Cessation of Somatostatin Analogues for Neuroendocrine Tumors

(STOPNET Trial)

Recruiting at 8 trial locations

Overseen By Julia Kuszewki

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 20 months

78 Participants Needed

Trial Summary

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. ^{1 2 3 4 5}

Is it safe to stop taking somatostatin analogues for neuroendocrine tumors?

Somatostatin analogues (SSAs) are generally safe and well-tolerated for treating neuroendocrine tumors, with most side effects being mild and manageable. Common side effects include diarrhea, which should be monitored, but severe adverse events are rare. ^{6 7 8 9 10}

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. ^{11 12 13 14 15}

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.

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

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

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
• Continuation of somatostatin analogues

Trial Overview The 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

Group I: Cease SSA Experimental Treatment 1 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 SSA Active Control 1 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.

Who Is Running the Clinical Trial?

Australasian Gastro-Intestinal Trials Group

Lead Sponsor

Trials

26

Recruited

8,000+

Canadian Cancer Trials Group

Collaborator

Trials

135

Recruited

70,300+

Findings from Research

In a study of 35 patients with progressive neuroendocrine tumors (NET), somatostatin analogues led to a partial response in 3% of patients and disease stabilization in 57% for a median duration of 11 months.

Patients with slower tumor progression (less than 50% increase in lesion size over 3 months) had a significantly better response to treatment compared to those with rapid progression, suggesting that somatostatin analogues may be more effective as a first-line treatment for certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Aparicio, T., Ducreux, M., Baudin, E., et al.[2019]

A phase III trial showed that octreotide long-acting repeatable (LAR) 30 mg significantly prolongs time to tumor progression in patients with metastatic midgut neuroendocrine tumors (NETs), indicating its efficacy as an antiproliferative agent.

Patients with low tumor burden are particularly likely to benefit from octreotide LAR, suggesting that early intervention with this treatment may be advantageous for those with metastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. Strosberg, J., Kvols, L.[2021]

Somatostatin analogs, particularly octreotide, have become crucial in treating neuroendocrine tumors, especially in advanced stages where surgery is not an option.

The development of slow-release formulations of somatostatin analogs allows for less frequent dosing and may help prevent resistance, indicating a promising direction for future treatment strategies that may combine these analogs with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New therapeutic strategies in gastroenteropancreatic neuroendocrine tumours]. Colao, A., Pulcrano, M., Dorato, M., et al.[2013]

Somatostatin analogs (SSAs) are effective in managing symptoms caused by hormone production in patients with gastrointestinal and pancreatic neuroendocrine tumors (GEP NETs), although their tumor-shrinking effects are less pronounced compared to other conditions like acromegaly.

Patients with progressive, non-functional GEP NETs who have positive octreotide scintigraphy and a low proliferation index may benefit from first-line treatment with SSAs, highlighting the need for better understanding of tumor biology and the development of new SSAs with improved receptor affinity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The antiproliferative effect of somatostatin analogs: clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours. Verslype, C., Carton, S., Borbath, I., et al.[2016]

In a study of 43 patients with pancreatic neuroendocrine tumors treated with octreotide, somatostatin analogues (SSA) demonstrated significant antiproliferative effects, with a median time to tumor progression of 13 months.

Patients with a lower proliferation index (Ki67 <10%) experienced a more durable response to treatment, suggesting that SSA can be an effective first-line therapy for managing metastatic pancreatic NET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of octreotide long-acting release on tumour growth control as a first-line treatment in neuroendocrine tumours of pancreatic origin. Jann, H., Denecke, T., Koch, M., et al.[2013]

Somatostatin analogues (SSAs) are effective for treating neuroendocrine tumors (NETs) and have a favorable safety profile, but they require careful monitoring due to specific side effects.

A comprehensive safety monitoring protocol has been developed for outpatient settings, emphasizing the importance of gallbladder imaging, laboratory tests, vital signs, and detailed assessments of gastrointestinal side effects, particularly diarrhea, to ensure patient safety during long-term SSA therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Acting Somatostatin Analogue Safety Monitoring Protocol for Outpatients With Neuroendocrine Tumors. Gabrielsen, J., Girone, G., Bennett, B., et al.[2021]

Escalated doses of somatostatin analogues are generally well-tolerated in patients with metastatic gastroenteropancreatic neuroendocrine tumors, showing significant disease control rates (30-100%) but modest tumor response rates (0-14%).

The most common side effects include fatigue, diarrhea, abdominal discomfort, and gallstones, with no severe or unexpected toxicities compared to standard doses, highlighting the need for further large-scale studies to better understand the efficacy and safety of higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Escalated-dose somatostatin analogues for antiproliferative effect in GEPNETS: a systematic review. Chan, DL., Ferone, D., Albertelli, M., et al.[2018]

Somatostatin analogs (SSAs) significantly improve disease control in advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), with a hazard ratio of 0.41 indicating a strong reduction in disease progression compared to placebo in a meta-analysis of 289 patients.

While SSAs have a good safety profile overall, they are associated with a higher risk of biliary stones compared to placebo, highlighting the need for monitoring this specific adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiproliferative effect of somatostatin analogs in advanced gastro-entero-pancreatic neuroendocrine tumors: a systematic review and meta-analysis. Merola, E., Panzuto, F., Delle Fave, G.[2018]

Somatostatin analogues (SSA) are safe and well tolerated for treating neuroendocrine neoplasms, with a very low rate of severe adverse events and treatment discontinuation.

Targeted therapies and peptide receptor radionuclide therapy (PRRT) also have manageable safety profiles, though PRRT may carry risks of severe renal and hematologic toxicity, highlighting the importance of monitoring cumulative toxicity in long-term treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of available treatments options for neuroendocrine tumors. Faggiano, A., Lo Calzo, F., Pizza, G., et al.[2017]

In a study of 140 patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET) who had disease progression on previous treatments, high doses of somatostatin analogs (HD-SSA) resulted in a median progression-free survival of 31 months, indicating significant efficacy as a second-line treatment.

The treatment was found to be safe, with only 15% of patients experiencing adverse events, and no patients discontinued treatment due to these side effects, suggesting that HD-SSA could be a viable option for managing progressive GEP-NET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor. Lamberti, G., Faggiano, A., Brighi, N., et al.[2020]

Oncologists must carefully evaluate when to stop active cancer treatments, especially when they no longer provide a clear benefit to the patient, emphasizing the importance of patient involvement in treatment decisions.

The distinction between curative treatments and palliative care is crucial; while curative treatments may be stopped upon achieving remission, palliative care should continue to focus on patient comfort regardless of treatment cessation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cessation of treatment in advanced cancer. Krakoff, IH.[2019]

In a study of 608 patients with metastatic colorectal cancer, drug holidays (DHs) were associated with improved overall survival compared to continuous treatment, suggesting that de-escalation strategies can be beneficial.

The research indicates that DHs and other non-continuous treatment strategies are safe and effective, allowing for better management of treatment-related toxicity and quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug Holidays and Overall Survival of Patients with Metastatic Colorectal Cancer. Garattini, SK., Basile, D., Bonotto, M., et al.[2021]

In a phase II study involving 116 patients with advanced non-small-cell lung cancer (NSCLC), the telomerase inhibitor imetelstat did not significantly improve progression-free survival (PFS) compared to observation, with median PFS of 2.8 months for imetelstat versus 2.6 months for control.

While imetelstat showed a trend toward improved median overall survival (14.3 months vs. 11.5 months), this was not statistically significant, and exploratory analysis suggested potential benefits for patients with short telomere length, indicating that further research is needed to explore this biomarker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Chiappori, AA., Kolevska, T., Spigel, DR., et al.[2020]

Vemurafenib and dabrafenib are effective treatments for BRAF V600E-mutant metastatic melanoma, but patients often face challenges like acquired drug resistance and toxicity, with resistance typically developing within 6-8 months.

A case study of an 89-year-old woman showed that after switching to an intermittent dosing regimen due to toxicity, she remained in complete clinical remission for 24 months after stopping vemurafenib, suggesting potential immune or epigenetic mechanisms at play.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ongoing Response in BRAF V600E-Mutant Melanoma After Cessation of Intermittent Vemurafenib Therapy: A Case Report. Dooley, AJ., Gupta, A., Middleton, MR.[2019]

A systematic review of 42 studies highlights that oncologists face significant challenges in deciding when to stop anticancer treatments, particularly molecular targeted agents (MTAs), as these drugs blur the lines between active treatment and palliative care.

Decisions to withdraw treatment are influenced by both clinical factors, like disease progression and side effects, and non-clinical factors, such as physicians' emotions and patients' hopes, indicating a need for clearer guidelines to support these complex decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Withdrawal of anticancer therapy in advanced disease: a systematic literature review. Clarke, G., Johnston, S., Corrie, P., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

[New therapeutic strategies in gastroenteropancreatic neuroendocrine tumours]. [2013]

4. Belgium pubmed.ncbi.nlm.nih.gov

The antiproliferative effect of somatostatin analogs: clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours. [2016]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of octreotide long-acting release on tumour growth control as a first-line treatment in neuroendocrine tumours of pancreatic origin. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Long-Acting Somatostatin Analogue Safety Monitoring Protocol for Outpatients With Neuroendocrine Tumors. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Escalated-dose somatostatin analogues for antiproliferative effect in GEPNETS: a systematic review. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Antiproliferative effect of somatostatin analogs in advanced gastro-entero-pancreatic neuroendocrine tumors: a systematic review and meta-analysis. [2018]

9. England pubmed.ncbi.nlm.nih.gov

The safety of available treatments options for neuroendocrine tumors. [2017]

10. United States pubmed.ncbi.nlm.nih.gov

Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Cessation of treatment in advanced cancer. [2019]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Drug Holidays and Overall Survival of Patients with Metastatic Colorectal Cancer. [2021]

13. England pubmed.ncbi.nlm.nih.gov

A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. [2020]

14. France pubmed.ncbi.nlm.nih.gov

Ongoing Response in BRAF V600E-Mutant Melanoma After Cessation of Intermittent Vemurafenib Therapy: A Case Report. [2019]

15. England pubmed.ncbi.nlm.nih.gov

Withdrawal of anticancer therapy in advanced disease: a systematic literature review. [2022]