Belinostat for Neuroendocrine Carcinoma
Recruiting in Palo Alto (17 mi)
Overseen byJaydira Del Rivero, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: UGT1A1 inhibitors, CYP3A4 inhibitors
Disqualifiers: Brain metastases, Cardiovascular disease, others
No Placebo Group
Prior Safety Data
Approved in 1 Jurisdiction
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.
12345What 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.
56789Eligibility 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.
+10 more
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.
+11 more
Trial 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)
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Arm 2Experimental Treatment3 Interventions
Belinostat at 600 mg/m\^2/day plus Cisplatin plus Etoposide
Group II: Arm 1Experimental Treatment3 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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
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]Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies.
Efficacy of adding high-dose In-111 octreotide therapy during Sandostatin treatment in patients with disseminated neuroendocrine tumors: clinical results of 14 patients. [2013]This study aimed to assess the outcome of high-dose In-111 octreotide treatment and efficacy of long-acting Sandostatin LAR in patients with disseminated neuroendocrine tumors.
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]The standard-of-care for advanced small cell lung cancer (SCLC) is chemotherapy with cisplatin+etoposide (C+E). Most patients have chemosensitive disease at the outset, but disease frequently relapses and limits survival. Efforts to improve therapeutic outcomes in SCLC and other neuroendocrine cancers have focused on epigenetic agents, including the histone deacetylase inhibitor belinostat. The primary objective was to determine the maximum tolerated dose of the combination of belinostat (B) with C+E. Belinostat was administered as a 48-h continuous intravenous infusion on days 1-2; cisplatin was administered as a 1-h intravenous infusion on day 2; and etoposide was administered as a 1-h intravenous infusion on days 2, 3, and 4. Twenty-eight patients were recruited in this single-center study. The maximum tolerated dose was belinostat 500 mg/m/24 h, cisplatin 60 mg/m, and etoposide 80 mg/m. The combination was safe, although some patients were more susceptible to adverse events. Hematologic toxicities were most commonly observed. Objective responses were observed in 11 (39%) of 28 patients and seven (47%) of 15 patients with neuroendocrine tumors (including SCLC). Patients carrying more than three copies of variant UGT1A1 (*28 and *60) had higher serum levels of belinostat because of slower clearance. DNA damage peaked at 36 h after the initiation of belinostat, as did global lysine acetylation, but returned to baseline 12 h after the end of infusion. The combination of B+C+E is safe and active in SCLC and other neuroendocrine cancers. Future phase II studies should consider genotyping patients for UGT1A1*28 and UGT1A1*60 and to identify patients at an increased risk of adverse events.
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]Label="PURPOSE">The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors.
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]Label="BACKGROUND">The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results.
Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). [2022]To review the response and outcomes of (177)Lu-DOTA-octreotate chemoradionuclide therapy (LuTate PRCRT) in patients with neuroendocrine tumour (NET) expressing high levels of somatostatin receptors with uncontrolled symptoms or disease progression.
Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review. [2022]In the last decades, the incidence of neuroendocrine neoplasia (NEN) increased from 1 to 5 new diagnoses/100,000 persons/year. The synthetic somatostatin analogues (SSAs) represent the first-choice treatment for both functionally active and inactive gastro-enteric-pancreatic NEN. This systematic review examines the role of octreotide long-acting release (LAR) in combination with other therapies for NEN management.
Somatostatin Analogue Therapy in MEN1-Related Pancreatic Neuroendocrine Tumors from Evidence to Clinical Practice: A Systematic Review. [2021]Neuroendocrine neoplasms (NENs) are relatively rare and complex tumors that can be sporadic or hereditary, as in the context of multiple endocrine neoplasia type 1 (MEN1) where patients display a 70% lifelong risk of developing a pancreatic NENs (pNENs). To date, specific personalized treatment for pNENs in patients with MEN1 are lacking. The aim of this study was to systematically analyze the efficacy and safety of somatostatin analogue (SSA) treatment in patients affected by MEN1-related pNENs. We performed a systematic review of the literature, searching for peer-reviewed articles on SSA (octreotide or lanreotide) treatment in MEN1 associated with pNENs. We selected 20 studies with a pooled population of 105 MEN1 patients with pNENs. Females were 58.5%, median age was 44 years (18-73). TNM stage at diagnosis was stage I-II in 84.8% and stage IV in 15.2%. The overall response rate (SD+PR+CR) was achieved in 88.3% of cases, with stable disease in 75.6% and objective response in 12.7% of patients. The safety profile was favorable with both SSA agents. SSAs appear to be an effective and safe treatment option for MEN1-related pNEN, either at localized or advanced stages.
Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. [2023]Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.