Ipsen has initiated the NAPOLI-3 Phase III
clinical study (NCT04083235) comparing the safety and efficacy of
liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) +
oxaliplatin (OX) (NALIRIFOX) to gemcitabine + nab-paclitaxel in the
first-line setting
Ipsen has been granted Fast Track Designation
by the FDA for investigational liposomal irinotecan + 5-FU/LV + OX
(NALIRIFOX) for the first-line treatment of patients with
metastatic pancreatic cancer
Ipsen (Euronext: IPN; ADR: IPSEY), today
announced the primary analysis of the Phase I/II study evaluating
the investigational use of irinotecan liposome injection (Onivyde®)
in combination with 5-fluorouracil/leucovorin (5-FU/LV) and
oxaliplatin (OX) together, known as NALIRIFOX in study patients
with previously untreated, unresectable, locally advanced and
metastatic pancreatic ductal adenocarcinoma (PDAC) during a
late-breaking oral presentation at the ESMO World Congress on
Gastrointestinal Cancer (WCGI), 1–5 July 2020. The results include
safety and efficacy analyses from the multicenter, open-label,
study consisting of dose-exploration safety run-in (traditional 3+3
design) to confirm the maximum tolerated dose and appropriate dose
regimen for NALIRIFOX in the dose-expansion phase.1
No new safety signals were observed in the 32 patients evaluated
from the recommended NALIRIFOX 50/60 mg/m2 dose (primary endpoint).
Study patients achieved median progression-free survival of 9.2
months and median overall survival of 12.6 months (secondary
endpoints).1
These data, in addition to promising anti-tumor activity
highlighted by secondary endpoints, have led to the initiation of
patient enrollment for the international Phase III NAPOLI-3
clinical study investigating the safety and efficacy of NALIRIFOX
versus gemcitabine + nab-paclitaxel in the first-line setting.2 On
5 June 2020, Ipsen was granted Fast Track designation from the U.S.
Food and Drug Administration (FDA) to facilitate the development
and potentially expedite the review of NALIRIFOX in this
indication. Programs with Fast Track designation may benefit from
early and frequent interactions with the FDA over the course of
drug development. In addition, the Fast Track designation program
allows for the eligibility for accelerated approval and priority
review if relevant study criteria are met and enables a company to
submit individual sections of a New Drug Application (NDA) for
review on a rolling-submission basis.
“Pancreatic cancer is aggressive, and we continue to investigate
opportunities to improve outcomes for more patients that can extend
survival. Unfortunately, current treatments, including
immunotherapies that are transforming outcomes for patients with
other solid tumors, have not demonstrated similar success in
pancreatic cancer,” said Zev Wainberg, M.D., lead investigator and
associate professor of medicine, University of California Los
Angeles. “The initial median progression-free and overall survival
data from our Phase I/II trial are promising and we look forward to
seeing how this investigational first-line treatment compares to
gemcitabine + nab-paclitaxel in the Phase III trial now
underway.”
“A year following the read out of the preliminary Phase I/II
study, we remain encouraged by the data, which demonstrated no new
safety signals and continued to show anti-tumor activity,” said
Howard Mayer, M.D., Executive Vice President, Head of Research and
Development at Ipsen. “Ipsen is committed to patients with
pancreatic cancer. We are currently enrolling patients in our
NAPOLI-3 Phase III clinical study across the U.S. and in other
countries to gain a better understanding of the role of liposomal
irinotecan as a potential first-line combination treatment for
locally advanced and metastatic pancreatic cancer.”
The Phase I/II, open-label trial (NCT02551991) was designed to
assess the safety, tolerability and dose-limiting toxicities (DLTs)
of NALIRIFOX for the first-line dosing of study participants with
locally advanced and metastatic pancreatic cancer. Secondary
objectives were to assess clinical efficacy, defined by median
progression-free survival (PFS) and median overall survival (OS),
best overall response rate, overall response rate (ORR), disease
control rate at 16 weeks (DCR) and duration of response (DoR).1
The final analysis as of the data cut off on 26 February 2020
included all study participants from the pooled population (n=32:
Part 1A-cohort B dose exploration phase n=7; Part 1B-dose expansion
phase n=25) who received the maximum tolerated dose of liposomal
irinotecan 50 mg/m2 [free-base], LV 400 mg/m2, 5-FU 2400 mg/m2, and
OX 60 mg/m2). Patients were aged ≥ 18 years with an Eastern
Cooperative Oncology Group (ECOG) performance status score ≤ 1 and
adequate organ function.1 The preliminary results from this study
were presented at the ESMO World Congress on Gastrointestinal
Cancer in July 2019.
Phase I/II Safety Results1:
- No reported Grade 3 or higher fatigue or peripheral
neuropathy.
- Treatment emergent adverse events (TEAEs) Grade 3 or higher
were reported by 22 of 32 study patients and included: neutropenia
(31.3%), febrile neutropenia (12.5%), hypokalemia (12.5%), anemia
(12.5%), diarrhea (9.4%), nausea (9.4%) and decreased neutrophil
count (9.4%); vomiting occurred in 6.3% of patients.
- 8 patients reported TEAEs leading to discontinuation of
oxaliplatin alone or all four study drugs (n=8/32), with 26 study
patients requiring dose adjustment due to AEs.
Phase I/II Efficacy Results1:
- Study patients saw a median PFS (95% CI) of 9.2 months (7.69,
11.96) and median OS of 12.6 months (8.74, 18.69).
- BOR (Best Overall Response) included: one complete response
(CR; study participant diagnosed with locally advanced Stage III
disease) in 3% (1/32), 10 partial responses (PR) in 31.3% (10/32)
and 15 stable diseases (SD) in 46.9% (15/32) (sum of CR+PR+SD =
81.3%).
- Disease control achieved by 71.9% (23/32) of study patients at
16 weeks.
ABOUT ONIVYDE® (irinotecan liposome injection)
Ipsen has exclusive commercialization rights for the current and
potential future indications for Onivyde® in the U.S. Servier is
responsible for the commercialization of Onivyde® outside of the
U.S. and Taiwan under an exclusive licensing agreement with Ipsen.
PharmaEngine has commercial rights to Onivyde® in Taiwan.
INDICATION - UNITED STATES
Onivyde® is approved by the U.S. FDA in combination with
fluorouracil (5-FU) and leucovorin (LV) for the treatment of
patients with metastatic adenocarcinoma of the pancreas after
disease progression following gemcitabine-based therapy. Limitation
of Use: Onivyde® is not indicated as a single agent for the
treatment of patients with metastatic adenocarcinoma of the
pancreas.
IMPORTANT SAFETY INFORMATION – UNITED STATES
BOXED WARNINGS: SEVERE NEUTROPENIA and
SEVERE DIARRHEA
Fatal neutropenic sepsis occurred in
0.8% of patients receiving ONIVYDE. Severe or life-threatening
neutropenic fever or sepsis occurred in 3% and severe or
life-threatening neutropenia occurred in 20% of patients receiving
ONIVYDE in combination with 5-FU and LV.
Withhold ONIVYDE for absolute
neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood
cell counts periodically during treatment.
Severe diarrhea occurred in 13% of
patients receiving ONIVYDE in combination with 5-FU/LV. Do not
administer ONIVYDE to patients with bowel obstruction. Withhold
ONIVYDE for diarrhea of Grade 2–4 severity. Administer loperamide
for late diarrhea of any severity. Administer atropine, if not
contraindicated, for early diarrhea of any severity.
CONTRAINDICATION
ONIVYDE is contraindicated in patients who have experienced a
severe hypersensitivity reaction to ONIVYDE or irinotecan HCl.
Warnings and Precautions
Severe Neutropenia: See Boxed WARNING. In patients
receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia
was higher among Asian (18/33 [55%]) vs White patients (13/73
[18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of
Asian vs 1% of White patients
Severe Diarrhea: See Boxed WARNING. Severe and
life-threatening late-onset (onset >24 hours after chemotherapy
[9%]) and early-onset diarrhea (onset ≤24 hours after chemotherapy
[3%], sometimes with other symptoms of cholinergic reaction) were
observed
Interstitial Lung Disease (ILD): Irinotecan HCl can cause
severe and fatal ILD. Withhold ONIVYDE I patients with new or
progressive dyspnea, cough, and fever, pending diagnostic
evaluation. Discontinue ONIVYDE in patients with a confirmed
diagnosis of ILD
Severe Hypersensitivity Reactions: Irinotecan HCl can
cause severe hypersensitivity reactions, including anaphylactic
reactions. Permanently discontinue ONIVYDE in patients who
experience a severe hypersensitivity reaction
Embryo-Fetal Toxicity: ONIVYDE can cause fetal harm when
administered to a pregnant woman. Advise females of reproductive
potential to use effective contraception during and for 1 month
after ONIVYDE treatment
Adverse Reactions
- The most common adverse reactions (≥20%) were diarrhea (59%),
fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased
appetite (44%), stomatitis (32%), and pyrexia (23%)
- The most common Grade 3/4 adverse reactions (≥10%) were
diarrhea (13%), fatigue/asthenia (21%), and vomiting (11%)
- Adverse reactions led to permanent discontinuation of ONIVYDE
in 11% of patients receiving ONIVYDE/5- FU/LV; The most frequent
adverse reactions resulting in discontinuation of ONIVYDE were
diarrhea, vomiting, and sepsis
- Dose reductions of ONIVYDE for adverse reactions occurred in
33% of patients receiving ONIVYDE/5 FU/LV; the most frequent
adverse reactions requiring dose reductions were neutropenia,
diarrhea, nausea, and anemia
- ONIVYDE was withheld or delayed for adverse reactions in 62% of
patients receiving ONIVYDE/5-FU/LV; the most frequent adverse
reactions requiring interruption or delays were neutropenia,
diarrhea, fatigue, vomiting, and thrombocytopenia
- The most common laboratory abnormalities (≥20%) were anemia
(97%), lymphopenia (81%), neutropenia (52%), increased ALT (51%),
hypoalbuminemia (43%), thrombocytopenia (41%), hypomagnesemia
(35%), hypokalemia (32%), hypocalcemia (32%), hypophosphatemia
(29%), and hyponatremia (27%)
Drug Interactions
- Avoid the use of strong CYP3A4 inducers, if possible, and
substitute non-enzyme inducing therapies ≥2 weeks prior to
initiation of ONIVYDE
- Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if
possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to
starting therapy
Special Populations
- Pregnancy and Reproductive Potential: See WARNINGS &
PRECAUTIONS. Advise males with female partners of reproductive
potential to use condoms during and for 4 months after ONIVYDE
treatment
- Lactation: Advise nursing women not to breastfeed during and
for 1 month after ONIVYDE treatment
Please see full U.S. Prescribing Information and Boxed WARNING
for ONIVYDE.
About the Phase I/II Study
The Phase I/II, open-label, comparative trial is designed to
assess the safety, tolerability and dose-limiting toxicities of
investigational irinotecan liposomal injection (Onivyde®) in
combination with 5-fluorouracil/leucovorin (5-FU/LV) and
oxaliplatin (OX) as a potential first-line treatment for metastatic
pancreatic ductal adenocarcinoma cancer patients. The study has
enrolled 56 patients at 15 sites across the United States, Spain
and Australia. It is being conducted in two parts:
- Part 1a: a safety run-in as initial dose exploration
- Part 1b: dose expansion of the liposomal irinotecan + 5-FU/LV +
oxaliplatin regimen
The study’s primary endpoint is safety and tolerability.
Secondary assessments of clinical efficacy include overall response
rate, disease control rate and best overall response. For more
information visit clinicaltrials.gov and use identifier
NCT02551991.3
About the NAPOLI-3 Phase III Study
The NAPOLI-3 clinical trial is an open-label, randomized,
multicenter, Phase III study of irinotecan liposome injection
(Onivyde®) in combination with oxaliplatin (OX) and
5-fluorouracil/leucovorin (5-FU/LV) versus nab-paclitaxel plus
gemcitabine in subjects who have not previously received
chemotherapy for metastatic adenocarcinoma of the pancreas. The
purpose of this study is to look at the efficacy and safety of
investigational irinotecan liposome injection in combination with
other FDA-approved drugs used for cancer therapy compared to
nab-paclitaxel + gemcitabine treatment in improving the overall
survival of patients not previously treated for metastatic
pancreatic cancer. The study’s primary endpoint is Overall survival
(OS), with secondary outcome measures defined as Progression free
survival (PFS) and Overall Response Rate (ORR).
Ipsen is currently enrolling patients. To learn more about the
study contact clinical.trials@ipsen.com or visit clinicaltrials.gov
and use identifier NCT04083235.2
About Ipsen
Ipsen is a global specialty-driven biopharmaceutical group
focused on innovation and Specialty Care. The Group develops and
commercializes innovative medicines in three key therapeutic areas
– Oncology, Neuroscience and Rare Diseases. Its commitment to
oncology is exemplified through its growing portfolio of key
therapies for prostate cancer, neuroendocrine tumors, renal cell
carcinoma and pancreatic cancer. Ipsen also has a well-established
Consumer Healthcare business. With total sales over €2.5 billion in
2019, Ipsen sells more than 20 drugs in over 115 countries, with a
direct commercial presence in more than 30 countries. Ipsen’s
R&D is focused on its innovative and differentiated
technological platforms located in the heart of the leading
biotechnological and life sciences hubs (Paris-Saclay, France;
Oxford, UK; Cambridge, US). The Group has about 5,800 employees
worldwide. Ipsen is listed in Paris (Euronext: IPN) and in the
United States through a Sponsored Level I American Depositary
Receipt program (ADR: IPSEY). For more information on Ipsen, visit
www.ipsen.com
Ipsen’s Forward Looking Statement
The forward-looking statements, objectives and targets contained
herein are based on the Group’s management strategy, current views
and assumptions. Such statements involve known and unknown risks
and uncertainties that may cause actual results, performance or
events to differ materially from those anticipated herein. All of
the above risks could affect the Group’s future ability to achieve
its financial targets, which were set assuming reasonable
macroeconomic conditions based on the information available today.
Use of the words "believes", "anticipates" and "expects" and
similar expressions are intended to identify forward-looking
statements, including the Group’s expectations regarding future
events, including regulatory filings and determinations, and the
outcome of this study or other studies. Moreover, the targets
described in this document were prepared without taking into
account external growth assumptions and potential future
acquisitions, which may alter these parameters. These objectives
are based on data and assumptions regarded as reasonable by the
Group. These targets depend on conditions or facts likely to happen
in the future, and not exclusively on historical data. Actual
results may depart significantly from these targets given the
occurrence of certain risks and uncertainties, notably the fact
that a promising product in early development phase or clinical
trial may end up never being launched on the market or reaching its
commercial targets, notably for regulatory or competition reasons.
The Group must face or might face competition from generic products
that might translate into a loss of market share. Furthermore, the
Research and Development process involves several stages each of
which involves the substantial risk that the Group may fail to
achieve its objectives and be forced to abandon its efforts with
regards to a product in which it has invested significant sums.
Therefore, the Group cannot be certain that favorable results
obtained during preclinical trials will be confirmed subsequently
during clinical trials, or that the results of clinical trials will
be sufficient to demonstrate the safe and effective nature of the
product concerned. There can be no guarantees a product will
receive the necessary regulatory approvals or that the product will
prove to be commercially successful. If underlying assumptions
prove inaccurate or risks or uncertainties materialize, actual
results may differ materially from those set forth in the
forward-looking statements. Other risks and uncertainties include
but are not limited to, general industry conditions and
competition; general economic factors, including interest rate and
currency exchange rate fluctuations; the impact of 6 pharmaceutical
industry regulation and health care legislation; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the Group's ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of the Group’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.
The Group also depends on third parties to develop and market some
of its products which could potentially generate substantial
royalties; these partners could behave in such ways which could
cause damage to the Group’s activities and financial results. The
Group cannot be certain that its partners will fulfil their
obligations. It might be unable to obtain any benefit from those
agreements. A default by any of the Group’s partners could generate
lower revenues than expected. Such situations could have a negative
impact on the Group’s business, financial position or performance.
The Group expressly disclaims any obligation or undertaking to
update or revise any forward-looking statements, targets or
estimates contained in this press release to reflect any change in
events, conditions, assumptions or circumstances on which any such
statements are based, unless so required by applicable law. The
Group’s business is subject to the risk factors outlined in its
registration documents filed with the French Autorité des Marchés
Financiers. The risks and uncertainties set out are not exhaustive
and the reader is advised to refer to the Group’s 2019 Universal
Registration Document available on its website (www.ipsen.com).
ONIVYDE® is a registered trademark of Ipsen Biopharm Ltd. All
other trademarks and registered trademarks are the property of
their respective owners.
© 2020 Ipsen Biopharmaceuticals, Inc. All Rights Reserved. June
2020, ONV-US-002591
References
- Wainberg, Z.A., et al. First-line liposomal irinotecan + 5
fluorouracil/leucovorin + oxaliplatin in patients with pancreatic
ductal adenocarcinoma: long-term follow-up results from a phase 1/2
study. Oral/abstract presented at the ESMO World Congress on
Gastrointestinal Cancer (WCGI 2020, abstract #LBA-1). Available at
www.worldgicancer.com/sites/2020v2.worldgicancer.com/files/2020-04/Abstract_Titles_and%20Authors_0.pdf.
Accessed: June 2020.
- A Study to Assess the Effectiveness and Safety of Irinotecan
Liposome Injection, 5-fluorouracil/Leucovorin Plus Oxaliplatin in
Patients Not Previously Treated for Metastatic Pancreatic Cancer,
Compared to Nab-paclitaxel+Gemcitabine Treatment (NAPOLI 3).
www.clinicaltrials.gov. Accessed: June 2020. Available:
https://clinicaltrials.gov/ct2/show/NCT04083235?term=NCT04083235&draw=2&rank=1.
- Study of Nanoliposomal Irinotecan (Nal-IRI)-Containing Regimens
Versus Nab-paclitaxel Plus Gemcitabine in Patients With Previously
Untreated, Metastatic Pancreatic Adenocarcinoma.
www.clinicaltrials.gov. Accessed: June 2020. Available:
https://clinicaltrials.gov/ct2/show/NCT02551991?term=NCT02551991&draw=2&rank=1.
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