This study has been transitioned to CTIS with ID 2023-507443-10-00 check the CTIS register for the current data. The pivotal Phase III NETTER-1 study showed that Lutathera with best supportive care (30mg octreotide long-acting) provided a…
ID
Source
Brief title
Condition
- Endocrine and glandular disorders NEC
- Endocrine neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To demonstrate that Lutathera is superior to active comparator in delaying the
time-to-first occurrence of progression or death (PFS) as first line treatment.
Secondary outcome
Key Secondary Objectives:
- To demonstrate the superiority of Lutathera, compared to active comparator,
in terms of objective response
- To demonstrate the superiority of Lutathera, compared to active comparator,
in terms of time to deterioration in selected QoL items/scales
Other Secondary Objectives:
- To evaluate the efficacy of Lutathera, compared to active comparator, in
keeping the disease under control
- To evaluate the efficacy of Lutathera, compared to active comparator, in
terms of duration of response
- To evaluate the safety and tolerability of Lutathera
- To evaluate the effect of Lutathera on survival
Background summary
The study drug contains a radioactive compound called lutetium. The radioactive
lutetium delivers strong radiation directly into tumor cells and works by
causing death of the cancerous tissues. The intent of giving the drug
internally into a vein is that it should focus the cell killing effects of the
radiation by binding to tumors. Due to the rapid excretion it will have less
effect on healthy tissue.
Treatment with the study drug is called Peptide Receptor Radionuclide Therapy
(PRRT). This PRRT treatment is based on the administration of a radioactive
product. PRRT is a form of targeted treatment that is performed using a small
radioactive molecule.
The study drug can be administered in combination with octreotide long-acting.
Octreotide long-acting binds to and prevents tumor cells from secreting
hormones and other substances that may cause symptoms such as flushing,
diarrhea, and tummy cramps. It gives relief of symptoms in patients with grade
2 or grade 3 GEP-NETs (gastro-entero-pancreatic neuroendocrine tumors).
Both treatments, the study drug and octreotide long acting, are used to try and
stop grade 2 or grade 3 GEP-NETs (gastro-entero-pancreatic neuroendocrine
tumors) from getting worse and perhaps to even reduce the size of tumor(s).
Study objective
This study has been transitioned to CTIS with ID 2023-507443-10-00 check the CTIS register for the current data.
The pivotal Phase III NETTER-1 study showed that Lutathera with best supportive
care (30mg octreotide long-acting) provided a significant increase in PFS to
patients with progressive midgut carcinoid tumors (at enrollment) compared to
patients treated with high dose (60 mg) octreotide long-acting. The NETTER-1
patient population included 34.5% of patients with G2 NET (65.5% G1), while G3
NETs were excluded. Only patients progressive on SSAs were eligible (2nd line),
SSA-naïve patients were excluded.
The aim of the NETTER-2 study is to determine if Lutathera in combination with
octreotide long-acting prolongs PFS in GEP-NET patients with high proliferation
rate tumors (G2 and G3), when given as a 1st line treatment in comparison to
treatment with high dose (60 mg) octreotide long-acting. SSA-naïve patients are
eligible, as well as patients previously treated with SSAs in the absence of
progression.
Based on extensive experience with Lutathera as well as octreotide LAR in adult
GEP NET patients, and the relevance of the molecular target in adolescent GEP
NET patients, the study will be open to adolescents aged >= 15 years and >40 kg
body weight (BW); younger patients are not expected to present with the disease
meeting the severity criteria for this trial.
Study design
Overall, 222 patients will be randomized (2:1 randomization ratio) to receive
treatment with Lutathera (7.4GBq/200 mCi x 4 administrations every 8± 1 weeks;
cumulative dose: 29.6 GBq/800mCi) plus octreotide long-acting (30 mg every 8
weeks during Lutathera treatment and every 4 weeks after last Lutathera
treatment) or high dose octreotide long-acting (60 mg every 4 weeks).
Randomization will be stratified by Grade (G2 vs G3) and tumor origin (pNET vs
other origin). The primary endpoint of the study is PFS centrally assessed
(target HR=0.5; 90% power, 1-sided α=2.5%). The primary analysis will be
performed after 99 PFS events (99 evaluable and centrally confirmed disease
progressions or death events) have occurred. The study consists of a Screening
Phase, a Treatment Phase, an optional Treatment Extension Phase (cross-over),
an optional Re-treatment Phase and a Follow up Phase.
Screening Phase
The screening phase must be shortened as much as possible, in order to treat
the patients possibly within 2 weeks after the consent signature. The
randomization must be performed immediately after all eligibility criteria are
verified. As Lutathera production and shipment will take circa 12 days to be
arranged, if a patient is randomized in the Lutathera arm, Lutathera first dose
must be ordered immediately after randomization. The baseline CT/MRI scan
should be taken possibly on the same day as randomization or immediately before
(within 1 week) to ensure that it reflects the disease status closely before
the therapy start.
Treatment Phase
During the Treatment Phase, objective tumor response will be assessed at W16±1,
W24±1 and then every 12±1 weeks from the randomization date, according to
RECIST 1.1 criteria (central + local assessment up to first progression, then
only local assessment).
Duration of the Treatment Phase:
Before the PFS primary analysis (i.e. 99 evaluable and centrally confirmed
disease progressions or death events), patients continue the Treatment Phase
until progression; after the PFS primary analysis, the Treatment Phase duration
is limited to 72 weeks. At any time during the study (before or after the PFS
primary analysis) any progressive patient (based on central imaging assessment)
immediately ceases the Treatment Phase and proceeds to the Follow-up Phase. In
addition, patients randomized in the control arm have the option, if eligible,
to enroll for post-progression cross-over with Lutathera).
Optional Treatment Extension Phase (cross-over)
In the control arm, any patient with radiological progression according to
RECIST (based on central assessment) has the option to enroll for
post-progression cross-over, upon signature of a new informed consent, to
receive maximum 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles; cumulative
dose: 29.6 GBq / 800mCi) plus 30 mg octreotide long acting every 8 weeks. If
RECIST progression occurs after Week 72 post the primary end point analysis,
the decision to enroll the patient in the cross-over phase will be based on
local assessment. The time window to start Lutathera during the cross-over
phase is within 4 years after the last patient has been randomized.
Optional Re-treatment Phase
Patients in the Lutathera arm with radiological progression based on RECIST
criteria in central assessment will be offered enrollment in the
optional re-treatment phase upon signature of a new informed consent. If RECIST
progression occurs after Week 72 post the primary end point
analysis, the decision to enroll the patient in re-treatment will be based on
local assessment. The criteria to enter the re-treatment phase include
achievement of stabilization of disease or radiological response to Lutathera
initial treatment for at least 6 months after receiving the 4th Lutathera dose
and good safety/tolerability. If a patient*s response has changed from PR/CR to
SD within 6 months after the 4th Lutathera dose, the patient is still eligible
for re-treatment, provided there is no documented progression within 6 months.
Patients who received other systemic treatments for GEP-NET after progression
(except somatostatin analogues) are not eligible for re-treatment. The time
window to start re-treatment in this study is within 4 years after the last
patient has been randomized. In the re-treatment phase, patients will initially
receive 2 administrations of
Lutathera 7.4 GBq/200 mCi at 8-week interval. Based on the physician*s judgment
of the clinical benefit derived from the first 2 doses, up to 2
additional doses of Lutathera may be administered. A maximum of 4 cycles of
Lutathera is allowed during the re-treatment period. All safety and
efficacy assessments in the re-treatment period will be performed locally (SRI
images must also be submitted to the central images reading center
possibly within 1 month) and following the schedule in the initial treatment
period. Assessments will be continued until disease progression is
documented by investigator or until End of Study, whichever occurs first.
Follow up Phase
At the end of the Treatment Phase or after discontinuation for any cause
(including disease progression), all patients will continue to be followed up
to 3 years to continue data collection for the secondary endpoints of the
study, such as long term safety and overall survival. Patients included in the
optional crossover or re-treatment phase will be followed up at least 6
months and up to 3 years (or until EoS, whatever comes first). During the
Follow-up Phase, serious adverse events and adverse events of
special interest (AESI) related to the study treatment as well as AESI of
secondary hematological malignancies irrespective of causality, will be
reported. Anti-tumor treatments administered after progression/discontinuation,
disease status based on local CT/MRI assessment, and OS data will be collected
every 6 months in both arms.
End of the Study
The End of Study is after 4 years have elapsed from the randomization of the
last patient or 6 months after the last cross-over or re-treatment dose in
the study, whichever occurs last. The time window to start cross-over or
re-treatment with Lutathera in this study is within 4 years after the last
patient
has been randomized. For patients in the Lutathera arm who progress beyond this
window, access to re-treatment with Lutathera may be granted via Post
Study Drug Supply (PSDS) programs.
Intervention
In this study, approximately 222 patients with advanced G2-3 GEP-NET will be
randomized (2:1 randomization ratio) to receive treatment with Lutathera (7.4
GBq or 200 mCi x 4 administrations every 8± 1 weeks; cumulative dose: 29.6 GBq
or 800 mCi) plus octreotide long-acting standard dose (30 mg every 8 weeks
during Lutathera treatment and every 4 weeks after last Lutathera treatment) or
octreotide long-acting high dose (60 mg every 4 weeks).
The investigational drug product Lutathera® (177Lu-DOTA0-Tyr3-Octreotate) will
be provided by the Sponsor. The Sponsor will also provide the 2.5% Lys-Arg
amino acid solution for infusion (if it can*t be compounded at the hospital
Pharmacy), as well as octreotide long-acting (Sandostatin® LAR Depot) for the
entire duration of the Treatment Phase (and optional Treatment Extension Phase
in case of cross-over) of the study. Patients will switch to prescribed drugs
in the follow up phase.
Anti-emetics, SRI imaging agents, short-acting octreotide or any other
supportive care medication will not be supplied by the Sponsor.
Study burden and risks
The study load for the test subject comprises:
23 visits of approximately 4 hours (group 1) or 20 visits of approximately 2
hours during the treatment phase. The subject should stay overnight in the
hospital after administration of Lutathera (minimum of 1 night).
Physical examination: combined 8 times in the screening phase and treatment
phase and every 12 weeks after the treatment period.
Measuring vital functions: combined 10 times in the screening phase and
treatment phase and every 12 weeks after the treatment period. 6 times extra in
the optional treatment phase.
Measuring heart ejection fraction: 1 time during screening.
Blood sample collection: 15 times combined in the screening phase and treatment
phase and every 12 weeks after the treatment period (15-30 ml of blood per
visit). 10 times extra in the optional treatment phase.
Pregnancy test: combined 4 times in the screening phase and treatment phase. 4
times extra in the optional treatment phase.
SRI-SCAN (PET scan): 1 time during screening (unless completed in the last 3
months before screening). 1 extra time in the optional treatment phase.
CT / MRI scan: combined 7 times in the screening phase and treatment phase and
every 12 weeks after the treatment period. 3 times extra in the optional
treatment phase.
ECG: 5 times in the screening phase and treatment phase. 5 times extra in the
optional treatment phase. The subject is asked to complete in 3 questionnaires
about the quality of his or her life.
Risks and inconveniences for the test subject
The subject is exposed to radiation and may experience physical and / or
psychological discomfort from the aforementioned tests, procedures and
questionnaires. For a comprehensive risk analysis, see the subjects'
information section 6 "possible side effects, risks and discomforts on pages 6
and 7 and Annex D, page 19, for less common side effects. Appendix E, pages
20-21, shows the risks and inconveniences of the measurements and actions that
are performed in this study. Below are the most common side effects.
Study drug treatment (study group 1) The most common side effects of
radioactivity are a decrease in the number of blood cells, mainly red blood
cells, platelets and other blood cells such as white blood cells. Due to a
decrease in the number of different blood cells, there are risks of bleeding,
fatigue, shortness of breath, and infection.
The most common side effect with amino acid solution: nausea (in approximately
1 in 4 subjects), vomiting (in approximately 1 in 10 subjects) and
hyperkalaemia (an increased level of potassium in the blood).
High dose Octreotide treatment (study group 2)
The most serious side effects are allergic reactions, stomach pain, nausea /
vomiting, feeling restless or dizzy, yellowing of the skin or whites of the
eyes of the patient, acute pancreatitis (sudden, severe pain in the lower
abdomen).
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Listed location countries
Age
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following
criteria:
1. Presence of metastasized or locally advanced, inoperable (curative intent)
histologically proven, well differentiated Grade 2 or Grade 3
gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months
prior to screening.
2. Ki67 index >=10 and <= 55%.
3. Patients >=15 years of age and a body weight of >40 kg at screening.
4. Expression of somatostatin receptors on all target lesions documented by
CT/MRI scans, assessed by any of the following somatostatin receptor imaging
(SRI) modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g.
Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging
or [68Ga]-DOTA-TATE PET/CT (or MRI
when applicable based on target lesions) imaging (e.g. NETSPOT®) or
Somatostatin Receptor scintigraphy (SRS) with 111In-pentetreotide (Octreoscan®
SPECT/CT), SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when
applicable based on target lesions) imaging.
5. The tumor uptake observed in the target lesions must be > normal liver
uptake observed on planar imaging.
6. Karnofsky Performance Score (KPS) *60.
7. Presence of at least 1 measurable site of disease.
8. Patients who have provided a signed informed consent form to participate in
the study, obtained prior to the start of any protocol related activities.
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion
in this study.
1. Creatinine clearance <40 mL/min calculated by the Cockroft Gault method.
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets
<75x109/L (75x103/mm3).
3. Total bilirubin >3 x ULN.
4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy or lactation.
6. A Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, are not allowed to participate in this study
UNLESS they are using highly effective methods of contraception throughout the
study treatment period (including cross-over and re-treatment, if applicable)
and for 6 months after study drug discontinuation. Sexually active male
patients, unless they agree to remain abstinent (refrain from heterosexual
intercourse) or be willing to use effective methods of contraception with
female partners of childbearing potential or pregnant female partners during
the treatment period (including cross-over and re-treatment, if applicable) and
for 6 months after study drug discontinuation. In addition, male patients must
refrain from donating sperm during this same period.
7. Peptide receptor radionuclide therapy (PRRT) at any time prior to
randomization in the study.
8. Documented RECIST progression to previous treatments for the current GEP-NET
at any time prior to randomization.
9. Patients for whom in the opinion of the investigator other therapeutic
options (eg chemo-, targeted therapy) are considered more appropriate than the
therapy offered in the study, based on patient and disease characteristics.
10. Any previous therapy with Interferons, Everolimus (mTOR-inhibitors),
chemotherapy or other systemic therapies of GEP-NET administered for more than
1 month and within 12 weeks prior to randomization in the study.
11. Any previous radioembolization, chemoembolization and radiofrequency
ablation for GEP-NET.
12. Any surgery within 12 weeks prior to randomization in the study.
13. Known brain metastases, unless these metastases have been treated and
stabilized for at least 24 weeks, prior to screening in the study. Patients
with a history of brain metastases must have a head CT or MRI with contrast to
document stable disease prior to randomization in the study.
14. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with
history of congestive heart failure who do not violate this exclusion criterion
will undergo an evaluation of their cardiac ejection fraction prior to
randomization, via echocardiography. The results from an earlier assessment
(not exceeding 30 days prior to randomization) may substitute the evaluation at
the discretion of the Investigator, if no clinical worsening is noted. The
patient*s measured cardiac ejection fraction in these patients must be >40%
before randomization.
15. QTcF > 470 msec for females and QTcF > 450 msec for males or congenital
long QT syndrome.
16. Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%.
17. Hyperkaleamia >6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to
study enrolment.
18. Any patient receiving treatment with short-acting octreotide, which cannot
be interrupted for 24 h before and 24 h after the administration of Lutathera,
or any patient receiving treatment with SSAs (eg octreotide long-acting), which
cannot be interrupted for at least 6 weeks before the administration of
Lutathera.
19. Patients with any other significant medical, psychiatric, or surgical
condition, currently uncontrolled by treatment, which may interfere with the
completion of the study.
20. Prior external beam radiation therapy to more than 25% of the bone marrow.
21. Current spontaneous urinary incontinence.
22. Other known co-existing malignancies except non-melanoma skin cancer and
carcinoma in situ of the uterine cervix, unless definitively treated and proven
no evidence of recurrence for 5 years.
23. Patient with known incompatibility to CT Scans with I.V. contrast due to
allergic reaction or renal insufficiency. If such a patient can be imaged with
MRI, then the patient would not be excluded.
24. Hypersensitivity to any somatostatin analogues, the IMPs active substance
or to any of the excipients.
25. Patients who have participated in any therapeutic clinical study/received
any investigational agent within the last 30 days.
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 |
|---|---|
| EU-CTR | CTIS2023-507443-10-00 |
| EudraCT | EUCTR2019-001562-15-NL |
| ClinicalTrials.gov | NCT03972488 |
| CCMO | NL71110.078.19 |