The primary objective of this study is to evaluate the overall survival (OS) rate (determined from the time of randomization in the study) of subjects who receive dendritic cell immunotherapy with MesoPher plus best supportive care (BSC) compared to…
ID
Source
Brief title
Condition
- Mesotheliomas
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is the overall survival. Overall survival
will be determined as the time from randomization until death. For subjects
who are alive at the end of the study or lost to follow-up, OS will be censored
on the last date when subjects are known to be alive.
Secondary outcome
• the estimated survival rate at 12 and 18 months after randomization will be
determined with the Kaplan Meier analysis.
• Progression-free survival (PFS), including symptomatic progression-free
survival. The time of the first CT scan showing progression will define the end
of the PFS.
• Overall response rate and duration of response.
Overall response rate is defined as the proportion of subjects with confirmed
CR or PR on CT scans, if possible measured following modified RECIST criteria.
• Change in quality of life: the European Organization for Research and
Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and its
lung cancer (LC)-specific module EORTC QLQ - LC13 will be used to evaluate
quality of life. Measures of QoL will be compared to baseline and changes over
time and compared to each other.
• safety and tolerability of MesoPher: adverse events and serious adverse
events, including local and systemic injection site reactions, laboratory
assessments, electrocardiogram, vital signs, physical examination, and ECOG
performance status.
Background summary
Malignant mesothelioma is a fatal disease with median survival time from first
signs of illness to death around 12 months. A chemotherapy regimen consisting
of a combination of pemetrexed and cisplatin or carboplatin is considered
standard of care. The survival benefit of treatment with pemetrexed/cisplatin
is around 3 months compared to cisplatin alone. Thus there is an unmet need for
treatment.
The immune system plays a major role in all malignant diseases. Especially in
mesothelioma, immune suppression induced by the tumor is high.
Dendritic cells can be loaded a lysate of tumor material of the patient itself
(autologous dendritic cell-therapy), with synthetic peptides coding for parts
of tumor-associated antigens, or with other sources of tumor-specific antigens
(allogeneic dendritic cell-therapy).
MesoPher:
Amphera has developed 5 well-characterized clinical grade human malignant
mesothelioma cell lines as an allogeneic source for the preparation of a tumor
cell-lysate. These 5 cell lines were selected based on distinctive tumor- and
immune-profiles in patients and represent cell lines generated from tumor
material with opposing immune properties. Thus a wide variety of tumor
associated antigens is present.
This lysate *PheraLys* is used to load dendritic cells of a subject with
malignant mesothelioma ex vivo. In this way a dendritic cell immunotherapeutic
product is prepared with the patient*s own dendritic cells exposed to an
allogeneic source of tumor associated antigens, outside of the
immunosuppressive environment in the patient. The lysate of these 5 cell lines
*PheraLys* is considered a key intermediate. The mature dendritic cells loaded
with PheraLys is the drug substance *MesoPher*.
The advantages of PheraLys over loading dendritics cells with autologous tumor
source are:
-unlimited access to tumor associated antigens
-no distressful, painful and risky tumor material resection from the patient
-immediate availability, superior quality and reliable comparative analysis of
clinical outcome facilitated
Previous studies have shown that PheraLys is well tolerated. This study aims to
evaluate its effects on overall survival.
Study objective
The primary objective of this study is to evaluate the overall survival (OS)
rate (determined from the time of randomization in the study) of subjects who
receive dendritic cell immunotherapy with MesoPher plus best supportive care
(BSC) compared to BSC alone.
Secondary objectives:
• to evaluate the overall survival rate at 12, and 18 months after
randomization, in subjects who receive dendritic cell immunotherapy with
MesoPher plus BSC compared to BSC alone.
• to evaluate progression free survival in subjects who receive dendritic cell
immunotherapy with MesoPher plus BSC compared to BSC alone.
• to evaluate the overall response rate and duration of response in subjects
who receive dendritic cell immunotherapy with MesoPher plus BSC compared to BSC
alone.
• to evaluate quality of life in subjects who receive dendritic cell
immunotherapy with MesoPher plus BSC compared to BSC alone.
• to evaluate the safety and tolerability of dendritic cell immunotherapy with
MesoPher.
Exploratory objectives:
• to evaluate the immunogenic effect of dendritic cell immunotherapy with
MesoPher.
• to evaluate the effect of dendritic cell immunotherapy with MesoPher on
immune-related cytokines in serum.
• to determine the T-cell response towards prespecified tumor antigens in
subjects who receive dendritic cell immunotherapy with MesoPher.
• to determine the T-cell response towards the tumor cells included in the cell
lines in subjects who receive dendritic cell immunotherapy with MesoPher.
• to determine the T-cell response towards Keyhole Limpet Hemocyanin (KLH) in
subjects who receive dendritic cell immunotherapy with MesoPher.
• to evaluate the estimated overall survival rate at 6 and 24 months after
randomization, in subjects who receive dendritic cell immunotherapy with
MesoPher plus BSC compared to BSC alone.
Study design
This is an open-label, randomized Phase II/III study in adult subjects with
mesothelioma. The study includes a screening phase, a 7-month open-label
treatment phase and follow-up evaluations.
Screening:
The signed ICF must be obtained before any study-specific procedures are
performed. During the screening phase, eligibility criteria will be reviewed
and a complete clinical evaluation will be performed as specified in Schedule
of Assessments.
Open-label treatment phase:
After screening subjects will be randomized in a 1:1 ratio to dendritic cell
immunotherapy maintenance treatment with MesoPher plus BSC or BSC alone (115
subjects per group). Randomization will be stratified by histology (epithelioid
vs other) and study center. Please see 'intervention' for study procedures
relating to the treatment.
Computer tomography (CT) scans of the thorax and upper abdomen to assess
response to treatment will begin at Week 6 (± 2 days) after start of MesoPher
treatment (for subjects in Arm A). This means that the first CT scan will be
made approximately 17 weeks after the last dose of chemo therapie. Therefore,
for the subjects in group B, the first CT scan will also be made approximately
17 weeks after the last dose of first-line chemo therapie. For both groups CT
scans will be repeated every 12 weeks. Blood samples for immuno-monitoring and
biomarker studies will be collected from all subjects. Subjects will be
monitored for adverse events by physical examinations and laboratory
assessments. Organ functioning will closely be monitored. Special attention
will be given to immune-related toxicity. One week after the 3rd MesoPher
injection subject in Arm A will have a DTH for MesoPher.
Follow-up:
Follow-up evaluations will be performed every 6 weeks after the last dose of
study drug in Week 30, with blood collection for safety labs every 6 weeks, and
a CT scan of the thorax and upper abdomen to be performed every 12 weeks until
the end of the study or disease progression. The last visit will be done at
week 102, when a blood sample will be taken for immuno-monitoring and
biomarkers. Thereafter, subjects will be followed up at regular intervals
according to standard-of-care to collect information on the subjects* survival
status. These contacts not part of this study protocol.
Intervention
Subjects in Arm A receive maintenance therapy.
After randomization subjects in Arm A will undergo leukapheresis to obtain
monocytes from which dendritic cells will be generated. These dendritic cells
will be loaded in vitro with an allogeneic tumor cell lysate (PheraLys).
Treatment for subjects randomized to Arm A will start approximately 5 weeks
after leukapheresis and within 9 to 13 weeks after the last dose of
chemotherapy. They will receive 3 bi-weekly injections with MesoPher in
addition to BSC. If not progressive and if the subject is in good clinical
condition, another 2 injections will be given 3 and 6 months. Progression will
be in comparison to the start of the injections and if the subject is in good
clinical condition. Subjects will receive a maximum of 5 doses of MesoPher (Day
1, Day 15, Day 29, Week 18, and Week 30).
Subjects in Arm B will be treated according to the discretion of the local
investigator, however maintenance treatment is not allowed.
Study burden and risks
The study is divided in 3 phases: screening, treatment and follow-up.
The screening visit may take up to 4 hours to assess eligibility, demographic
and other baseline characteristics. The potential subjects will have a physical
examination, review of their medical history, smoking- and ECOG performance
status. They will complete Quality of Life questionnaires. Blood will be taken
for serology, hematology and chemistry. Urinalyses and if applicable a
pregnancy test will be done. Vital signs (blood pressure, pulse rate,
respiratory rate, body temperature and pulse oximetry) will be measured, ECG
and CT scan performed.
For patients in arm A the treatment phase consists of 14 visits. It starts with
leukapheresis, which may take up to one day. Treatment starts 5 weeks later.
The patient will come for 5 visits where they receive MesoPher, each followed
by one visit where no treatment is given. Extra visits are planned at week 6,
12 and 26. During 6 visits 30 ml blood is taken for either immunomonitoring
and biomarkers and 8 times 20 ml for evaluation of the safety of MesoPher. The
blood draws will be combined as much as possible to keep the burden for the
patient as low as possible. 3 CT scans and 6 ECG's will be made. At almost
every visit physical examination will be done.
Patients in arm B do not have leukapheresis and will not receive MesoPher
treatment but do attend the last 5 visits of the treatment phase. In this phase
they will have 3 CT scans and 3 ECG's.
The follow-up phase consists of 12 visits. During each visit physical exam will
be done and every other visit 20 ml blood will be taken for evaluation of the
safety of MesoPher. During the last visit 38,5 ml will be taken for
immuno-monitoring and biomarkers. In this phase a CT scan will be made every
other visit, 6 in total.
Throughout treatment and follow-up the subjects ECOG performance statuses and
Quality of Life questionnaires will be completed.
All patients will receive Best Supportive Care throughout the whole study.
The greatest burden of the study for subjects will be the leukapheresis and the
MesoPher injections. Subjects from the AvL-NKI will have to travel to the
Erasmus MC, which usually will cost more travel time.
Subjects in arm B will not benefit from study participation, but they also will
not have to undergo these procedures.
In the standard care these patients also have regular CT scans. Therefore
making CT scans is not mentioned here as an extra burden related to the study.
Onderwijsboulevard 225
s-Hertogenbosch 5223 DE
NL
Onderwijsboulevard 225
s-Hertogenbosch 5223 DE
NL
Listed location countries
Age
Inclusion criteria
- Signed informed consent within 8 weeks of their last chemo and the date of
the informed consent must be such that it is possible to schedule the first
study treatment 9 to 13 weeks after their last chemo therapy.
- Histologically confirmed diagnosis of pleural malignant mesothelioma,
non-progressive after 4 to 6 cycles with first line chemotherapy with
antifolate/cisplatin (as determined by CT scanning)
- Measurable disease on CT scanning, by modified RECIST criteria or RECIST 1.1.
In absence of measurable disease a CT scan is needed to evaluate the disease.
- At least 18 years old
- WHO-ECOG performance status of 0 or 1
Exclusion criteria
- any concurrent medical, psychological or psychiatric disease or condition
that is likely to interfere with study procedures or results, or that in the
opinion of the investigator would constitute a hazard for participating in this
study
- serious intercurrent chronic or acute illness such as cardiac or hepatic
disease considered by the investigator to constitute an unwarranted high risk
for investigational dendritic cell treatment
- known active acute or chronic infection, including human immunodeficiency
virus (HIV) and hepatitis B or C
-history of autoimmune disease
-subjects with an organ allograft
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 | EUCTR2017-001774-41-NL |
| CCMO | NL62105.000.17 |