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Neuroendocrine TumorsPhase 2/3LUTIANCT03590119

Intra-arterial Lutetium-177-dotatate for Treatment of Patients With Neuro-endocrine Tumor Liver Metastases

A Phase 2/3 study testing Lutetium Lu 177-DOTATATE in people with Neuroendocrine Tumors and Liver Metastases, run by Marnix Lam at 3 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The objective is to investigate the impact of intra-arterial administration of 177Lu-dotatate on the intrahepatic biodistribution in patients with NET liver metastases. Our primary objective is to evaluate if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Neuroendocrine Tumors, Liver Metastases
What is being tested?
Lutetium Lu 177-DOTATATE
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
26 participants
Where
3 sitesNetherlands
Study dates
1 Aug 2018to 1 Sep 2022
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have given written informed consent.
  • Female or male aged 18 years and over.
  • Inoperable histologically proven neuro-endocrine tumor with indication for 177Lu-dotatate at enrollment time.
  • Well-differentiated neuro-endocrine tumor with a Ki67-index ≤20% and a mitotic count of ≤20.
  • Confirmed presence of somatostatin receptors on target lesions, based on somatostatin receptor imaging.
  • Life expectancy of 6 months or longer.
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  • Eastern Cooperative Oncology Group (ECOG) performance score 0-1.
  • Hepatic metastases with at least one lesion ≥3 cm on cross sectional imaging in both the right and left liver lobe (i.e. left and right lobes are based on the hepatic arterial perfusion territory).
  • Presence of excessive liver metastases, defined as >25% tumor load, with or without extrahepatic metastases.
  • Patients must have clinical or radiological progressive disease.
  • Negative pregnancy test for women of childbearing potential.

Who cannot join

  • Any previous radioembolization, chemoembolization, or bland embolization, at any time, or surgery or radiofrequency ablation (or other ablative therapies) within 12 weeks prior to randomization in the study.
  • Prior external beam radiation therapy to the liver.
  • Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
  • Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 hours before and 24 hours after the administration of 177Lu-dotatate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 4 weeks before the administration of 177Lu-dotatate, unless the tumor uptake on target lesions observed by imaging during continued Octreotide LAR treatment is higher than normal liver uptake.
  • Any unresolved toxicity greater than National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE version 4.03) grade 2 from previous anti-cancer therapy.
  • Serum bilirubin > Upper Limit of Normal (ULN), serum albumin <3.0 g/dL.
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  • Glomerular filtration rate <50 ml/min.
  • Hb <5.5 mmol/L; leucocytes <3.0x109/L; platelets <100x109/L (at baseline; 75x109/L is sufficient for cycles 2-4).
  • Uncontrolled congestive heart failure (NYHA II, III, IV).
  • Uncontrolled diabetes mellitus.
  • Patients suffering from diseases with an increased chance of liver toxicity.
  • Patients suffering from psychic disorders that make a comprehensive judgement impossible, such as psychosis, hallucinations and/or depression. Patients who are declared incompetent.
  • Previous enrolment in the present study or previous treatment with 177Lu-dotatate.
  • Female patients who are not using an acceptable method of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation) OR are less than 1 year postmenopausal or surgically sterile during their participation in this study (from the time they sign the consent form) to prevent pregnancy.
  • Male patients who are not surgically sterile or do not use an acceptable method of contraception during their participation in this study (from the time they sign the consent form) to prevent pregnancy in a partner.
  • Body weight over 150 kg.
  • Current spontaneous urinary incontinence.
  • Severe allergy for i.v. contrast (Visipaque®), used for CT evaluation and treatment angiography.

Trial locations and contacts

3 sites in 1 country.

Netherlands3 sites

  • Antoni van Leeuwenhoek Cancer Institute

    Amsterdam

  • Erasmus MC

    Rotterdam

  • University Medical Center Utrecht

    Utrecht

Other trials in Netherlands

About this study

The objective is to investigate the impact of intra-arterial administration of 177Lu-dotatate on the intrahepatic biodistribution in patients with NET liver metastases. Our primary objective is to evaluate if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe.

Read the detailed description

Rationale: The majority of neuroendocrine tumor (NET) patients present with metastases, most often including liver metastases. These patients have a poorer prognosis and lower quality of life.

Currently, intravenous administered somatostatin-bound radionuclides (177Lu-dotatate) have shown to improve tumor response rates and progression free survival (PFS). Despite of the increased tumor response rate and PFS, liver metastases still remain the major cause of morbidity and mortality in these patients. Patients with liver metastases have a worse outcome in terms of overall survival after treatment with 177Lu-dotatate compared to patients with limited or no liver metastases.

Objective: to investigate the impact of intra-arterial (IA) administration of 177Lu-dotatate on the intrahepatic biodistribution in patients with NET liver metastases. Our primary objective is to evaluate if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe.

Study design: Multicenter, interventional, block randomized, phase 2 clinical trial. We use a within-subject controlled design where the administration of 177Lu-dotatate is randomized between the right or left hepatic artery. Selective IA administration of 177Lu-dotatate allows for intra-patient comparison between IA administration (one lobe) versus IV 'administration' (the other lobe). The contralateral liver lobe and the rest of the body receive treatment by second pass IV route.

Study population: 26 patients with NET liver metastases (> 18 years old). Intervention: Treatment will be randomized between selective right or left hepatic artery administration of 177Lu-dotatate (Four administrations of 7.4 GBq; each via the same randomly allocated hepatic artery during angiography).

Main study parameters/endpoints: To assess if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe. The T/N activity concentration will be measured on SPECT/CT. The primary endpoint will be assessed after the first treatment cycle. The T/N activity ratios of the second, third, and final treatment cycle will be assessed as secondary endpoint. Tumor response, toxicity, extrahepatic uptake and kidney uptake are secondary endpoints. Intra- and inter-patient differences will be studied.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: As with the standard IV treatment with 177Lu-dotatate, the treatment consists of four cycles. During each cycle, patients will be admitted for 1 night and undergo physical examination, laboratory examination, angiography with administration of the treatment dose, and post-treatment imaging. Risks include standard complication risks related to angiography (bleeding or infection). No additional risks with relation to the treatment itself are expected compared to the standard IV treatment (nausea, vomiting).

Being tested
Lutetium Lu 177-DOTATATE
Keywords
LUTIA, neuroendocrine tumor, lutetium-177-dotatate, intra-arterial, liver metastases
Medical subject headings
Neuroendocrine Tumors

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Lutetium Lu 177-DOTATATEDrug

    Also called Lutathera

    Intra-arterial infusion of Lu-177-DOTATATE

Study groups in NCT03590119
Study groupRoleWhat they receive
Intra-arterially treated liver lobeExperimentalDepending on the allocation after randomization, Lu-177-dotatate will be infused in either the left or the right hepatic artery, following catheterization using the Seldinger-technique.
Receives: Drug: Lutetium Lu 177-DOTATATE
'Intravenously' treated liver lobeActive comparatorThe lobe that is not treated intra-arterially, will act as the intravenously treated lobe, due to the first-pass effect.
Receives: Drug: Lutetium Lu 177-DOTATATE

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe.

    To assess if there is a difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe. The T/N activity concentration will be measured on SPECT/CT. The primary endpoint will be assessed after the first treatment cycle. For each liver lobe up to three tumors (i.e. all >3 cm) will be selected based on size (i.e. the largest lesions without central necrosis). The weighted average activity per voxel of these lesions will be divided by the normal liver tissue mean activity per voxel (i.e. a VOI with 3 cm diameter will be placed in the normal liver tissue) to calculate the T/N ratio. The T/N activity ratios of the second, third, and final treatment cycle will be assessed as secondary endpoint. Intra- and inter-patient differences will be studied.

    Measured: 24 hours

Secondary outcomes (7)

  1. The difference in absolute values of mean tumor and healthy liver absorbed dose on post-treatment SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe

    Difference in absolute values of mean tumor and healthy liver absorbed dose (in Gy) on post-treatment SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe: Dosimetry will be performed to measure mean tumor and healthy liver absorbed dose. Dosimetry will be performed on post-treatment SPECT/CT, which is performed 24 hours after administration of 177Lu-dotatate. The absolute absorbed dose in the IA treated liver lobe will be compared to the IV treated lobe.

    Measured: 24 hours

  2. The difference in post-treatment tumor response between the intra-arterial treated liver lobe and the intravenous treated liver lobe

    -Difference in post-treatment tumor response between the intra-arterial treated liver lobe and the intravenous treated liver lobe: The tumors are measured on CT and scored according to the Southwest Oncology Group (SWOG) solid tumor response criteria, RECIST 1.1, and mRECIST criteria. Scoring systems will be applied on the patient and liver level, separately.

    Because the eventual maximal shrinkage of the tumors may take months after completion of the therapy, we added the tumor response class 'minimal response (MR)', pertaining to a decrease in summed squares of tumor diameter more than 25% but less than 50%.

    Measured: 3 and 6 months

  3. The dose-response relation between tumor absorbed dose and post-treatment tumor response

    To assess if there is a dose-response relation between tumor absorbed dose and post-treatment tumor response: The tumor absorbed dose in both the IA and IV treated liver lobe will be calculated based on SPECT/CT as mentioned above. Tumor response will be measured on post-treatment follow-up imaging. With these parameters, a possible dose-response relation will be evaluated.

    Measured: 3 and 6 months

  4. Toxicity and how toxicity is compared to historical controls

    To assess safety and toxicity according to the common toxicity criteria on adverse events (CTCAE) version 4.03. The grade of toxicity refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE. Especially myelo-toxicity, renal toxicity and hepatic toxicity will be evaluated.

    Measured: 6 months

  5. Sufficient uptake of 177Lu-dotatate in extrahepatic lesions

    To assess if there is sufficient uptake of 177Lu-dotatate in extrahepatic lesions (comparison will be made with historical data): The 177Lu-dotatate uptake of the extrahepatic lesions (e.g. pancreas, intestine) will be calculated on post-treatment SPECT/CT. These results will be compared to historical data in order to evaluate if these extrahepatic tumor sites show sufficient uptake.

    Measured: 24 hours

  6. Sufficient uptake of 177Lu-dotatate in the contralateral lobe, compared to historical controls

    To assess if there is sufficient uptake of 177Lu-dotatate in the contralateral lobe (comparison will be made with historical data): The 177Lu-dotatate uptake of the contralateral lobe will be calculated on post-treatment SPECT/CT. These results will be compared to historical data in order to evaluate if the other lobe shows sufficient uptake.

    Measured: 24 hours

  7. The difference in kidney uptake of 177Lu-dotatate between the IA treated patients and historical controls

    To assess if there is a difference in kidney uptake of 177Lu-dotate between the IA treated patients and historical controls: Kidney uptake will be calculated on post-treatment SPECT/CT and compared to historical controls in order to assess differences in uptake.

    Measured: 24 hours

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jul 2018
  2. Study start1 Aug 2018
  3. Primary completion1 Sep 2022
  4. Study completion1 Sep 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
This study uses a with-in subject randomization between intra-arterial treatment via the left or right hepatic artery.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
26 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03590119
Sponsor's protocol ID
NL60725.041.17
Acronym
LUTIA
Status last verified
Nov 2022
First submitted
3 Jul 2018
Last updated
8 Nov 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Ebbers SC, Braat AJAT, Moelker A, Stokkel MPM, Lam MGEH, Barentsz MW. Intra-arterial versus standard intravenous administration of lutetium-177-DOTA-octreotate in patients with NET liver metastases: study protocol for a multicenter, randomized controlled trial (LUTIA trial). Trials. 2020 Feb 5;21(1):141. doi: 10.1186/s13063-019-3888-0.

    PubMed 32024533

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Lutetium Lu 177-DOTATATE in people with Neuroendocrine Tumors and Liver Metastases, run by Marnix Lam at 3 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The difference in post-treatment tumor-to-non-tumor (T/N) activity concentration ratio on SPECT/CT between the intra-arterial treated liver lobe and the intravenous treated liver lobe. (time frame: 24 hours). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03590119, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Nov 2022.

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