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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether people with high-grade neuroendocrine carcinomas (a type of cancer that can occur in various body parts) respond better to different doses of belinostat (also known as Beleodaq or PXD101) when combined with etoposide and cisplatin. Researchers aim to determine if adjusting belinostat doses based on gene variants can improve treatment outcomes. This trial may suit adults with these cancers who lack other standard treatment options to extend life expectancy. Participants will receive the drugs through an IV over 21-day cycles, with regular check-ups and tests to monitor progress.

As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that belinostat is generally safe. One study found that belinostat does not harm the bone marrow when combined with other chemotherapy drugs. This finding is significant because bone marrow issues are a common concern with many cancer treatments.

The FDA has approved belinostat for treating a type of lymphoma, indicating it has been tested and found safe for that condition. In the BELIEF clinical trial, 129 patients received belinostat, and the most common side effects were mild.

Overall, belinostat appears to be well-tolerated by patients. However, individual responses can vary, and side effects may differ. Patients should always discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for neuroendocrine carcinoma, which typically involve chemotherapy drugs like cisplatin and etoposide, Belinostat introduces a new mechanism by inhibiting histone deacetylase (HDAC). This action can potentially alter gene expression in cancer cells, making them more susceptible to treatment. Researchers are excited about Belinostat because it could enhance the effectiveness of existing chemotherapy drugs, possibly leading to better outcomes for patients. Additionally, the trial is investigating two different dosing strategies, which may help identify the most effective and tolerable regimen for patients.

What evidence suggests that this trial's treatments could be effective for neuroendocrine carcinoma?

This trial will evaluate the effectiveness of Belinostat combined with cisplatin and etoposide for treating high-grade neuroendocrine carcinomas (HGNEC). Participants will be assigned to one of two arms: Arm 1 will receive Belinostat at 400 mg/m²/day, and Arm 2 will receive Belinostat at 600 mg/m²/day, both with cisplatin and etoposide. Research has shown that Belinostat, when combined with cisplatin and etoposide, may improve survival rates compared to cisplatin alone. In one study, patients lived a median of 13 months, and 56% were still alive after one year. Additionally, nearly half of the patients with neuroendocrine tumors responded well to the treatment. Belinostat works by blocking a process that helps cancer cells grow and spread. ^{1 4 6 7 8}

Who Is on the Research Team?

Jaydira Del Rivero, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 continuing my hormone therapy for neuroendocrine prostate cancer.

My organs and bone marrow are functioning well.

I can take care of myself but might not be able to do heavy physical work.

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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]

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]

Citations

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Phase II study of Belinostat (PXD101), a histone ... The median survival of 13 months and a 1-year survival rate of 56% with the combination were superior when compared to monotherapy with cisplatin in a ...

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Anticancer clinical efficiency and stochastic mechanisms of ... The molecular mechanisms investigated underline the clinical efficacy of Belinostat as an HDAC inhibitor for various cancers.

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Phase I trial of belinostat with cisplatin and etoposide in ... Objective responses were observed in 11 (39%) of 28 patients and seven (47%) of 15 patients with neuroendocrine tumors (including SCLC). Patients carrying more ...

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The histone deacetylase inhibitor belinostat (PXD101 ... Herein, we show that belinostat treatment inhibited cell growth and proliferation in a dose-dependent fashion and caused cell cycle arrest in ...

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Complexation of histone deacetylase inhibitor belinostat to ... Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, ...

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A phase I study of the safety and pharmacokinetics of the ... This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and ...

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Belinostat (Beleodaq) - Medical Clinical Policy Bulletins Median times to progression and survival were 5.8 and 19.1 months, respectively. Survival of patients with thymoma was significantly longer than that of ...

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Beleodaq (Belinostat) Receives FDA Approval for the ... The safety of belinostat was assessed in 129 patients with relapsed or refractory PTCL in the BELIEF clinical trial. Adverse reactions of any severity level ...