The purpose of this study is to evaluate the efficacy and safety of NIS793 in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel and placebo in first-line mPDAC.This study aims to explore whether blockade of Transforming…
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alvleesklier kanker
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Outcome measures
Primary outcome
Safety run-in part:
The primary objective of the safety run-in part is to confirm the recommended
phase 3 dose (RP3D) of NIS793 in combination with gemcitabine and
nab-paclitaxel (SOC).
Randomized part:
The primary objective of the randomized part is to compare OS in participants
with mPDAC treated as the first line treatment with the combination of NIS793,
gemcitabine and nab-paclitaxel to the combination of placebo with gemcitabine
and nab-paclitaxel.
The primary clinical question of interest of the randomized part is to estimate
the treatment effect on the primary endpoint of OS of NIS793 in combination
with gemcitabine and nab-paclitaxel (arm A) compared to placebo in combination
with gemcitabine and nab-paclitaxel (arm B) for the target population,
regardless of discontinuation from study treatment, or start of a new
subsequent antineoplastic therapy.
Secondary outcome
Safety run-in part:
To evaluate:
• Safety and tolerability of NIS793 in combination with gemcitabine and
nab-paclitaxel
• Preliminary anti-tumor activity of NIS793 in combination with gemcitabine and
nab-paclitaxel
• Pharmacokinetics (PK) of NIS793 in combination with gemcitabine and
nab-paclitaxel
Randomized part:
• To evaluate the efficacy (progression-free survival (PFS), overall response
rate (ORR), disease control rate (DCR), duration of response (DOR), time to
response (TTR)) in participants treated as the first line treatment of NIS793
in combination with gemcitabine and nab-paclitaxel versus placebo plus
gemcitabine and nab-paclitaxel
• To evaluate safety and tolerability in each treatment arm
• To explore PK of NIS793 in combination with gemcitabine and nab-paclitaxel
• To characterize the incidence of immunogenicity of NIS793 in combination with
gemcitabine/nab-paclitaxel
• To evaluate health-related quality of life and other patient reported
outcomes in each treatment arm
Background summary
Pancreatic ductal adenocarcinoma (PDAC) represents a significant public health
burden, with a 5-year survival rate of approximately 2.9%. In the absence of
improvements in early diagnosis and treatment, PDAC will likely become the
second leading cause of death worldwide by 2030. There are two recommended
first-line chemotherapy treatments for metastatic PDAC, FOLFIRINOX (a
combination of 5-fluorouracil, folinic acid, irinotecan plus oxaliplatin) or
gemcitabine plus nab-paclitaxel and the reported median overall survival (mOS)
for both regimens is less than 12 months.
FOLFIRINOX is usually reserved for patients with good performance status (e.g.,
ECOG performance status 0-1) due to the toxicity associated with this
combination regimen. Unlike other common cancers, survival gains have only
improved slightly for advanced pancreatic cancer patients over the past decades
and additional treatments are urgently needed.
One of the reasons for the poor response to therapeutic treatments in PDAC has
been attributed to the extensive stromal response in this indication. PDAC
displays in fact the most prominent desmoplastic reaction of all epithelial
tumors, characterized by an abundance of activated stroma and progressive
accumulation of extracellular matrix (ECM) proteins such as hyaluronic acid,
which altogether contribute to tissue structural rigidity and poor perfusion.
These structural aberrations significantly reduce penetration of
macromolecules, hindering the tumor intake of therapeutics. Intra-tumoral
fibrosis in PDAC is known to correlate with poor survival even after resection.
New agents targeting the desmoplastic tumor microenvironment may therefore
represent an opportunity to establish novel therapeutic paradigms in the
treatment of PDAC.
In this context, TGFβ-blockade offers the potential to address some of the
aberrations of the PDAC microenvironment, due to its pleiotropic effects on
stroma. In particular, TGFβ plays a pivotal role in the activation of
pancreatic stellate cells (PSC), the most abundant type of fibroblasts in the
pancreas and the chief organizers of the desmoplastic reaction. As the
expression of TGFβ increases throughout disease progression, so does the
conversion of stellate cells into myofibroblasts, as well as the fibrotic
response.
Notably, studies have shown that TGFβ signaling components are often
genetically silenced in the pancreatic cancer cells, disabling the tumor
intrinsic suppressive activity of TGFβ and cooperating instead with other
genetic alterations to promote tumor initiation and malignant progression.
These molecular alterations likely represent a mechanism for pancreatic cancer
cells to grow and spread in an overly high TGFβ microenvironment.
Study objective
The purpose of this study is to evaluate the efficacy and safety of NIS793 in
combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel
and placebo in first-line mPDAC.
This study aims to explore whether blockade of Transforming Growth Factor β
(TGFβ) in combination with gemcitabine/nab-paclitaxel can reduce fibrosis in
PDAC, restore chemo-sensitivity and ultimately lead to improvements in overall
survival (OS) and other clinically relevant outcomes. A safety run-in part will
be conducted before opening a randomized part to confirm the recommended phase
3 dose (RP3D) of NIS793 in combination with SOC anti-cancer therapy.
Study design
This is a multicenter, double-blind, two-arm, randomized phase III study that
will have two parts: a safety run-in part and a 2-arm randomized part. The
study will be conducted in multiple geographical regions.
Safety run-in part: Approximately 10 participants will be enrolled at the
starting dose to achieve at least 6 evaluable patients; however, if the
starting dose is not recommended and a lower dose level is tested, 10
additional participants will be enrolled
Randomized part: Approximatively 480 participants will be recruited and
randomized
(1:1 ratio) to the two treatment arms (~240/per arm). Participants will be
stratified at randomization by performance status (0 vs. 1), presence of liver
metastasis (yes vs. no), and region (North America, Europe, and Australia vs.
other countries).
Intervention
Safety run-in:
combination of NIS793, gemcitabine and nab-paclitaxel
Randomized part:
Participants will be randomized to one of two treatment arms:
• Investigational arm (Arm A): combination of NIS793, gemcitabine and
nab-paclitaxel
• Control arm (Arm B): combination of placebo, gemcitabine and nab-paclitaxel
A cycle of treatment is defined as 28 days.
Study burden and risks
The extra burden for the patient is mainly the duration of the visits, the
extra blood samples (especially PK and biomarker tests), if applicable
pregnancy tests, and the completion of the questionnaires. The visits take
longer because of extra blood draws, observation period after NIS793
administration. There are a number of additional visits such as screening, end
of trial and if applicable the folllow up visits. The frequency of visits
follows the dosing schedule of standard of care gemcitabine and nab-paclitaxel,
however visits take longer.
As with any administration of the drugs, side effects may occur. However, the
patient is observed before being allowed to go home and blood values are
checked regularly. If necessary, a dose reduction of chemo treatment may be
given. Also, chemo and NIS793 gift can be skipped delayed if physician deems it
medically necessary/or justified.
If patient gives consent, additional biopsies are taken.
Haaksbergweg 16
Amsterdam 1101 BX
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Haaksbergweg 16
Amsterdam 1101 BX
NL
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Age
Inclusion criteria
- Age >= 18 years
- Histologically or cytologically confirmed mPDAC eligible for treatment in
first line setting and not amenable for potentially curative surgery
- Presence of at least one measurable lesion assessed by CT and/or MRI
according to RECIST 1.1
- ECOG performance status 0-1
- Adequate organ function
- WCBP must have negative pregnancy test during screening and before starting
study treatment
- Must have recovered from treatment-related toxicities of prior anticancer
therapies to grade <= 1 (CTCAE v 5.0), except alopecia
Exclusion criteria
- previous systemic anti-cancer treatment for mPDAC
- pancreatic neuroendocrine, acinar or inslet tumors
- known status of MSI-H or MMR-deficient pancreatic cancer
- presence of symptomatic CNS metastases, or CNS metastases that
requires direct therapy or increasing doses of corticosteroids 2 weeks prior to
study entry
- known history of severe allergy or hypersensitivity to any of the study drug
or their excipients
- currently receiving any of the prohibited medications which cannot be
discontinued within >= 7 days or 5 half-lifes, whichever is longer
- not recovered from a major surgery or has a major surgery within 4 weeks
prior to start of the study
- radiation therapy or brain radiotherapy <= 4 weeks prior to study start
- impaired cardiac function or clinically significant cardio-vascular disease
- history of positive test for HIV infection
- active or chronic HBV or HCV infections (patients with a history of HCV
infection must have been treated with confirmation of cure to be eligible)
- active untreated or uncontrolled systemic fungal, bacterial or viral
infections
- use of hematopoietic growth factors or transfusion support <= 2 weeks prior
to start the study
- conditions that are considered to have a high risk of clinically significant
gastrointestinal track bleeding or any other condition associated with or
history of significant bleeding
- serious, non-healing wounds
- pre-existing peripheral neuropathy > grade 1
- concurrent malignancy other than disease under treatment
- pregnant or breast-feeding woman
- WCBP, unless using highly effective method of contraception during and up to
90 days after the study drug treatment NIS793
- currently receiving other anti-cancer therapy or received other
investigational product within 30 days or 5 half-lives prior to study
treatment, whichever is longer
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000591-10-NL |
| ClinicalTrials.gov | NCT04935359 |
| CCMO | NL80537.056.22 |