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Cessation of Somatostatin Analogues After PRRT in Mid, Hind-Gut and Pancreatic Neuroendocrine Tumours

PHASE2RECRUITING

Neuroendocrine tumours (NETs) are slow growing cancers, which commonly present as metastatic incurable disease. Some neuroendocrine tumours, termed functional NETs, overproduce hormones which result in a variety of symptoms. However, approximately 75% of NETs are considered non-functional meaning that they do not result in hormone overproduction.

The main treatment for both functional and non-functional NETs is somatostatin analogues (SSA, a type of inhibitory hormone). These drugs slow tumour growth and reduce hormone production. Over time, the majority of patients will experience tumour growth despite treatment with SSA therapy.

When this occurs, the addition of Peptide Receptor Radionuclide Therapy (PRRT, a type of targeted radiotherapy) in combination with ongoing SSA therapy is given. However, it is not known if continuing SSA therapy after commencement of PRRT is beneficial or not. The aim of this study is to estimate the outcomes of patients with grade 1 and 2 well differentiated mid, hind-gut or pancreatic neuroendocrine tumours who have progressed on SSA therapy and receive subsequent PRRT with or without concurrent SSA.

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Study details:

Neuroendocrine tumours commonly originate from the gut and metastasise widely including to the liver, lymph nodes and bones. Originally called "carcinoid tumours", these cancers are most commonly treated with somatostatin analogues (SSA) first line. These analogues treat carcinoid syndrome and slow tumour growth.

Despite SSA therapy, progression develops over time. Upon progression, peptide receptor radionuclide therapy (PRRT) is the next standard therapeutic option. After PRRT is initiated, it is unclear if continuing SSA injections is beneficial.

There are reasons to believe it might be necessary to continue SSAs, but other reasons to believe they should cease. Given that SSA injections are expensive and associated with side effects, this study aims to clarify the utility of continuing SSA injections after progression on SSA therapy and commencement of PRRT. STOPNET aims to explore outcomes in grade 1 and 2 mid, hind gut or pancreatic neuroendocrine tumours, that have progressed on SSA therapy, are eligible to receive PRRT and in whom the SSA is either continued or ceased after PRRT is commenced.

The two primary objectives include. 1. To estimate the 20-month progression free survival rate after PRRT commencement in patients who cease and who continue SSA.

2. Feasibility as measured by:. 1.

Recruitment rate and. 2. Patient acceptance of ceasing and staying off SSA over the 20 month follow up period.

The study design of STOPNET is prospective, randomised, non-comparative, open label, multicentre phase II study. Patients meeting the inclusion and exclusion criteria will be randomised, prior to commencing PRRT, to either continue or cease SSA treatment. Randomisation will occur centrally in REDCap by the AGITG STOPNET study team.

Randomisation will be 2:1 (the majority being randomised to cease SSA) and will be stratified by WHO tumour grade (1 V 2), sites of metastases (visceral only verse visceral and bone) and institution.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Adults over 18 years of age with well or moderately differentiated mid or hindgut neuroendocrine tumour, or pancreatic neuroendocrine tumour, metastatic and inoperable, demonstrating progression despite SSA treatment of sufficient disease magnitude to warrant PRRT as determined by the treating clinician and/or the NET Multidisciplinary Team (MDT).

Must have measurable disease on triphasic CT/MRI as per RECIST 1.1.

Ki67 ≤ 20% AND mitotic count 20 per HPF (i.e., WHO grade 1 or 2)

Patient has been receiving growth-controlling doses of SSA for at least 12 weeks prior to study entry. This is a minimum of 30 mg Octreotide or120mg lanreotide monthly.

Uptake on SSTR PET scan demonstrating somatostatin receptor expression that is suitable for PRRT as judged by the clinical team. FDG PET scans are to be done at the judgement of the treating team and are not required for enrolment into this study.

PRRT is deemed the most appropriate next treatment step (i.e., patient is inoperable, and liver directed therapies are not preferred)

ECOG performance status 0 -2

Written informed consent. Patients must be willing to either cease or continue SSA, depending on which study arm they are randomised to. Patients must be willing to comply with all other study requirements

Adequate renal, hepatic and haematologic function as judged by the treating team

Life expectancy of at least 12 months

Availability of tissue from resection or biopsy samples is desired but is not mandatory for study inclusion. Tissues will only be retrieved if the patient consents to optional translational research sample collection. Similarly, bloods for research purposes will only be collected from those patients who consent to optional translational research sample collection.

Non-functioning NET: SSA treatment will have been commenced for control of tumour growth and not for carcinoid or other hormone overproduction syndrome, as judged by the clinician and/or NET MDT. Non-functioning NET is judged by the treating clinical team based on patient symptomatology. In addition, for this study, non-functioning tumour is defined as:

24-hour urine 5-hydroxyindoleacetic acid (5HIAA) of <1.5x upper limit of normal (applies to mid and hind gut patients only).

Please note: routine measurement of gastrin, insulin, C-peptide levels, glucagon etc. is not required unless clinically indicated.

Never had escalation of the SSA treatment dose to control carcinoid carcinoid or other hormone-related symptoms

Never required short acting SSA treatment to control carcinoid carcinoid or other hormone-related symptoms

No significant carcinoid induced valvular heart disease IE: Echocardiogram to be done in all patients within 26 weeks of study enrolment and deemed safe to proceed with PRRT by the treating team.

Exclusion criteria

This study is for pancreatic, mid-gut and hind-gut NET only. Gastric and lung NETs are excluded

Any patient on an SSA dose lower than the standard growth-control dose. Patients must have been on octreotide 30 mg or lanreotide 120 mg for at least 3 months prior to study entry.

Prior chemotherapy or targeted therapy (e.g., everolimus). Patients who have received prior local therapy, including external beam radiotherapy and liver directed therapy prior to or during SSA therapy are eligible.

Any contraindication to PRRT, as per local institutional practice.

Pregnancy. For female patients of childbearing potential and male patients with a female partner who is of childbearing potential, contraception and counselling is required.

Prior PRRT. Patients being considered for re-treatment with PRRT are not eligible

Uncontrolled central nervous system metastases. Patients must have completed any surgery or radiation at least 4 weeks prior to registration and must be off corticosteroids for at least 2 weeks

Any patient, in the opinion of the investigator, who will not comply with study assessments and follow up visits. These might include any social, psychological, or geographical concerns, including alcohol/drug abuse

Any poorly controlled concurrent medical illness that may prevent the patient from complying with study assessments and follow up. This is to be judged by the treating team

Any concurrent or prior malignancy that, in the opinion of the treating team, may interfere with study assessments and endpoints

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-09-09

Primary completion: 2027-09-01

Study completion finish: 2028-06-01

Study type

TREATMENT

Phase

PHASE2

Trial ID

NCT06345079

Intervention or treatment

DRUG: Cessation of somatostatin analogues

DRUG: Continuation of somatostatin analogues

Conditions

• Neuroendocrine Tumors

Condition: Neuroendocrine Tumors
DRUG: Cessation of somatostatin analogues and other drugs
Brisbane, Queensland, Australia
Sponsor: Australasian Gastro-Intestinal Trials Group

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Find a site

Closest Location:

Royal Brisbane and Womens Hospital

Research sites nearby

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Royal Brisbane and Womens Hospital
Brisbane, Queensland, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Continue SSA Patients randomised to continue SSA will receive a SSA injection ≥28 days prior to the first PRRT cycle, during PRRT cycle, and every 4 weeks after completion of PRRT.	DRUG: Continuation of somatostatin analogues Patients randomised to continue SSA will receive a SSA injection ≥28 days prior to their first cycle of PRRT, during PRRT and will continue receiving SSA every 4 weeks after PRRT.
EXPERIMENTAL: Cease SSA Patients randomised to cease SSA will receive SSA injection ≥28 days prior to their first cycle of PRRT. Patients will not receive any further long acting SSA injections after this time.	DRUG: Cessation of somatostatin analogues Patients randomised to cease SSA will receive their last SSA injection ≥28 days prior to their first cycle of PRRT and will remain off SSA for the duration of the study. If there is concern from the treating team that a patient may experience a carcinoid flare after PRRT, then short acting octreotide is allowed to be used to control any symptoms.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
20-month progression free survival rate after PRRT	Estimate the 20-month progression free survival rate after PRRT in patients who cease and who continue SSA.	20 months
Assess the barriers which would impede the feasibility of a subsequent phase 3 trial	1. Proportion of participants that remained on the SSA cessation arm for the duration of the 20-month study follow up (patient acceptance of SSA cessation). 2. Rate of recruitment: ability to complete recruitment over the 24-month recruitment period	20 months

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Measure Quality of life using the European Organisation For Research And Treatment Of Cancer (EORTC) Core Quality of Life questionnaire (QLQ-C30) scales	Responses to the QLQ-C30 scale from 0-100 using EORTC guidelines, with higher scores reflecting better level of functioning.	20 months
Measure Quality of life using the EORTC QLQ-GINET21 scales	Responses to the QLQ-GINET21 scale from 0-100 using EORTC guidelines, with higher scores reflecting more severe symptoms.	20 months
Cost-effectiveness of SSA therapy cessation	Access to Medicare and PBS data to asses use of other healthcare providers, diagnostic tests and imaging services funded via public health care systems and use of pharmaceutical services respectively.	The MBS/PBS data will be obtained for the period six months prior to study entry, and until the end of 2 years follow-up post PRRT for patients who have provided consent.
Psycho-oncological impacts of SSA therapy cessation: Decision Regret	Psycho-oncological impacts of SSA therapy cessation using the self-reported measures of Decision Regret Scale from 1 - 5 (1-Strongly Agree, 2-Agree, 3-Neither Agree Nor Disagree, 4-Disagree, 5-Strongly Disagree)	20 months
Psycho-oncological impacts of SSA therapy cessation: Fear of Cancer Progression	Psycho-oncological impacts of SSA therapy cessation using the self-reported measures of the Fear of Cancer Progression Scale from 1 - 5 (1-Never, 2-Seldom, 3-Sometimes, 4-Often, 5-Very often)	20 months
Psycho-oncological impacts of SSA therapy cessation: Decisional Conflict	Psycho-oncological impacts of SSA therapy cessation using the self-reported measures of the Decisional Conflict Scale from 0 - 4 (0-Strongly Agree, 1-Agree, 2-Neither Agree Nor Disagree, 3-Disagree, 4-Strongly Disagree)	20 months
Time to commencement of subsequent therapy	Time to commencement of subsequent therapy (e.g re-challenge with PRRT, liver directed therapies, chemotherapy, targeted therapies)	20 months
Overall survival	Estimate the 20-month overall survival rate in patients who cease and who continue SSA.	20 months
Rates of SSA being recommenced over time	Cumulative percentage of SSA recommencement over time.	20 months

Frequently Asked Questions

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References

Clinical Trials Gov: Cessation of Somatostatin Analogues After PRRT in Mid, Hind-Gut and Pancreatic Neuroendocrine Tumours