Objectives:Primary:• To assess progression free survival (PFS) when treated with lanreotide Autogel® 120 mg administered every 14 days based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.0, and according to central review.Secondary:•…
ID
Source
Brief title
Condition
- Endocrine neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is median PFS (defined as time from first injection of
lanreotide Autogel® 120 mg every 14 days to progression or death). Disease
progression will be assessed by tumour response evaluation according to RECIST
v1.0, every 12 weeks, measured using the same imaging technique (CT scan or
MRI) for each subject throughout the study, and by independent central review
to ensure intra and intersubject consistency and reliability.
Secondary outcome
Secondary endpoints and evaluations:
- Median time to progression (defined as time from first injection of
lanreotide Autogel® 120 mg every 14 days to progression).
- Proportion of subjects alive and without progression every 12 weeks.
- Overall survival at Week 48 and at the end of the study for each cohort.
- ORR every 12 weeks as per RECIST v1.0. ORR is defined as the proportion of
subjects who achieve either complete response (CR) or partial response (PR).
- DCR evaluated according to RECIST v1.0 at Weeks 24 and 48 and at the end of
study period in each cohort. The DCR is defined as the rate of CR plus PR plus
SD.
- Best overall response according to RECIST v1.0 (defined as the best response
recorded from the initiation of treatment until disease progression).
- Median duration of SD according to RECIST v1.0 (defined as the time from
first injection of lanreotide Autogel® 120 mg every 14 days until the first
occurrence of progressive disease by central assessment).
- Factors associated with PFS will include but will not be limited to: hepatic
tumour olume <=25% versus >25%, grade 1 versus grade 2, previous surgery of the
primary tumour (yes/no), Ki67 <10% versus >=10%, duration of treatment with
lanreotide Autogel® 120 mg every 28 days, time from diagnosis to progressive
disease during the study.
- Symptom control (diarrhoea, flushing) at Baseline, Weeks 8 and 12 and every
12 weeks thereafter, and at the End of Study visit, as measured by the total
number of stools and flushing episodes during the 7 days prior to the visit
reported orally by the subject to the investigator.
- Quality of life measured at Baseline, Week 12 and every 12 weeks thereafter,
and at the End of Study visit, after diagnosis of progression, using European
Organisation into the Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire Core 30 (QLQ-C30) v3.0 and Quality of Life Questionnaire
Gastrointestinal Neuroendocrine Tumour 21 (QLQ-GI.NET21; 2006), and the EuroQoL
5 dimensions, 5 levels (EQ-5D-5L) v1.0 questionnaires.
- pNET cohort:
• nonspecific tumour biomarkers (CgA, NSE and 5 HIAA) at Baseline, every
12 weeks thereafter and at the End of Study visit (plasma 5 HIAA at all
scheduled visits; urinary 5 HIAA at Baseline, Week 12 and at the End of Study
visit only). Note: at all scheduled visits, except Baseline, plasma/urinary 5
HIAA should only be performed in subjects with symptoms of carcinoid syndrome
(diarrhoea and/or flushing) or if urinary 5-HIAA was elevated (above ULN) at
Baseline.
• pNET specific tumour biomarkers (e.g. pancreatic polypeptide, gastrin,
glucagon, SST, *) at Baseline, every 12 weeks thereafter and at the End of
Study visit: only for the tumour biomarkers above normal range at Baseline.
- Midgut cohort:
• nonspecific tumour biomarkers (CgA, NSE and 5 HIAA) at Baseline, every
12 weeks thereafter and at the End of Study visit (plasma 5 HIAA at all
scheduled visits; urinary 5 HIAA at Baseline, Week 12 and at the End of Study
visit only).
Tertiary endpoints and evaluations:
- Variation in TGR across *retrospective* (lanreotide Autogel® 120 mg every 28
days) and *prospective* (reduced dosing interval) treatment periods. The TGR is
calculated from tumour size (sum of the longest diameters of target lesions as
per RECIST criteria) and tumour volume. Tumour size will be measured from MRI
(optimal) or CT scans collected during lanreotide Autogel® 120 mg every 28 day
treatment period
(i.e. the scan used for disease progression evaluation), and using MRI every 12
weeks during the reduced dosing interval period.
- Tumour response as per exture analysis on CT or MRI.
Background summary
Neuroendocrine tumors (NETs ) are rare tumors that originate in the
neuroendocrine system . Neuroendocrine cells are located in many tissues in the
body. In NET these cells grow uninhibited and they produce hormones and
hormone-like substances. Pancreatic neuroendocrine and Midgut Tumors are two
types of gastro- intestinal neuroendocrine Tumors.
Initial treatment, when possible, is the surgical removal of the tumour. The
study drug, lanreotide Autogel, is a manmade form of a natural hormone called
somatostatin. Lanreotide Autogel® 120 mg every 28 days is used for the
treatment and control of the growth of some advanced tumors of the intestine
and the pancreas called gastro-enteropancreatic neuroendocrine tumors or
GEP-NETS.
Previous research studies have shown that lanreotide and similar drugs may
decrease and stabilise the size of tumours. They also showed the activity of
Lanreotide Autogel® 120 mg every 28 days on tumour control and their positive
effect relief of clinical symptoms.
This study is designed to assess whether the study drug Lanreotide Autogel® 120
mg, given every 14 days can stop your tumour growing after treatment with
Lanreotide Autogel® (120 mg every 28 days).
Study objective
Objectives:
Primary:
• To assess progression free survival (PFS) when treated with lanreotide
Autogel® 120 mg administered every 14 days based on Response Evaluation
Criteria in Solid Tumours (RECIST) v1.0, and according to central review.
Secondary:
• To evaluate the clinical and biological safety profile.
• To evaluate time to progression.
• To evaluate PFS rate every 12 weeks.
• To evaluate overall survival at Week 48 and at the end of the study period in
each cohort.
• To evaluate the objective response rate (ORR) as per RECIST v1.0 every 12
weeks.
• To evaluate the disease control rate (DCR) as per RECIST v1.0 at Weeks 24 and
48 and at the end of study period in each cohort.
• To evaluate the best overall response as per RECIST v1.0.
• To evaluate the duration of stable disease (SD) as per RECIST v1.0.
• To detect predictive factors of PFS.
• To evaluate the effect on symptoms (diarrhoea, flushing).
• To evaluate quality of life.
• To evaluate the changes in tumour biomarkers:
- pNET cohort: nonspecific tumour biomarkers (Chromogranin A (CgA), neuron
specific enolase (NSE) and 5 hydroxyindoleacetic acid (5 HIAA); 5-HIAA only in
subjects with symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if
urinary 5-HIAA was elevated (above upper limit of normal (ULN)) at Baseline)
and pancreatic neuroendocrine tumours (pNET) specific tumour biomarkers (e.g.
pancreatic polypeptide, gastrin, glucagon, somatostatin (SST), *; only for the
tumour biomarkers above normal range at Baseline).
- Midgut cohort: nonspecific tumour biomarkers (CgA, NSE and 5 HIAA).
• To evaluate the appearance of antilanreotide antibodies.
• To evaluate the pharmacokinetic (PK) profile of lanreotide and to evaluate,
if any, the relationship between PK and pharmacodynamics (PD; PFS, tumour
response or CgA).
• To evaluate, if any, the relationships between PK parameters and the safety
outcomes.
Tertiary:
• To evaluate the effect on tumour growth rate (TGR) prior to and during
reduced dosing interval administrations.
• To evaluate changes in texture analysis on computed tomography (CT) or
magnetic resonance imaging (MRI).
Study design
This is a phase II, multicentre, prospective, open label, noncomparative,
exploratory study.
Intervention
Following the Screening visit (Visit 1) and a Screening period of up to 28
days, where eligibility tests and assessments will be performed, eligible
subjects will be treated with lanreotide Autogel® at a reduced dosing interval
(i.e. 120 mg every 14 days) beginning at Baseline (Visit 2).
Study visits will be performed at Weeks 2, 4, 8, 12, 24, 36 and 48 (both
cohorts), and Weeks 60, 72, 84 and 96 (midgut cohort only). An End of Study
visit is scheduled approximately 2 weeks after the study visit at which
progression is confirmed or after Weeks 48 (pNET cohort) or 96 (midgut cohort)
for nonprogressive subjects, once central review of the radiological imaging is
available.
As long as 25 events have not been observed in the respective cohorts, subjects
who have not progressed at Week 48 (pNET cohort) or Week 96 (midgut cohort)
will continue study treatment with lanreotide Autogel® 120 mg every 14 days and
additional visits will be performed every 12 weeks until disease progression,
death or unacceptable toxicity or tolerability.
Tumour response will be assessed every 12 weeks by tumour response evaluation
according to RECIST v1.0, measured using the same imaging technique (CT scan or
MRI) for each subject throughout the study, and by independent central review.
Additional efficacy assessments include symptom control (diarrhoea and
flushing) and quality of life, as well as factors associated with PFS, and
nonspecific (both cohorts) and pNET-specific (pNET cohort only) tumour
biomarker concentrations. Safety evaluations will be performed throughout the
study and will include the collection of clinical and biological safety data,
including adverse events (AEs), vital signs, physical examination findings,
serum haematology and biochemistry panels, urinalysis, and liver and pancreatic
enzyme concentrations, as well as electrocardiogram (ECG) and gallbladder
echography. PK evaluations will consist of lanreotide concentrations at
selected timepoints throughout the study. The presence of lanreotide antibodies
will be measured and blood samples for biobanking may also be taken from
subjects who consent to the optional biobanking programme. The overall duration
of the study will be approximately 102 weeks assuming at least 25 subjects
progress within 48 and 96 weeks in the 2 cohorts respectively.
Study burden and risks
The study overall has more frequent clinic visits (e.g. PK sampling) and more
comprehensive monitoring compared with normal clinical practice.
Possible side effects and other undesirable effects
- Blood sampling: painful or may cause some bruising
- CT or MRI-scan: exposure to radiation
- Adverse Events of the study medication (as described in the Investigator's
Brochure)
Avenue du Canada, zone Industrielle de Courtaboeuf 5
les Ulis 91940
FR
Avenue du Canada, zone Industrielle de Courtaboeuf 5
les Ulis 91940
FR
Listed location countries
Age
Inclusion criteria
1) Male or female subjects aged 18 years old or older.;2) Histopathologically confirmed well differentiated (grade 1 or grade 2 according to the WHO 2010 classification), metastatic or locally advanced, unresectable pNET (pNET cohort) or midgut NET (midgut cohort) with or without hormone related syndromes, with a proliferation index (Ki67) <=20%.;3) Positive somatostatin receptors type 2 (SSTR2) as assessed by imaging (scintigraphy or positron emission tomography (PET) scan) in the organs of target lesions.;4) Progression as assessed by an independent central reviewer according to RECIST v1.0 from radiological imaging (CT scan or MRI) while receiving first line treatment with lanreotide Autogel® at a standard dose of 120 mg every 28 days for at least 24 weeks (6 injections). Progression must be radiologically documented using the same technique of images (CT scan or MRI) within 24 months prior to enrolment. Inclusion into the study must be within 28 days of the radiological imaging that is performed to document progression.;5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2.;6) Provision of written informed consent prior to any study related procedures. ;7) Female subjects of childbearing potential (not surgically sterile or 2 years postmenopausal) must provide a negative urine pregnancy test at Screening, and use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 2 months after participation in the study. Acceptable methods of contraception include double barrier method, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted and injected).;8) Subjects must be willing and able to comply with study restrictions and willing to return to the clinic for the follow up evaluation as specified in the protocol.
Exclusion criteria
1) Has poorly differentiated grade 3 NET or rapidly progressive NET (within 12 weeks of initiation of lanreotide Autogel® 120 mg every 28 days) as per RECIST v1.0. ;2) Has been diagnosed with VIPoma (i.e. Verner Morrison syndrome), insulinoma, foregut (except for pNET), hindgut NET, unknown primary NET or multiple endocrine neoplasms (MEN).;3) Has progressed during treatment with somatostatin analogues (SSAs) other than lanreotide Autogel® 120 mg.;4) Has been previously treated with any antitumour agent for NET other than lanreotide Autogel® 120 mg every 28 days: chemotherapy, molecular targeted therapy, peptide receptor radionuclide therapy (PRRT) or interferon.;5) Has had major surgery related to the studied disease within 3 months prior to entering the study. Previous debulking surgery and liver-directed therapies are acceptable as long as tumour burden is measurable (other target lesions).;6) Has gallbladder lithiasis at Screening echography or a history of cholelithiasis with no cholecystectomy since then.;7) Has had previous cancer, except basocellular carcinoma of the skin and/or in situ carcinoma of the cervix/uterus and/or subjects treated with curative intent and free from disease for more than 5 years.;8) Was treated with any other investigational medicinal product (IMP) within the last 30 days before study entry.;9) Is pregnant or lactating. ;10) Has abnormal findings at Screening, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardise the subject's safety.;11) Has any mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.;12) Has been previously screened in this study.;13) Has a history of hypersensitivity to lanreotide Autogel® or drugs with a similar chemical structure, or any excipient used in the formulation.;14) Is likely to require treatment during the study with drugs that are not permitted by the study protocol. ;15) Has a history of, or known current, problems with substance or alcohol abuse.;16) Vulnerable subjects (i.e. subjects who are under legal protection, who are interned due to a mental disease and who are kept in detention).;17) Subjects who have a link with the sponsor, the clinical trial site or the investigator (medical, pharmacy, dental and nursing students, subordinate hospital and laboratory personnel, employees of the sponsor).
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 | EUCTR2014-005607-24-NL |
| CCMO | NL54223.078.15 |
| Other | The trial will be registered in http://www.ClinicalTrials.gov but registration is not yet complete |