Primary:• To compare overall survival (OS) in patientsrandomized to NGR-hTNF plus BIC versuspatients randomized to placebo plus BICSecondary:• To compare progression-free survival (PFS)• To compare disease control rate (DCR, defined asthe percentage…
ID
Source
Brief title
Condition
- Mesotheliomas
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary variable:
• Overall Survival (OS) is defined as the time from the
date of randomization until the date of death due to any
cause.
Secondary outcome
Secondary variables:
• Progression-free survival (PFS) is defined as the time
from the date of randomization until disease
progression, or death due to any cause.
• Disease control rate (DCR) is defined as the percentage
of patients who have a best-response rating of
complete response, partial response, or stable disease.
The tumor thickness perpendicular to the chest wall or
mediastinum will be assessed according to modified
RECIST criteria for MPM. All other measurable
lesions will be measured unidimensionally as per
standard RECIST criteria.
• Complete remission (CR): Disappearance of all target
lesions. Any pathological lymph nodes must have
reduction in short axis to <10 mm.
• Partial remission (PR): At least a 30% decrease in the
sum of diameters of target lesions, taking as reference
the baseline sum diameters.
• Stable Disease (SD): neither sufficient shrinkage to
qualify for PR nor sufficient increase to qualify for PD
taking as reference the smallest sum diameters while
on study.
• Progressive disease (PD): At least a 20% increase in
the sum of diameters of target lesions, taking as
reference the smallest sum on study (this includes the
baseline sum if that is the smallest on study). In
addition to the relative increase of 20%, the sum must
also demonstrate an absolute increase of at least 5 mm.
(Note: the appearance of one or more new lesions is also considered
progression).
• Duration of disease control: In the subset of patients
who achieve disease control, the duration of disease
control will be measured from the date of
randomization until disease progression, or death due
to any cause.
Background summary
Tumor Necrosis Factor (TNF) was first identified by Carswell et al. in the
serum of Bacillus
Calmette-Guerin sensitized animals, treated with an endotoxin which caused the
release of a factor
able to induce hemorrhagic necrosis of murine tumors. Based on these initial
findings two distinct
molecules have been recognized, TNF-α, produced by macrophages and monocytes,
and TNF-β,
mainly produced by lymphocytes.1-3
Although TNF-β shows similar, but not identical, biological profile to TNF-α,
in general the term
TNF refers only to TNF-α and not to TNF-β, considering that the overwhelming
majority of reports
published to date on the therapeutic use of TNF describe the use of TNF-α.4
In in vitro experiment TNF has been shown to have cytostatic and cytotoxic
effects against a wide
range of human tumor cells but have no such effects against normal human
fibroblast.5 Anti-tumor
effects have been demonstrated in both syngeneic murine tumors and human tumor
xenografts in
nude mice.6 In addiction to the well known cytostatic/cytotoxic properties, TNF
has a broad
spectrum of immunomodulatory activities.7 Like interferon (INF), TNF has shown
antiviral activity
and in some cell lines promotes 2-5A synthetase activity, an enzyme that is
strongly induced by
INFs. 8, 9
Furthermore, TNF enhances the expression of Class I major histocompatibility
antigens on human
endothelial cells, dermal fibroblasts and human tumor cell lines10,11 and the
expression of Class II
major histocompatibility antigens on human T cells and tumor cells.12 TNF has
been demonstrated
to be an effector molecule involved in monocyte cytotoxicity,13,14 a
cell-associated molecule able to
kill TNF-sensitive target cells on direct contact in the absence of any
measurable secreted TNF15
and an enhancer of in vivo and in vitro macrophage tumoricidal activity using
peritoneal exudates
macrophages.16 Like IFN-γ, IFN-β and interleukin-2 (IL-2), TNF increases
urinary neopterin
levels,17 a monocyte product. Moreover, TNF has multiple actions on natural
killer cells, including
an enhancement of HLA-DR antigens, IL-2 receptors and IL-2 effects.18 Finally,
TNF has positive
effects on granulocyte function, including chemotaxis activity19, increased
phagocytosis and
enhanced antibody-dependent cellular cytotoxicity.20,21
TNF exerts its effects by binding to two types of receptor, TNF-R1 and TNF-R2,
which are present
on nearly all mammalians cells and in soluble form in the circulation.22
Several lines of evidence suggest that the anti-tumor activity of TNF depends
on indirect
mechanisms associated with selective obstruction and damage of tumor-associated
blood vessels
and on activation of immune mechanisms rather than a direct toxic effect on
tumor cells.23
Although numerous pre-clinical studies have demonstrated that TNF has notable
anti-tumor
activity,1,6,16,24 early trials in humans showed that its clinical use is
limited by severe systemic
toxicity.5,7,25-27
However, loco-regional therapy by isolated limb perfusion using high doses of
TNF in combination
with chemotherapy led to high response rates in patients with melanoma or
sarcoma of the
extremities,28-30 regression of bulky hepatic cancers confined to the liver31
and peritoneal
carcinomas.32 The clinical results obtained with these treatments indicate that
TNF can induce
tumor regression, provided that high concentrations of the cytokine are
achieved at tumor level.
The coupling of murine TNF (mTNF) with the peptide NGR
(asparagine-glycine-arginine), an aminopeptidase N (CD13) ligand capable of
binding to tumor blood vessels, demonstrated therapeutic properties superior to
those of mTNF in animal
models. Considering a potential therapeutic use, a modified human TNF (hTNF)
containing the
cyclic CNGRC peptide sequence was subsequently prepared using recombinant DNA
techniques.
The resulting NGR-hTNF will enable targeted delivery of TNF to tumor vessels in
humans.
Study objective
Primary:
• To compare overall survival (OS) in patients
randomized to NGR-hTNF plus BIC versus
patients randomized to placebo plus BIC
Secondary:
• To compare progression-free survival (PFS)
• To compare disease control rate (DCR, defined as
the percentage of patients who have a bestresponse
rating of complete or partial response or
stable disease, according to MPM-modified
RECIST criteria)
• To compare duration of disease control
• To evaluate safety and toxicity profile related to
NGR-hTNF
• To assess changes in quality of life (QoL) in the
two treatment arms
• To evaluate medical care utilization in the two
treatment arms
Study design
This is a multicenter, double-blind, placebo-controlled,
randomized, 2-arm (1:1 ratio), phase III study with a
comparison of NGR-hTNF plus BIC versus placebo plus
BIC in patients with advanced malignant pleural
mesothelioma previously treated with a pemetrexed-based
chemotherapy regimen for advanced or metastatic disease.
Best investigator*s choice (BIC) includes either best
supportive care alone or combined with a single-agent
chemotherapy (doxorubicin, gemcitabine, or vinorelbine).
Before randomization, the physician has to decide for each
patient if he/she is candidate to either best supportive care
(BSC) alone or combined with single-agent chemotherapy.
Patients will be randomly assigned to the treatment group
through a centralized randomization system using the
following stratification factors: candidate for
chemotherapy (yes vs no and, if yes, for type of
chemotherapy ) and ECOG performance status (0 vs 1-2).
The experimental group A will receive NGR-hTNF plus
the current treatment option (best supportive care with or
without single-agent chemotherapy).
The control group B will receive placebo plus the current
treatment option (best supportive care with or without
single-agent chemotherapy).
Arm A (experimental group = NGR-hTNF + BSC ±
single-agent chemotherapy)
• NGR-hTNF: 0.8 µg/m² as 60-minute intravenous
infusion every week until confirmed evidence of
disease progression.
• Best Supportive Care: where applicable and as
appropriate according to Institutional clinical practice
and literature guidelines
• Investigator*s Choice: At Investigator discretion, one
of the following single-agent chemotherapy might be
administered in combination:
a) Doxorubicin: 60-75 mg/m2 iv every 3 weeks, for a
maximum of 6 cycles, OR
b) Gemcitabine: 1,000-1,250 mg/m2 iv on days 1 and
8, every 3 weeks, for a maximum of 6 cycles, OR
c) According to results of sub-study:
Vinorelbine: 25mg/m2 iv on days 1 and 8 every
3 weeks, for a maximum of 6 cycles (or weekly for 12
weeks) or, if approved in the Country, 60 mg/m2
per os on days 1 and 8 every 3 weeks for a maximum
of 6 cycles (or weekly for 12 weeks).
Arm B (control group = Placebo + BSC ± single-agent
chemotherapy)
• Placebo: 0.8 µg/m² as 60-minute intravenous infusion
every week until confirmed evidence of disease
progression or unacceptable toxicity occurs.
• Best Supportive Care: as above
• Investigator*s Choice: as above.
Intervention
The experimental group A will receive NGR-hTNF plus
the current treatment option (best supportive care with or
without single-agent chemotherapy).
The control group B will receive placebo plus the current
treatment option (best supportive care with or without
single-agent chemotherapy).
Arm A (experimental group = NGR-hTNF + BSC ±
single-agent chemotherapy)
• NGR-hTNF: 0.8 µg/m² as 60-minute intravenous
infusion every week until confirmed evidence of
disease progression.
• Best Supportive Care: where applicable and as
appropriate according to Institutional clinical practice
and literature guidelines
• Investigator*s Choice: At Investigator discretion, one
of the following single-agent chemotherapy might be
administered in combination:
a) Doxorubicin: 60-75 mg/m2 iv every 3 weeks, for a
maximum of 6 cycles, OR
b) Gemcitabine: 1,000-1,250 mg/m2 iv on days 1 and
8, every 3 weeks, for a maximum of 6 cycles, OR
c) According to results of sub-study:
Vinorelbine: 25mg/m2 iv on days 1 and 8 every
3 weeks, for a maximum of 6 cycles (or weekly for 12
weeks) or, if approved in the Country, 60 mg/m2
per os on days 1 and 8 every 3 weeks for a maximum
of 6 cycles (or weekly for 12 weeks).
Arm B (control group = Placebo + BSC ± single-agent
chemotherapy)
• Placebo: 0.8 µg/m² as 60-minute intravenous infusion
every week until confirmed evidence of disease
progression or unacceptable toxicity occurs.
• Best Supportive Care: as above
• Investigator*s Choice: as above.
Study burden and risks
At the screening visit patient will be given a full clinical examination, blood
will be drawn for laboratory tests and radiological evaluation will be
performed to establish the general overall state of health. Other procedures
foreseen at screening visit 12-lead electrocardiogram (EKC) and if r treatment
will include doxorubicin, echocardiogram or a Multi Gated Acquisition (MUGA)
scan.
Patient will be asked to complete a quality of life questionnaire at this visit
and after every 6 weeks.
Treatment Phase:
Patient will be and treated once per week, receiving either treatment according
to treatment arm A (NGR-hTNF) or treatment arm B (Placebo) for entire study.
Before each chemotherapy treatment a blood sample will be taken and also a
physical examination is foreseen.
Every 6 weeks a 12-lead EKG and radiological evaluation will be performed.
Chemotherapy will be administered for a maximum of 6 cycles, while the
treatment with NGR-hTNF/placebo will be continued weekly in monotherapy, until
evidence of progressive disease.
Follow up phase:
Every 6 weeks (only before evidence of Progressive Disease): radiological
evaluation, collection of information about subsequent anticancer therapies
Every 12 weeks: survival follow up
Benefits
Benefits cannot guarantee the outcome of the treatment, since the effective
action of this therapy is not quantifiable at this stage of the study. However,
this clinical trial will provide precious indications, thus leading to
improvements in treatment and to helping other patients in the future.
Risks
The most common side effect are shivering that in majority of cases cleared up
without any treatment and in other cases simply by taking paracetamol. Other
common side effects are fever, high blood pressure and fatigue, which occurred
in about 10 to 15 of 100 patients as well as feeling cold, nausea, vomiting,
headache, low blood pressure and weakness, which occurred in about 2 to 7 of
100 patients.
Since NGR-hTNF is in the clinical development phase, it is not possible to
exclude the appearance of other side effects, even unexpected, serious ones.
Known toxicities that could occur following the administration of doxorubicin,
gemcitabine and vinorelbine, drugs already on the market and widely used in
clinical practice in combination treatments, include those of a
gastrointestinal (diarrhea, nausea, vomiting and inflammation of the mouth),
related to blood (decrease of the number in blood cells, such as the white
blood cells and the platelets) and neurological (tingling/loss of sensitivity
in the hands, lack of reflexes) nature, changes in kidney and/or liver
function, as well as fatigue, reddening of the skin and hair loss.
Via Lavoratori Autobianchi 1
Desio (MB) 20832
IT
Via Lavoratori Autobianchi 1
Desio (MB) 20832
IT
Listed location countries
Age
Inclusion criteria
1.Age >= 18 years;
2. Histologically or cytological confirmed malignant pleural mesothelioma of any of the following subtype;
epithelial, sarcomatoid, mixed, or unknown;
3. Prior treatment with no more than one sistemic pemetrexed-based chemotherapy regimen administered;
for advanced or metastatic disease. Prior use of a biological agent in combination with a pemetrexed based;
regimen and prior administration of intrapleural cytotoxic agents are allowed. Patients who have previously received anthracyclines should not receive doxorubicin.;
4. ECOG Performance Status 0 - 2;
5. Life expectancy of >=12 weeks;
6. Adequate baseline bone marrow, hepatic and renal function, defined as follows;
a. Neutrophils >= 1.5 x 109/L; platelets >= 100 x 109/L; hemoglobin >= 9 g/dL;
b. Bilirubin <= 1.5 x ULN;
c. AST and/or ALT <= 2.5 x ULN in absence of liver metastasis or <= 5 x ULN in presence of liver metastasis;
d. Serum creatinine <1.5 x ULN;
7. Measurable or non-measurable disease according to MPM-modified RECIST criteria;
8. Patients may have had prior therapy providing the following conditions are met:;
a. Surgery: wash-out period of 14 days;
b. Systemic anti-tumor and radiation therapy: wash-out period of 28 days;
9. Patients must give written informed consent to participate in the study;
Exclusion criteria
1. Patients must not receive any other investigational agents while on study;
2. Patients with myocardial infarction within the last six months, unstable angina, New York Heart association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication;
3. Uncontrolled hypertension;
4. QTc interval (congenital or acquired)> 450 ms;
5. History or evidence upon physical examination of CNS disease unless adequately treated (e.g., primary brain tumor, any brain metastasis, seizure not controlled with standard medical therapy, or history of stroke);
6. Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol;
7. Known hypersensitivity/allergic reaction to human albumin preparations or to any of the excipients;
8. Any psychological, familial, sociological or geographical condition potentially tampering compliance with the study protocol;
9. Pregnancy or lactation.
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 | EUCTR2009-016879-29-NL |
| ClinicalTrials.gov | NCT01098266 |
| CCMO | NL38729.100.11 |