Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03693677 |
| Other study ID # |
PRODIGE 61 - FUNGEMAX |
| Secondary ID |
FFCD 17022017-00 |
| Status |
Active, not recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
November 16, 2018 |
| Est. completion date |
December 2024 |
Study information
| Verified date |
January 2024 |
| Source |
Federation Francophone de Cancerologie Digestive |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 gemcitabine/Nab-paclitaxel combination therapy is more
effective in PC than gemcitabine-based therapy alone. In addition, multidrug therapy
approaches (Irinotecan-5FU/LV) 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-IRI/5FU/LV
or Nal-IRI and 5FU/LV alone; in this key study, the combination Nal-IRI/5FU/LV treatment was
more effective than monotherapies (Nal-IRI or 5FU/LV alone).
Based on all these data, a Phase II trial testing the standard of care
gemcitabine/nab-paclitaxel vs Nal-IRI/5FU/LV vs Nal-IRI/5FU/LV 2-months sequential regimen
followed by gemcitabine/nab-paclitaxel will be performed. This will allow us to i) know the
tolerance and efficacy of Nal-IRI/5FU/LV 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.
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 4/ACCORD 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 FOLFIRI.3, 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 37.5%, 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 FOLFIRI.3 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 FOLFIRI.3 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 44.9% in the FIRGEM arm while gemcitabine alone
failed (25.7%). This good PFS rate at 6 months was maintained at 12 and 18 months (26.2% and
18% respectively) though median PFS was 5.0 months. Moreover, an impressive objective
response rate was observed in the FIRGEM arm (40%) as compared to the gemcitabine arm
(11.4%). These results confirm those of the initial phase II trial evaluating the FOLFIRI.3
regimen (37.5% objective response rate)(15) in PC patients and compare favourably with the
31.6% and 23% reported in the two trials evaluating FOLFIRINOX and gemcitabine +
nab-paclitaxel, respectively.
Median overall survival was 11 months with FIRGEM versus 8.2 months with gemcitabine
(HR:0.710 95% CI: 0.457-1.103). Here again the experimental arm gave good results, with
median OS in the range of those reported with FOLFIRINOX (11.1 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 5.2 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 5FU/LV was more effective than 5FU alone or Nal-IRI alone (median OS of 6.1 vs. 4.2 and
4.9 months respectively (HR: 0.67; p=0.012). 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-IRI+5FU/LV vs
Nal-IRI+5FU/LV 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-IRI/5FU 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.
