Belinostat for Neuroendocrine Carcinoma

Overseen By Anna L Rivero

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: UGT1A1 inhibitors, CYP3A4 inhibitors

Disqualifiers: Brain metastases, Cardiovascular disease, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

Duration: 18 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: High-grade neuroendocrine carcinomas (HGNEC) are cancers that develop in different parts of the body, including the digestive tract, genitals, neck, and head. One drug (belinostat), combined with 2 other drugs (etoposide and cisplatin), is approved to treat HGNEC. But some people may have a gene variant that affects how quickly their body gets rid of the drug; these people may do better with different dosages of belinostat. Objective: To test higher or lower doses of belinostat based on gene variants in people with HGNEC. Eligibility: People aged 18 years and older with HGNEC. Design: Participants will be screened. They will have a physical exam with blood tests. Some blood will be used for genetic testing. They will have imaging scans and a test of their heart function. Samples of tumor tissue may be collected. All 3 study drugs (belinostat, etoposide, cisplatin) are given through a tube attached to a needle inserted into a vein. Treatment will be given in 21-day cycles. For cycles 1 through 6: Participants will come to the clinic for the first 4 days. They will be given all 3 drugs. Imaging scans and other tests will be repeated. Each visit will last 4 to 8 hours. After cycle 6: Participants may continue treatment with belinostat alone. They will come to the clinic for the first 3 days of each cycle. They may continue treatment for up to 5 years if the drug is helping them. Participants will have a follow-up visit 30 days after their last dose of belinostat. Then they will receive follow-up visits by phone or email every 3 to 6 months.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you must stop taking strong UGT1A1 or CYP3A4 inhibitors or inducers at least 5 half-lives before starting the trial. If you are on hormonal therapy for other cancers, you may continue if stopping it could increase the risk of disease progression.

Is Belinostat safe for humans?

Belinostat has been tested in combination with other drugs for advanced solid tumors, including neuroendocrine cancers, and was generally found to be safe, though some patients experienced side effects, especially related to blood cell counts. The maximum tolerated dose was identified, and patients with certain genetic variants may be at higher risk for side effects. ^{1 2 3 4 5}

What makes the drug Belinostat unique for treating neuroendocrine carcinoma?

Belinostat is unique because it is a histone deacetylase inhibitor, which means it works by altering the expression of certain genes to stop cancer cell growth, a different mechanism compared to the commonly used somatostatin analogues for neuroendocrine tumors. ^{5 6 7 8 9}

Research Team

Jaydira Del Rivero, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults with high-grade neuroendocrine carcinomas (HGNEC) are eligible for this trial. Participants must be over 18 and have a specific gene variant that affects drug metabolism, which will be determined through genetic testing. They should also have adequate organ function and not be receiving other cancer treatments.

Inclusion Criteria

I am 18 years old or older.

I am continuing my hormone therapy for neuroendocrine prostate cancer.

My organs and bone marrow are functioning well.

Exclusion Criteria

Participants who have not recovered from non-heme adverse events due to prior treatments

I have a serious heart condition.

I am not currently taking any specific inhibitors or will stop them before the trial starts.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive belinostat, etoposide, and cisplatin in 21-day cycles for up to 6 cycles

18 weeks

4 visits per cycle (in-person)

Maintenance Treatment

Participants may continue treatment with belinostat alone if beneficial, for up to 5 years

Up to 5 years

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Follow-up visits every 3 to 6 months (phone or email)

Treatment Details

Interventions

• Belinostat

Trial Overview The study is examining the effects of varying doses of belinostat based on participants' gene variants, alongside standard chemotherapy drugs etoposide and cisplatin. The treatment involves multiple cycles, with potential continuation up to five years if beneficial.

Participant Groups

Group I: Arm 2 Experimental Treatment 3 Interventions

Belinostat at 600 mg/m\^2/day plus Cisplatin plus Etoposide

Group II: Arm 1 Experimental Treatment 3 Interventions

Belinostat at 400 mg/m\^2/day plus Cisplatin plus Etoposide

Belinostat is already approved in United States for the following indications:

Approved in United States as Beleodaq for:

• Peripheral T-cell lymphoma (PTCL)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Entinostat, an oral HDAC inhibitor, was well tolerated in a phase I trial with 21 pediatric patients, showing no dose-limiting toxicities at doses of 3 mg/m2 and 4 mg/m2, indicating a favorable safety profile for this age group.

The recommended phase 2 dose (RP2D) for entinostat in children with relapsed or refractory solid tumors is established at 4 mg/m2, with pharmacokinetic studies revealing a significantly higher drug exposure in children compared to adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN). Bukowinski, A., Chang, B., Reid, JM., et al.[2022]

In a study of 14 patients with disseminated neuroendocrine tumors, high-dose In-111 octreotide treatment resulted in stable disease in 50% of patients and a partial response in 14%, indicating some efficacy in managing the disease.

The combination of high-dose In-111 octreotide and long-acting Sandostatin LAR was well-tolerated, suggesting that this treatment approach can be safely administered to patients with neuroendocrine tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of adding high-dose In-111 octreotide therapy during Sandostatin treatment in patients with disseminated neuroendocrine tumors: clinical results of 14 patients. Ozkan, E., Tokmak, E., Kucuk, NO.[2013]

The combination of belinostat with cisplatin and etoposide (C+E) is safe and shows activity in treating advanced small cell lung cancer (SCLC), with 39% of patients responding positively to the treatment.

The study identified a maximum tolerated dose for the combination therapy and highlighted the importance of genotyping patients for UGT1A1 variants, as those with more than three copies had higher serum levels of belinostat, which could influence treatment outcomes and adverse event risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. Balasubramaniam, S., Redon, CE., Peer, CJ., et al.[2020]

In a phase I study involving 51 patients with advanced solid tumors, the combination of belinostat and 13-cis-retinoic acid was well-tolerated, with no maximum tolerated dose (MTD) reached even at doses higher than the established MTD for belinostat alone.

The treatment showed promising results, with ten patients experiencing stable disease and partial responses in two patients, indicating potential efficacy of this combination therapy in managing advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. Luu, T., Frankel, P., Beumer, JH., et al.[2020]

In the phase 3 NETTER-1 trial involving 231 patients with advanced midgut neuroendocrine tumors, the addition of 177Lu-Dotatate to long-acting octreotide did not significantly improve overall survival compared to high-dose long-acting octreotide alone, with median overall survival times of 48.0 months versus 36.3 months, respectively.

Long-term safety results showed that only 3% of patients in the 177Lu-Dotatate group experienced serious treatment-related adverse events, and no new safety concerns were identified during follow-up, indicating that the treatment has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Strosberg, JR., Caplin, ME., Kunz, PL., et al.[2022]

In a study of 68 patients with neuroendocrine tumors (NET) treated with (177)Lu-DOTA-octreotate chemoradionuclide therapy (LuTate PRCRT), 70% of those with uncontrolled symptoms experienced sustained benefits for at least 6 months, indicating its efficacy in symptom management.

Among patients with disease progression, 68% showed stabilization or regression of their tumors on imaging, and achieving objective responses was linked to improved overall survival, highlighting the potential of LuTate PRCRT combined with 5-FU chemotherapy in treating advanced NET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Kong, G., Thompson, M., Collins, M., et al.[2022]

A systematic review of 13 studies involving 1,206 patients found that octreotide long-acting release (LAR) combined with other therapies achieved an 85% disease control rate in advanced neuroendocrine neoplasia (NEN).

Patients receiving octreotide LAR had a progression-free survival (PFS) of 15 to 16.4 months and an overall survival (OS) ranging from 25 to 61.9 months, with the treatment being well tolerated and associated with few mild side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review. Rinzivillo, M., De Felice, I., Magi, L., et al.[2022]

In a systematic review of 20 studies involving 105 patients with MEN1-related pancreatic neuroendocrine neoplasms (pNENs), somatostatin analogues (SSAs) demonstrated an overall response rate of 88.3%, indicating they are effective in managing these tumors.

The safety profile of SSAs, such as octreotide and lanreotide, was favorable, suggesting that they are a safe treatment option for patients with MEN1-related pNENs, regardless of whether the disease is localized or advanced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Somatostatin Analogue Therapy in MEN1-Related Pancreatic Neuroendocrine Tumors from Evidence to Clinical Practice: A Systematic Review. La Salvia, A., Sesti, F., Grinzato, C., et al.[2021]

The combination of everolimus (RAD001) and octreotide LAR showed promising antitumor activity in patients with advanced neuroendocrine tumors, achieving a 20% response rate and a median progression-free survival of 60 weeks across 60 enrolled patients.

The treatment was well tolerated, with the most common side effect being mild aphthous ulceration, and significant reductions in tumor proliferation markers were observed, indicating a potential mechanism of action for the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. Yao, JC., Phan, AT., Chang, DZ., et al.[2023]

References

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

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN). [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

Efficacy of adding high-dose In-111 octreotide therapy during Sandostatin treatment in patients with disseminated neuroendocrine tumors: clinical results of 14 patients. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung. [2020]

4. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial. [2020]

5. England pubmed.ncbi.nlm.nih.gov

177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). [2022]

7. China pubmed.ncbi.nlm.nih.gov

Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Somatostatin Analogue Therapy in MEN1-Related Pancreatic Neuroendocrine Tumors from Evidence to Clinical Practice: A Systematic Review. [2021]

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

Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. [2023]