these data a Phase II trial testing the standard of care gemcitabinenab-paclitaxel vs Nal-IRI5FULV vs Nal-IRI5FULV 2-months sequential regimen followed by gemcitabinenab-paclitaxel will be performed This will allow us to i know the tolerance and efficacy of Nal-IRI5FULV in the first line of treatment ii test a new sequential strategy with Nal-IRI but also iii compare our results in the experimental arms with one of the two world standard therapeutic regimens gemcitabine nab-Paclitaxel All this in order to improve the management of patients with PC from the first line of treatment
Detailed Description:
Pancreatic cancer PC is the seventh cause from cancer and the fifth cause from cancer-related death in Europe Nearly as many deaths occur from PC than the number of new cases diagnosed each year reflecting the poor prognosis typically associated with this disease PC is insidious in onset and is often diagnosed late at the stage of metastatic spread In spite of advances made in the management of other more common gastrointestinal cancers the treatment of PC did take only a small advantage of recent progresses in gastrointestinal oncology and targeted therapies did not significantly modify its prognosis to date
Thus for more than 10 years gemcitabine has been the standard of care to treat metastatic PC Recently two positive phase III trials in metastatic PC were reported
First the gemcitabine with nab-paclitaxel combination therapy was compared to gemcitabine alone in 861 randomized patients with metastatic PC Results showed a significant improvement in response rate RR progression free survival PFS and overall survival OS Second the results of the PRODIGE 4ACCORD 11 trial testing the FOLFIRINOX regimen in metastatic PC patients finally gave a hope showing a major improvement in PFS and OS as compared to gemcitabine However though manageable the safety profiles of FOLFIRINOX and of gemcitabine plus nab-paclitaxel were less favourable than that of gemcitabine These regimens were associated with a higher incidence of grade 3-4 neutropenia febrile neutropenia thrombocytopenia diarrhoea and grade 2-3 sensory neuropathy
Irinotecan has a stronger growth-inhibiting effect than cisplatin mitomycin C and fluorouracil on cultured pancreatic adenocarcinoma cells In most trials testing this molecule in PC patients however the response rates were low 10 and survivals were poor Intensive regimens with irinotecan and 5-FU have been developed in colorectal cancer patients to increase the anti-tumor effects of this combination therapy From those the FOLFIRI3 in which the irinotecan is administered before and after a 5-FU 46h continuous infusion gave promising results The investigator has tested this regimen in a phase II trial in advanced PC patients with an objective RR of 375 a median OS time of 12 months and acceptable tolerability Considering these encouraging results the investigator has proposed a new approach to improve outcomes for patients with metastatic PC using FOLFIRI3 and gemcitabine alone sequentially to increase patient survival with a preserved quality of life QOL Indeed some authors have reported that the administration of different patterns of sequential polychemotherapy was independently associated with OS in patients with PC and other gastrointestinal tumors such as metastatic colorectal cancer Such strategies using drugs without cross-resistance sequentially may increase anti-tumor effects and limit cumulative and non-cumulative toxicities
The investigator thus performed a randomized multicentre phase II trial to assess this sequential treatment strategy using FOLFIRI3 and gemcitabine alternately in one arm and gemcitabine alone in the other arm in patients with metastatic non pre-treated pancreatic adenocarcinoma In this study the FIRGEM strategy seems to be an effective first line treatment option in good condition patients with metastatic PC The primary endpoint was reached with a rate of PFS at 6 months of 449 in the FIRGEM arm while gemcitabine alone failed 257 This good PFS rate at 6 months was maintained at 12 and 18 months 262 and 18 respectively though median PFS was 50 months Moreover an impressive objective response rate was observed in the FIRGEM arm 40 as compared to the gemcitabine arm 114 These results confirm those of the initial phase II trial evaluating the FOLFIRI3 regimen 375 objective response rate15 in PC patients and compare favourably with the 316 and 23 reported in the two trials evaluating FOLFIRINOX and gemcitabine nab-paclitaxel respectively
Median overall survival was 11 months with FIRGEM versus 82 months with gemcitabine HR0710 95 CI 0457-1103 Here again the experimental arm gave good results with median OS in the range of those reported with FOLFIRINOX 111 months The safety profile of the FIRGEM strategy showed that hematological and GI toxicities were more important than with gemcitabine alone Interestingly no limiting sensory neuropathy was observed with our treatment schedule and a significant increase in the time to definitive deterioration of the QoL was observed in the FIRGEM group as compared with the gemcitabine group This effect was observed for all domains
Considering that nab-paclitaxel improves significantly patients outcome in metastatic PC when combined to gemcitabine the addition of this drug to the FIRGEM strategy may be of particular interest And the PRODIGE 37 trial tested this combination in a randomized phase II trial recently closed for inclusions This trial allowed to fight the cancer with 4 different drugs without any cross resistance described between them given sequentially in the first 4 months of treatment Moreover the resting period without nab-paclitaxel may delay significantly the occurrence of the cumulative neuropathy induced by this molecule and optimised its used with such a stop and go like strategy Results are awaited for early 2018
More recently a liposomal irinotecan has been developed and tested in pancreatic cancer patients it comprises irinotecan free base encapsulated in liposome nanoparticles which keep irinotecan into the circulation sheltered from conversion to its active metabolite SN-38 longer and use local macrophage-mediated activation which would increase and prolong intratumoral levels of both irinotecan and SN-38 In a phase II study of 40 patients with MPA previously treated with gemcitabine-based therapy monotherapy with nal-IRI resulted in a median overall survival of 52 months and a manageable toxicity profile The NAPOLI-1 phase III trial was then conducted comparing three arms of chemotherapy in patients previously treated with gemcitabine-based therapy liposomal irinotecan MM-398 or nal-IRI alone or combined with 5FU and folinic acid and 5FU and folinic acid alone Combination of nal-IRI and 5FULV was more effective than 5FU alone or Nal-IRI alone median OS of 61 vs 42 and 49 months respectively HR 067 p0012 Increased hematologic and GI toxicities were also seen in the Nal-IRI arms but were manageable Nal-IRI plus 5FU and folinic acid extends survival in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy In a setting where there is a paucity of second line treatment option this combination is an important emerging treatment option for metastatic adenocarcinoma of the pancreas
Considering all these data the investigator proposes to run a randomized phase II trial testing the standard continuous Gemcitabine Nab-paclitaxel schedule vs Nal-IRI5FULV vs Nal-IRI5FULV for two months followed by Gemcitabine Nab-paclitaxel for two months before starting again Nal-IRI This will allow i to generate efficacy and tolerability data on the Nal-IRI5FU combination in the first line setting ii to test a new sequential strategy with Nal-IRI in regards of the interesting results obtained in second and third line pancreatic cancer treatment iii to control our results in the experimental arms with one of the two first line worldwide standard regimen Gemcitabine Nab-paclitaxel
Thus for more than 10 years gemcitabine has been the standard of care to treat metastatic PC Recently two positive phase III trials in metastatic PC were reported
First the gemcitabine with nab-paclitaxel combination therapy was compared to gemcitabine alone in 861 randomized patients with metastatic PC Results showed a significant improvement in response rate RR progression free survival PFS and overall survival OS Second the results of the PRODIGE 4ACCORD 11 trial testing the FOLFIRINOX regimen in metastatic PC patients finally gave a hope showing a major improvement in PFS and OS as compared to gemcitabine However though manageable the safety profiles of FOLFIRINOX and of gemcitabine plus nab-paclitaxel were less favourable than that of gemcitabine These regimens were associated with a higher incidence of grade 3-4 neutropenia febrile neutropenia thrombocytopenia diarrhoea and grade 2-3 sensory neuropathy
Irinotecan has a stronger growth-inhibiting effect than cisplatin mitomycin C and fluorouracil on cultured pancreatic adenocarcinoma cells In most trials testing this molecule in PC patients however the response rates were low 10 and survivals were poor Intensive regimens with irinotecan and 5-FU have been developed in colorectal cancer patients to increase the anti-tumor effects of this combination therapy From those the FOLFIRI3 in which the irinotecan is administered before and after a 5-FU 46h continuous infusion gave promising results The investigator has tested this regimen in a phase II trial in advanced PC patients with an objective RR of 375 a median OS time of 12 months and acceptable tolerability Considering these encouraging results the investigator has proposed a new approach to improve outcomes for patients with metastatic PC using FOLFIRI3 and gemcitabine alone sequentially to increase patient survival with a preserved quality of life QOL Indeed some authors have reported that the administration of different patterns of sequential polychemotherapy was independently associated with OS in patients with PC and other gastrointestinal tumors such as metastatic colorectal cancer Such strategies using drugs without cross-resistance sequentially may increase anti-tumor effects and limit cumulative and non-cumulative toxicities
The investigator thus performed a randomized multicentre phase II trial to assess this sequential treatment strategy using FOLFIRI3 and gemcitabine alternately in one arm and gemcitabine alone in the other arm in patients with metastatic non pre-treated pancreatic adenocarcinoma In this study the FIRGEM strategy seems to be an effective first line treatment option in good condition patients with metastatic PC The primary endpoint was reached with a rate of PFS at 6 months of 449 in the FIRGEM arm while gemcitabine alone failed 257 This good PFS rate at 6 months was maintained at 12 and 18 months 262 and 18 respectively though median PFS was 50 months Moreover an impressive objective response rate was observed in the FIRGEM arm 40 as compared to the gemcitabine arm 114 These results confirm those of the initial phase II trial evaluating the FOLFIRI3 regimen 375 objective response rate15 in PC patients and compare favourably with the 316 and 23 reported in the two trials evaluating FOLFIRINOX and gemcitabine nab-paclitaxel respectively
Median overall survival was 11 months with FIRGEM versus 82 months with gemcitabine HR0710 95 CI 0457-1103 Here again the experimental arm gave good results with median OS in the range of those reported with FOLFIRINOX 111 months The safety profile of the FIRGEM strategy showed that hematological and GI toxicities were more important than with gemcitabine alone Interestingly no limiting sensory neuropathy was observed with our treatment schedule and a significant increase in the time to definitive deterioration of the QoL was observed in the FIRGEM group as compared with the gemcitabine group This effect was observed for all domains
Considering that nab-paclitaxel improves significantly patients outcome in metastatic PC when combined to gemcitabine the addition of this drug to the FIRGEM strategy may be of particular interest And the PRODIGE 37 trial tested this combination in a randomized phase II trial recently closed for inclusions This trial allowed to fight the cancer with 4 different drugs without any cross resistance described between them given sequentially in the first 4 months of treatment Moreover the resting period without nab-paclitaxel may delay significantly the occurrence of the cumulative neuropathy induced by this molecule and optimised its used with such a stop and go like strategy Results are awaited for early 2018
More recently a liposomal irinotecan has been developed and tested in pancreatic cancer patients it comprises irinotecan free base encapsulated in liposome nanoparticles which keep irinotecan into the circulation sheltered from conversion to its active metabolite SN-38 longer and use local macrophage-mediated activation which would increase and prolong intratumoral levels of both irinotecan and SN-38 In a phase II study of 40 patients with MPA previously treated with gemcitabine-based therapy monotherapy with nal-IRI resulted in a median overall survival of 52 months and a manageable toxicity profile The NAPOLI-1 phase III trial was then conducted comparing three arms of chemotherapy in patients previously treated with gemcitabine-based therapy liposomal irinotecan MM-398 or nal-IRI alone or combined with 5FU and folinic acid and 5FU and folinic acid alone Combination of nal-IRI and 5FULV was more effective than 5FU alone or Nal-IRI alone median OS of 61 vs 42 and 49 months respectively HR 067 p0012 Increased hematologic and GI toxicities were also seen in the Nal-IRI arms but were manageable Nal-IRI plus 5FU and folinic acid extends survival in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy In a setting where there is a paucity of second line treatment option this combination is an important emerging treatment option for metastatic adenocarcinoma of the pancreas
Considering all these data the investigator proposes to run a randomized phase II trial testing the standard continuous Gemcitabine Nab-paclitaxel schedule vs Nal-IRI5FULV vs Nal-IRI5FULV for two months followed by Gemcitabine Nab-paclitaxel for two months before starting again Nal-IRI This will allow i to generate efficacy and tolerability data on the Nal-IRI5FU combination in the first line setting ii to test a new sequential strategy with Nal-IRI in regards of the interesting results obtained in second and third line pancreatic cancer treatment iii to control our results in the experimental arms with one of the two first line worldwide standard regimen Gemcitabine Nab-paclitaxel
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2017-004309-41 | EUDRACT_NUMBER | FFCD Number | None |
| FFCD 1702 | OTHER | None | None |