Cessation of Somatostatin Analogues for Neuroendocrine Tumors
(STOPNET Trial)
Recruiting in Palo Alto (17 mi)
+7 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Australasian Gastro-Intestinal Trials Group
Must be taking: Somatostatin analogues
Must not be taking: Chemotherapy, Targeted therapy
Disqualifiers: Gastric, Lung NETs, Pregnancy, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
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.
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications, but you may need to either stop or continue your somatostatin analogue (SSA) treatment depending on which study group you are placed in.
What data supports the effectiveness of the drug somatostatin analogues for neuroendocrine tumors?
Research shows that somatostatin analogues can help stabilize tumor growth in patients with neuroendocrine tumors, especially those with a low tumor burden. In some studies, these drugs have been shown to prolong the time before the tumor progresses, making them a useful option for managing these types of tumors.12345
Is it safe to stop taking somatostatin analogues for neuroendocrine tumors?
How is the cessation of somatostatin analogues for neuroendocrine tumors different from other treatments?
The cessation of somatostatin analogues for neuroendocrine tumors is unique because it involves stopping the treatment when it is no longer effective or when the patient has achieved complete remission, which is not commonly defined in standard treatment protocols. This approach focuses on evaluating the necessity of continuing treatment based on the patient's response and overall health, rather than following a fixed treatment schedule.1112131415
Eligibility Criteria
Adults over 18 with certain slow-growing cancers called neuroendocrine tumors, which have worsened despite hormone-inhibiting treatment. They must be inoperable but stable enough for targeted radiotherapy, and their cancer should show on specific scans. Participants need to agree to possibly stop or continue current hormone therapy.Inclusion Criteria
I've been on SSA therapy for my condition for at least 12 weeks.
PRRT is considered my best treatment option because surgery and liver treatments aren't suitable for me.
Life expectancy of at least 12 months
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Exclusion Criteria
My cancer is a pancreatic, mid-gut, or hind-gut neuroendocrine tumor.
I have had chemotherapy or targeted therapy before.
Pregnancy. For female patients of childbearing potential and male patients with a female partner who is of childbearing potential, contraception and counselling is required
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive Peptide Receptor Radionuclide Therapy (PRRT) with or without concurrent Somatostatin Analogues (SSA) based on randomization
20 months
Every 4 weeks for SSA injections if continuing
Follow-up
Participants are monitored for progression-free survival and other outcomes after treatment
20 months
Extension
Exploratory analyses including biomarker validation and other secondary outcomes
20 months
Treatment Details
Interventions
- Cessation of somatostatin analogues (Hormone Therapy)
- Continuation of somatostatin analogues (Hormone Therapy)
Trial OverviewThe trial is testing whether it's beneficial to stop or continue hormone treatments (somatostatin analogues) after starting a targeted radiotherapy (PRRT) in patients whose neuroendocrine tumors have progressed despite previous treatment.
Participant Groups
2Treatment groups
Experimental Treatment
Active Control
Group I: Cease SSAExperimental Treatment1 Intervention
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.
Group II: Continue SSAActive Control1 Intervention
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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Ottawa Hospital Research InstituteOttawa, Canada
Odette Cancer Centre Sunnybrook Health Sciences CentreToronto, Canada
Allan Blair Cancer CentreRegina, Canada
Saskatoon Cancer CentreSaskatoon, Canada
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Who Is Running the Clinical Trial?
Australasian Gastro-Intestinal Trials GroupLead Sponsor
Canadian Cancer Trials GroupCollaborator
References
Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. [2019]A few studies have suggested an antitumour activity of somatostatin analogues in neuroendocrine tumours (NET). The aim of this study was to evaluate the antitumour efficacy of somatostatin analogues in patients with documented progressive tumours. 35 consecutive patients with documented tumour progression were treated with somatostatin analogues. Patients were classified into two groups. In Group 1, tumours were progressing rapidly (an increase of 50% or more in the lesion surface area in 3 months) and in Group 2, tumours were progressing more slowly (an increase of less than 50% in the lesion surface area in 3 months but greater than 25% in 6 months). Treatment consisted of subcutaneous (s.c.) octreotide, 100 microg thrice daily for 17 patients, intramuscular lanreotide, 30 mg/every 14 days for 11 patients and for 7 patients both somatostatin analogues were used successively during the follow-up. Primary tumour sites were the small intestine (n=12), pancreas (n=13), lungs (n=5), and other sites (n=5). 18 patients had the carcinoid syndrome with flushing and/or diarrhoea. The median duration of treatment was 7 months. Treatment was discontinued in 3 patients due to side-effects. One patient (3%) achieved a partial response and the disease was stabilised in 20 patients (57%) for a median duration of 11 months (6-48 months). Stabilisation of patients in Group 1 was significantly less frequent at 6 months than that of patients in Group 2 (4/12 and 13/17 respectively, P
Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. [2021]Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors. A phase III, randomized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolong time to tumor progression among patients with metastatic midgut NETs regardless of functional status, chromogranin A level or age. In addition to significantly lengthening time to tumor progression in the overall study population, subset analysis suggests that patients with low tumor burden are most likely to experience disease stabilization with octreotide LAR 30 mg, supporting the early use of octreotide LAR in patients with metastatic disease. Further research efforts are underway to evaluate the use of somatostatin analogs as antiproliferative agents in other types of gastroenteropancreatic-NETs. Ongoing studies are also evaluating novel somatostatin analogs and somatostatin analogs in combination with other anti-tumor therapies.
[New therapeutic strategies in gastroenteropancreatic neuroendocrine tumours]. [2013]Neuroendocrine tumours are frequently malignant and have often reached an advanced stage by the time of diagnosis when they are inoperable, accompanied by severe symptoms, sometimes of an endocrine nature. Current therapeutic procedures include surgery, embolisation of hepatic metastases, local radiotherapy, biotherapy and chemotherapy. Over the years somatostatin analogs, of which octreotide is the first form, have become increasingly important in the treatment of patients with neuroendocrine tumours. A major step forward in analog treatment is represented by the development of slow-release formulas which do not require multiple daily injections and reduce the onset of resistance. The treatment of neuroendocrine tumours in the future will be based on the increased use of somatostatin analogs alone or in association with interferon or chemotherapy, and will also include surgery, radiometabolic therapy and targeted irradiation of the tumour.
The antiproliferative effect of somatostatin analogs: clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours. [2016]Somatostatin analogs (SSAs) have an important role in the management of patients with neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP NETs). These compounds can control the symptoms induced by the production of hormones and peptides. The antiproliferative effects of SSAs and especially tumour shrinkage are less obvious in patients with GEP NETs than in those with acromegaly. However, based upon phase II experience there is a strong suggestion of a disease stabilizing effect of SSAs in selected patients. Those patients with a progressive, non-functional GEP NET, positive octreotide scintigraphy, a low proliferation index and in the absence of surgical options may benefit from a first-line medical therapy with SSAs. The exploration of the mechanisms of this effect are unclear and hampered by the lack of suitable preclinical models. The better understanding of the tumour biology of GEP NETs, together with the development of new SSAs with better affinity on all somatostatin receptors, represent an unmet medical need.
Impact of octreotide long-acting release on tumour growth control as a first-line treatment in neuroendocrine tumours of pancreatic origin. [2013]Somatostatin analogues (SSA) are widely used in the treatment of patients with functioning and non-functioning neuroendocrine tumours (NET). The aim of our investigation was to evaluate the antiproliferative effect of SSA in patients with pancreatic NET.
Long-Acting Somatostatin Analogue Safety Monitoring Protocol for Outpatients With Neuroendocrine Tumors. [2021]Somatostatin analogues (SSAs) are widely used in the long-term treatment of neuroendocrine tumors (NETs) and have a relatively favorable safety profile. However, SSAs are associated with specific side effects that are important to monitor. Currently, there is no standardized safety monitoring protocol for health-care professionals to use as a reference when initiating patients on long-acting SSAs. With the expansion of SSA use from symptomatic control to include antiproliferative tumor treatment in patients with NETs, it is increasingly important that patients taking these medications are properly monitored. The purpose of this analysis was to develop a comprehensive, practical SSA safety monitoring protocol for patients with NETs in the outpatient setting. This strategy was based on side effect frequencies that were reported and the monitoring parameters used in influential clinical and safety trials. Based on our assessment, we consider monitoring gallbladder imaging, laboratory tests (including blood chemistry, thyroid-stimulating hormone, hemoglobin A1c, and stool studies), vital signs, and physical examinations as the most important parameters when evaluating the safety of long-term SSA therapy. Due to the frequency at which patients experienced diarrhea as a side effect in clinical trials, questions about urgency, frequency, timing, consistency, odor, and color of bowel movements should be asked as part of the follow-up visits every 6 months to help differentiate between drug-induced vs. disease-associated causes. This broad monitoring strategy for patients receiving long-term SSAs was developed specifically for patients with NETs; however, the use of this protocol could be expanded to other indications in the future.
Escalated-dose somatostatin analogues for antiproliferative effect in GEPNETS: a systematic review. [2018]Somatostatin analogues are the cornerstone of systemic therapy for metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours for both hormonal control and antiproliferative effect. Dose escalation of somatostatin analogues is often utilized in clinical practice, but small studies have yielded mixed results. The aim of this study was to systematically determine the efficacy and safety of escalated-dose somatostatin analogues in the above setting.
Antiproliferative effect of somatostatin analogs in advanced gastro-entero-pancreatic neuroendocrine tumors: a systematic review and meta-analysis. [2018]A meta-analysis has systematically investigated the antineoplastic efficacy and safety of somatostatin analogs (SSAs) in advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Randomized controlled trials (RCTs) reporting the hazard ratio (HR) for disease progression (DP) were evaluated. Response rate and risk ratio (RR) for adverse events were also analyzed. A total of 289 patients (143 receiving SSAs vs. 146 placebo) were evaluated from two RCTs. A significant benefit from SSAs in terms of disease control was observed (HR 0.41, 95% CI: 0.29 to 0.58, P
The safety of available treatments options for neuroendocrine tumors. [2017]Neuroendocrine neoplasms (NEN) represent a heterogeneous group of malignancies generally characterized by low proliferation and indolent course. However, about half of the newly diagnosed cases are metastatic and require long-term systemic therapies. Areas covered: This review revises the literature to summarize the current knowledge upon safety of all systemic treatment options available. Thirty three different clinical studies have been considered, including 4 on somatostatin analogues (SSA), 5 on targeted therapies, 10 on peptide receptor radionuclide therapy (PRRT), and 14 on chemotherapy. Expert opinion: SSA are safe and well tolerated without any relevant severe adverse event and very low treatment discontinuation rate. Targeted therapies show a satisfying safety profile. Most adverse events are grade 1-2 and easy manageable with dose reduction or temporary interruption. PRRT is manageable and safe with a low rate of grade 3-4 adverse events. However, severe renal and hematologic toxicity may occur. Chemotherapy is usually considered after previous therapeutic lines. Therefore, these subjects are more susceptible to experience adverse events due to cumulative toxicities or poor performance status. The available systemic treatment options are generally well tolerated and suitable for long-term administration. Cumulative toxicity should be taken in account for the definition of therapeutic sequence.
Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor. [2020]To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment.
Cessation of treatment in advanced cancer. [2019]A major responsibility for all physicians, but particularly for oncologists, is to recognize the time when active antitumor treatment ceases to have a rational basis. The decision to treat or not to treat at any stage of disease requires an analysis of "the legitimate aims of therapy." We have acquired the ability to cure or prolong survival in an increasing proportion of patients with several types of cancer. For patients who fail to achieve those results and for those with tumors that are rarely amenable to specific therapy, the choice of less surely effective therapy is an option; the patient must participate in the decision, armed with as much information and insight as possible, for conventional and experimental treatment. A distinction must be made between specific antitumor therapy and palliative measures for which cessation is never an option. Happily, cessation of treatment must also be considered when therapy has been so successful that the patient has achieved complete remission. At what point may treatment be discontinued without the danger of relapse? These issues are rarely crisply defined, but primary concern for the patient and careful analysis of the available data can lead to appropriate value judgements.
Drug Holidays and Overall Survival of Patients with Metastatic Colorectal Cancer. [2021]Different de-escalation strategies have been proposed to limit the risk of cumulative toxicity and guarantee quality of life during the treatment trajectory of patients with metastatic colorectal cancer (mCRC). Programmed treatment interruptions, defined as drug holidays (DHs), have been implemented in clinical practice. We evaluated the association between DHs and overall survival (OS). This was a retrospective study, conducted at the University Hospital of Udine and the IRCCS CRO of Aviano. We retrieved records of 608 consecutive patients treated for mCRC from 1 January 2005 to 15 March 2017 and evaluated the impact of different de-escalation strategies (maintenance, DHs, or both) on OS through uni- and multivariate Cox regression analyses. We also looked at attrition rates across treatment lines according to the chosen strategy. In our study, 19.24% of patients received maintenance therapy, 16.12% DHs, and 9.87% both, while 32.07% continued full-intensity first-line treatment up to progression or death. In uni- and multivariate analyses first-line continuous treatment and early discontinuation (treatment for less than 3 months) were associated to worse OS compared to non-continuous strategies (HR, 1.68; 95% CI, 1.22-2.32; p = 0.002 and HR,4.89; 95% CI, 3.33-7.19; p < 0.001, respectively). Attrition rates were 22.8%, 20.61%, and 19.64% for maintenance, DHs, or both, respectively. For continuous therapy and for treatment of less than 3 months it was 21.57% and 49%. De-escalation strategies are safe and effective options. DHs after initial induction chemotherapy may be considered in clinically selected patients with metastatic colorectal cancer.
A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. [2020]Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC.
Ongoing Response in BRAF V600E-Mutant Melanoma After Cessation of Intermittent Vemurafenib Therapy: A Case Report. [2019]The selective BRAF inhibitors vemurafenib and dabrafenib yield high response rates and improved overall survival in patients with BRAF V600E-mutant metastatic melanoma. Treatment traditionally continues until disease progression or the development of unacceptable toxicity. Acquired drug resistance and toxicity are key challenges with the use of these drugs. Resistance to vemurafenib usually develops within 6-8 months. Management of drug toxicity typically involves stopping vemurafenib until resolution, before restarting at a lower dose, or permanently ceasing vemurafenib therapy. We have recently considered whether intermittent dosing could be used as an alternative to dose reduction/termination in the management of vemurafenib toxicity. One patient treated with intermittent vemurafenib was an 89-year-old woman with metastatic melanoma, who initially showed a good response to continuous dosing. Recurrent toxicity meant that the continuous vemurafenib dosage was repeatedly ceased before restarting at a lower dose. Ten months after vemurafenib was first begun, an intermittent dosing regimen was introduced in an attempt to control toxicity. This continued for 2 months, before cessation due to continued unacceptable toxicity. A further 24 months later, the patient remains fit and well in complete clinical remission, with no recurrence of her previous melanoma and no new primary malignancies. To the best of our knowledge, a continued response after the cessation of selective BRAF inhibitors has never before been described in melanoma. Induction of an immune response and/or epigenetic changes could explain continued disease response after cessation of vemurafenib therapy. Care should be taken when extrapolating the findings from the continued response after vemurafenib cessation to other tumour types. We recommend the collection and analysis of data to investigate the clinical responses seen after cessation of vemurafenib due to intolerable toxicities, which could help further explain vemurafenib's mechanism of action.
Withdrawal of anticancer therapy in advanced disease: a systematic literature review. [2022]Current guidelines set out when to start anticancer treatments, but not when to stop as the end of life approaches. Conventional cytotoxic agents are administered intravenously and have major life-threatening toxicities. Newer drugs include molecular targeted agents (MTAs), in particular, small molecule kinase-inhibitors (KIs), which are administered orally. These have fewer life-threatening toxicities, and are increasingly used to palliate advanced cancer, generally offering additional months of survival benefit. MTAs are substantially more expensive, between £2-8 K per month, and perceived as easier to start than stop.