Primary Objective(s) & Hypothesis(es) In subjects with advanced ROC:1) Objective: To evaluate clinical anti-tumor activity of pembrolizumab monotherapy based on ORR as assessed by CIV per RECIST 1.1 in Cohort A-All Comer group as defined in…
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Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective (1) is to evaluate objective response rate (ORR) in the first
180 enrolled subjects who fulfill the eligibility criteria for Cohort A.
Primary objective (2) is to evaluate ORR in subjects who fulfill the
eligibility criteria for Cohort A and with higher expression of program death
ligand protein 1 (PD-L1) in tumor tissue samples.
Primary objective (3) is to evaluate ORR in all enrolled subjects who fulfill
the eligibility criteria for Cohort B.
Primary objective (4) is to evaluate ORR in subjects enrolled into Cohort B who
have tumor tissue PD-L1 expression above the clinical cutpoint established from
the Cohort A training set.
Secondary outcome
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Background summary
Ovarian cancer is the most lethal gynecologic cancer and the fifth -leading
cause of cancer death among women in the United States (US). In the US, the
estimated number of new cases and deaths from ovarian cancer in 2014 was 21,980
and 14,270, respectively. Due to lack of tumor-specific signs and symptoms and
effective screening tests for early detection, over
70% of ovarian cancer patients are first diagnosed at advanced stages. Based on
the US data from 2003 to 2009, at initially diagnosis, 61% had distant
metastasis, 18% had regional disease and only 21% had localized disease. The
overall 5-year survival rate of ovarian cancer was approximately 44% counting
all stages; the 5-year survival rate in patients with distant metastasis was
only 27% [3].
Epithelial ovarian cancer (EOC) accounts for >90% of the ovarian cancer and has
been recognized as a group of heterogeneous diseases with distinct
histopathologic features, genetic alterations and clinical behaviors. Five main
EOC subtypes have recently been designated by The International Federation of
Gynecology and Obstetrics (FIGO): high - grade serious carcinoma (HGSC,
accounts for ~70% EOC), endometrioid carcinoma (EC,
~10% EOC), clear cell carcinoma (CCC, ~10% EOC), mucinous carcinoma (MC, ~3%
EOC), low grade serous carcinoma (LGSC, 5% EOC), and those that are
unclassifiable [ 4;
5]. Primary peritoneal carcinoma and fallopian tube carcin oma have typically
been managed and studied together with EOC as they share similar
clinic-pathologic characteristics with HGSC.
The standard primary treatments for advanced EOC include primary
cytoreductive/debulking surgery followed by postoperative front line (i.e.,
adjuvant) systemic treatment with carboplatin and paclitaxel Q3W IV for 6
cycles. However, weekly paclitaxel has also been frequently used to replace Q3W
paclitaxel. In suitable cases, postoperative chemotherapy, usually cisplatin
plus paclitaxel, can be delivered via intraperitoneal (IP) route. In cases with
bulky diseases that are initially non-operable, neoadjuvant therapy can be
given prior to cytoreductive surgery (i.e. interval cytoreductive surgery) then
followed by standard platinum/taxane-based chemotherapy [6; 7].
The goal of cytoreductive surgery is to achieve resection of all visible tumors
and the goal of postoperative first line chemotherapy are: 1) to help achieving
complete remission in those with residual disease, and 2) to prevent disease
recurrence for those with complete tumor resection. However, after these
primary treatments, only a small proportion of patients will achieve long-term
disease-free and survival status. In a meta-analysis performed by du Bois et al
[8] on data from three randomized trials following the standard primary
treatment with surgery and platinum-taxane based chemotherapy (N = 3126), only
24% of patients were recurrent free after a median follow up time of 53.9
months and the remaining 76% had disease recurred or progressed. The overall
5-year PFS and OS rate was 22.6% and 39.0%, respectively. Based on time to
recurrence (TTR) since the last dose of platinum treatment,
22% recurred 0-6 months, 22.5% recurred 6-12 months, and 31.6% recurred >12
months. By
12 months, the 12 months survival rate was 30.6%, 55.1% and 66.1% in the group
with TTR
0-6 months, TTR 6-12 months, and TTR >12 months, respectively; the 24-month
survival rate was 13.8%, 24.4% and 34.9% in these three groups, respectively.
This data showed an overall poor prognosis for patients with recurrent disease
especially in those with a short TTR.
At present, ROC is considered not curable with the available choices of
therapies and is an area of highly unmet medical need.
Selection of treatment for ROC should take into consideration several factors
including: sensitivity to first line platinum-based therapy, as measured by
platinum-free interval (PFI), prior toxicity, comorbidity, age and performance
status etc. PFI, which is defined as the period from the cessation of the
primary platinum-based chemotherapy to disease recurrence or progression, has
been recognized as an important surrogate for prognosis and predicting response
to chemotherapy. Based on PFI, ROC can be divided into the following subgroups:
platinum-sensitive (PFI >12 months), partiallyplatinum sensitive (PFI of 6-12
months), platinum resistant (PFI >1 to < 6 months), and platinum-refractory
(PFI * 4 weeks or progression on treatment) according to the consensus achieved
by the GCIG in 2010 [9].
Based on the current National Comprehensive Cancer Network (NCCN) and European
Society for Medical Oncology (ESMO) guidelines, patients with
platinum-resistant ROC can be treated with either single agent chemotherapy
such as gemcitabine, pegylated liposomal doxorubicin (PLD), weekly paclitaxel,
topotecan and docetaxel, or bevacizumab in combination with gemcitabine or
weekly paclitaxel or topotecan. These single agents had shown similar clinical
efficacy with a response rate around 15-20%, median PFS of 3-5 months and
median OS of 10-12 months [10; 11]. Bevacizumab plus single agent chemotherapy
showed an improved PFS compared to single agent chemotherapy alone (6.7 vs. 3.4
months, HR: 0.48, p <0.001) and an improved response rate (27.3% vs. 11.8%) via
a randomized Phase III trial, AURELIA [12]. However, the study didn*t
demonstrated overall survival benefit; and based on the Kaplan-Meier curve,
less than 20% of subjects in the bevacizumab chemotherapy arm remained
progression-free by 12 months, and even less in the single agent chemotherapy
arm. Platinum resistant ROC, hence, this is an area with high unmet medical
need for novel therapies that can deliver durable clinical benefit.
Partially platinum-sensitive ROC (i.e. PFI > 6-12 months), which used to be
classified as part of the platinum-sensitive group, has been considered a
challenging group to manage [13; 14]. Even though the recommended treatment for
partially platinum -sensitive ROC remains the same as those for
platinum-sensitive ROC, i.e., re-treated with a platinum-containing doublet,
the partially platinum-sensitive group has significantly reduced clinical
benefit compared to those with PFI > 12 months. For example, in a review of 583
ROC patients from six Phase II-III clinical trials by Pujade-Lauraine et. Al.
[15] on the impact of TFI, on clinical response to salvage therapy, patients
with TFI of 3-12 months showed an ORR of 35% compared to an ORR of 52% in the
group with TFI of 12 -18 months. Median time to progression (TTP) and OS in the
group with TFI of 3 -12 months was much shorter (174 days and 393 days,
respectively) compared to the group with TFI of 12-18 months (275 days and 657
days, respectively). In the Phase III trial CALYPSO [16] that compared
carboplatin plus PLD (CD) versus carboplatin plus paclitaxel (CP), OS was
significantly longer in subjects with TFI * 12 months versus subjects with TFI
6-12 months based on multivariate analysis (HR = 0.5; 95% CI 0.43, 0.59; p <
0.001). In the CALYPSO trial, median PFS in the partial platinum- sensitive
subpopulation was 9.4 months for the CD arm and 8.8 months for the CP arm; ORR
was 39% in the CD arm and 45% in the CP arm . However, when taking a closer
look at the Kaplan-Meier PFS curve for partial platinum-sensitive subgroup in
this study, less than 20% patients in the CP arm and a little over 20% in the
CD arm remained progre ssion-free at 12 months [17].
In a meta-analysis by Hanker et al [18] charterizing impact of second to sixth
line of therapy on survival of relapsed ovarian cancer, data of n = 1620
patients from three large randomized phase III trials investigating primary
therapy was included. The results showed that median PFS after the first,
second, third, fourth and fifth relapse was 10.2 [95% confidence interval (CI)
9.6*10.7], 6.4 (5.9*7.0), 5.6 (4.8*6.2), 4.4 (3.7*4.9) and 4.1 (3.0*5.1)
months, respectively. Median OS after the first, second, third, fourth and
fifth relapse was 17.6 (95% CI 16.4*18.6), 11.3 (10.4*12.9), 8.9 (7.8*9.9), 6.2
(5.1*7.7) and 5.0 (3.8*10.4) months, respectively. The overall clinical benefit
greatly reduced with increased lines of therapy.
In addition to reduced clinical benefit and lack of long-lasting clinical
activities from the existing therapies in this group, toxicities from prior or
planned platinum doublets further limit the utility of these treatments in this
subgroup [13]. Novel therapies with durable clinical efficacy and better
safety profile are highly needed for the treatment of partially
platinum-sensitive as well as platinum-resistant ROC.
Study objective
Primary Objective(s) & Hypothesis(es)
In subjects with advanced ROC:
1) Objective: To evaluate clinical anti-tumor activity of pembrolizumab
monotherapy based on ORR as assessed by CIV per RECIST 1.1 in Cohort A-All
Comer group as defined in Section 2.1
2) Objective: To evaluate clinical anti-tumor activity of pembrolizumab
monotherapy based on ORR as assessed by CIV per RECIST 1.1 in Cohort A-PD-L1H
subgroup, as defined in Section 2.1, using a PD-L1 expression cutpoint
established in the training set.
3) Objective: To evaluate clinical anti-tumor activity of pembrolizumab
monotherapy based on ORR as assessed by CIV per RECIST 1.1 in Cohort B -All
Comer group as defined in Section 2.1
4) Objective: To evaluate clinical anti-tumor activity of pembrolizumab
monotherapy based on ORR as assessed by CIV per RECIST 1.1 in Cohort B PD-L1H
subgroup, as defined in Section 2.1, using a PD-L1 expression cutpoint
established in the training set from Cohort A
The primary objectives will focus on estimation of ORR, and no formal
hypothesis testing is planned.
Secondary Objective(s) & Hypothesis(es)
In subjects with advanced ROC:
1) Objective: To evaluate duration of response (DOR), disease control rate
(DCR) and progression-free survival (PFS) as assessed by CIV per RECIST 1.1 in
Cohort A-All Comer group, Cohort A-PD-L1H subgroup, Cohort B-All Comer group,
Cohort B- PD-L1H subgroup respectively, after treated with pembrolizumab
monotherapy. PFS rate at 6, 12 and 18 months will also be evaluated.
2) Objective: To evaluate ORR, DOR, DCR, and PFS as assessed by investigator
per RECIST1.1 in Cohort A-All Comer group, Cohort A-PD-L1H subgroup, Cohort
B-All Comer group, Cohort B-PD-L1H subgroup, respectively, after
treated with pembrolizumab monotherapy
3) Objective: To evaluate ORR, DOR, DCR and PFS as as sessed by CIV and by
investigator per RECIST 1.1, in Cohort A-All Comer subgroup with PFI/TFI * 3 *
6 months and the subgroup with PFI/TFI >6 -12 months, respectively, after
treated with pembrolizumab monotherapy.
4) Objective: To evaluate OS in Cohort A-All Comer group, Cohort
A-PD-L1H subgroup, Cohort A-All Comer subgroup with PFI/TFI * 3 * 6 months and
the subgroup with PFI/TFI >6-12 months, Cohort B-All Comer group, Cohort
B-PD-L1H subgroup, after treated with pembrolizumab monotherapy.
5) Objective: To evaluate and characterize the tolerability and safety
profile of the entire study population and by cohorts and subgroups ,
respectively, after treated with pembrolizumab monotherapy
6) Objective: To assess population pharmacokinetics (PK) No formal hypotheses
will be tested for secondary objectives.
Study design
This is a Phase II, open-label, single-arm, two-cohort, multi-center study to
evaluate efficacy and safety of pembrolizumab monotherapy 200 mg every 3 weeks
(Q3W) in subjects with advanced epithelial ovarian cancer (EOC), fallopian
tube cancer, or primary peritoneal cancer (will collectively refer as
advanced EOC) who have demonstrated recurrent disease following the primary or
interval cytoreductive/debulking surgery and the standard front line platinum*
based combination therapy. The study will enroll the following two cohorts of
subjects with recurrent ovarian cancer (ROC):
Cohort A will enroll ROC subjects who have received 0 to 2 prior lines for
treating ROC (i.e., 1-3 total prior lines counting the front line) and must
have a platinum-free interval (PFI) or a treatment-free interval (TFI) of 3 to
12 months based on the last regimen received. Cohort B will enroll ROC subjects
who have received 3-5 prior lines for treating ROC (i.e.,
4-6 total prior lines counting the front line) and must have a PFI or TFI * 3
months based on the last regimen received. Refer to Section 5.1.for definition
of PFI and TFI and detailed inclusion and exclusion criteria for each Cohort.
The trial will be conducted in conformance with Good Clinical Practices.
The study has 4 primary objectives. Primary objectives (1) and (2) are
designated for Cohort
A. Primary objectives (3) and (4) are designated for Cohort B.
Primary objective (1) is to evaluate objective response rate (ORR) in the first
180 enrolled subjects who fulfill the eligibility criteria for Cohort A. This
group is designated as Cohort A-All Comer group. Within Cohort A-All Comer
group, a minimum of 75 subjects will be enrolled for the subgroup with a PFI or
TFI of 3- <6 months and the subgroup with a PFI or TFI of 6 * 12 months. The
primary analysis of ORR will be based on the assessment by a central imaging
vendor (CIV) per Response Evaluation Criteria in Solid Tumors (RECIST) version
1.1 [1].
Primary objective (2) is to evaluate ORR in subjects who fulfill the
eligibility criteria for Cohort A and with higher expression of program death
ligand protein 1 (PD-L1) in tumor tissue samples. It is expected that higher
PD-L1 expression in tumor tissue will be associated with better clinical
responses to pembrolizumab ( refer to Section 4 for background and rationale).
In order to achieve this primary objective, a PD -L1 expression cutpoint will
first be established with a goal to enrich the popula tion for better clinical
benefit. The cutpoint will be determined during the planned interim analysis
using the clinical efficacy data and PD-L1 expression data from the first 100
enrolled Cohort A subjects. This data set is designated as the *training
set* (refer to Section 8.7 on the approach for determining the PD- L1
cutpoint). In order to confirm the association of higher PD-L1 expression with
increased clinical activity by pembrolizumab treatment, another 150 subjects
who fulfill eligibility criteria for Cohort A will be enrolled, which is
designated as the *confirmation set*. Cohort A will therefore, enroll a total
of 250 subjects. Based on the established PD-L1 cutpoint from the training set,
subjects in the confirmation set will be assigned into the subgroup with PD -
L1 expression above or equal to the cutpoint (i.e. , Cohort A PD-L1H) or the
subgroup with
PD-L1 expression below the cutpoint (i.e., Cohort A PD-L1L). Enrollment into
Cohort A will not be interrupted for interim analysis. However, in order to
ensure data integrity, samples from the *confirmation set* will not be assessed
for PD-L1 expression until the cutpoint has been established and the assay has
been confirmed. Based on the prevalence data regarding higher PD-L1 expression,
the total enrollment of Cohort A may be increased to up to 280 to ensure a
minimum of 60 subjects from the confirmation set (see below) will have PD-L1
expression above the expected cutpoint.
Approximately 75 subjects will be enrolled in to Cohort B regardless of PD-L1
expression status. Primary objective (3) is to evaluate ORR in all enrolled
subjects who fulfill the eligibility criteria for Cohort B. This group is
designated as Cohort B-All Comer group. Primary objective (4) is to evaluate
ORR in subjects enrolled into Cohort B who have tumor tissue PD-L1 expression
above the clinical cutpoint established from the Cohort A training set. The
population supporting primary objective (4) is designated as Cohort B PD-L1H
group. Tumor tissue samples from Cohort B will not be evaluated until a
cutpoint has been established from Cohort A training set.
As part of the inclusion criteria, all subjects must provide a tumor tissue
sample collected either from a recent biopsy or prior cytoreductive surgery in
order to be enrolled. Part of the tumor tissue sample will be submitted to a
designated central laboratory for assessing PD -L1 expression via an
immunohistochemistry (IHC) assay. PD-L1 positivity is determined using the
combined positive score (CPS) which is defined as the percent PD-L1 positive
cells counting tumor cells, immune infiltrating cells and cells from adjacent
stroma relative to total tumor cells. Details will be provided in a separate
document.
Clinical cutoff for interim analysis will be at least 4 months after the 100th
Cohort A subject has been enrolled to allow adequate clinical follow up. For
each designated study population (i.e., Cohort A-All Comer, Cohort A PD-L1H,
or Cohort B), the clinical cutoff for the final analysis of the primary
endpoint ORR will be at least 8 months after the last subject for each
population has been enrolled. The final clinical cutoff for the study (i.e. ,
study completion) will be 3 years after the last subject is enrolled for final
overall survival (OS) analysis. Refer to Sections 3.2 and 3.3 for details
regarding secondary and exploratory study objectives, and Figure 1 in Section
2.2 for illustration of the overall study design.
Intervention
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Study burden and risks
The patient will visit the doctor every three weeks. The first visit a tumor
biopsy will take place (if necessary). Each visit, a physical examination will
be performed, and blood samples will be taken.
The patient may experience physical and or psychological discomfort with some
of the procedures performed during a visit, such as blood sampling, the IV
line, ECG, CT scan, MRI and tumor biopsy.
The main side effect reported with the use of MK3475 are fatigue, itching,
rash, frequent or excessive bowel movements, joint pain and nausea.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
1. Be willing and able to provide written informed consent for the trial. The
subject may also provide consent for Future Biomedical Research. However, the
subject may participate in the main trial without participating in Future
Biomedical Research.
2. Be > or <= 18 years of age on day of signing informed consent.
3. Have histologically confirmed epithelial ovarian cancer, fallopian tube
cancer or primary peritoneal cancer
4. Have received a front line platinum-based regimen (administered via either
IV or IP route) per local SOC or treatment guideline following the primary or
interval debulking surgery with documented disease recurrence.
Note: Maintenance treatment following the front line treatment is permitted and
counted together as part of the front line treatment.
5. Have fulfilled the following additional requirements regarding prior
treatments for recurrent ovarian cancer (ROC) depending on the cohort subject
is to be enrolled. Each subject must have documented evidence of clinical
response or disease stabilization to the last regimen received.
Cohort A: Have received 0 to 2 additional prior lines for treating ROC (or 1-3
total prior lines counting the front line) and must have a platinum-free
interval (PFI) of > or <= 3 to 12 months if the last regimen received is a
platinum-based, or a treatment-free interval (TFI) of > or <= 3 to 12 months
if the last regimen received is a non-platinum-based.
Cohort B: Have received 3 to 5 additional prior lines for treating ROC (or 4-6
total prior lines counting the front line) and must have a PFI of > or <=3
months if the last regimen received is a platinum-based, or a TFI of > or <=
3 months if the last regimen received is a non-platinum-based.
Note: PFI is defined as the time elapsed between the last dose of platinum and
the documented evidence of disease progression per RECIST 1.1. TFI is defined
as the time elapsed between the last dose of the regimen received and the
documented evidence of disease progression per RECIST 1.1.
6. Have measurable disease at baseline based on RECIST 1.1 as determined by the
central imaging vendor.
Note: Tumor lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions.
7. Have an ECOG performance status of 0 or 1
8. Have a life expectancy of > or <=16 weeks.
9. Have provided a tumor tissue sample either collected from prior
cytoreductive surgery or fresh newly obtained tumor tissue at screening.
Formalin-fixed paraffin-embedded (FFPE) block specimens are preferred to
slides. Additional samples may be requested if tumor tissue provided is not
adequate for quality and/or quantity as assessed by the central laboratory.
Note 1: Tumor tissue samples from recent biopsy are much preferred as it
represents the current disease status and is much more informative for
understanding the correlation between clinical activity and tumor
microenvironment.
If available, paired tumor tissue samples from prior cytoreductive surgery and
recent biopsy are strongly encouraged in order to understand the changes in
tumor microenvironment during the course of the treatments.
Note 2: For archival tumor tissue samples, block specimens are much preferred
than slides. If submitting unstained cut slides, freshly cut slides should be
submitted to the testing laboratory within 14 days from when the slides are
cut. See Section 4.2.3.3 in protocol for an explanation.
10. Have demonstrated adequate organ function as defined in Table 1 of the
protocol. All screening labs should be performed within 10 days of treatment
initiation.
11. Female subjects of childbearing potential (see Section 5.7.1) must be
willing to use an adequate method of contraception as outlined in Section 5.7.1
* Contraception, for the course of the study through 120 days after the last
dose of study medication. Note: Abstinence is acceptable if this is the usual
lifestyle and preferred contraception for the subject.
12. Female subjects of childbearing potential must have a negative urine or
serum pregnancy test within 72 hours prior to receiving the first dose of study
medication. If the urine test is positive or cannot be confirmed as negative,
a serum pregnancy test will be required.
Exclusion criteria
1. Is currently participating in or has participated in a clinical study and
received an investigational agent or used an investigational device within 4
weeks prior to the first dose of study treatment.
Note: Subjects who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks since the last dose of the
previous investigational agent or device.
2. Has an active autoimmune disease that has required systemic treatment in the
past 2 years (i.e. use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to the
planned first dose of the study. The use of physiologic doses of
corticosteroids may be approved after consultation with the Sponsor.
4. Has had prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted
small molecule therapy, or radiation therapy within 4 weeks prior to the
planned first dose of the study
5. Has not recovered from adverse events to < or = Grade 1 or prior
treatment level due to a previously administered agent.
Note: Subjects with < or = Grade 2 neuropathy or alopecia of any grade are
an exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
6. Has EOC with mucinous histology subtype. Or has a known additional
malignancy that progressed or required active treatment within the last 5
years. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in
situ cervical cancer.
7. Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain metastases may
participate provided they have stable brain metastases.
8. Has known history of, or any evidence of active, non-infectious pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has symptoms of bowel obstruction in the past three months
11. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject*s participation for the full duration of the trial, or is not in the
best interest of the subject to participate, in the opinion of the treating
investigator.
12. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive children within the
projected duration of the trial, starting with the screening visit through 120
days after the last dose of trial treatment.
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent
or with an agent directed to another co-inhibitory T-cell receptor (e.g.
CTLA-4, OX-40, CD137) or has participated in prior pembrolizumab trials.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g.,
HCV RNA [qualitative] is detected).
17. Has received a live vaccine within 30 days of the planned first dose of the
study.
Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g.,
Flu-Mist®) are live attenuated vaccines, and are not allowed.
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 | EUCTR2015-003338-29-NL |
| CCMO | NL56470.056.16 |