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.
Participants must have histologically confirmed diagnosis of Extrapulmonary High-Grade Neuroendocrine Neoplasms (HGNENs) for which there is no known standard therapy capable of extending life expectancy.
Age >= 18 years.
Participants with neuroendocrine prostate cancer may continue ongoing LHRH agonist therapy.
Participants with bone metastases or hypercalcemia who began intravenous bisphosphonate treatment prior to study entry may continue this treatment while on study.
Participants with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 14 days prior to the first drug administration. Additionally, FDA-approved hormonal therapy for the treatment or prevention of other malignancies (e.g., breast cancer, prostate cancer) may be continued where in the opinion of the investigator stopping such therapies may increase the risk of disease progression. Potential drug-drug interactions with the hormonal agent will be assessed by the investigator prior to enrollment.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to belinostat, cisplatin, etoposide or other agents used in study. Participants with a history of allergic reactions to medications containing polysorbate 80 will be evaluated on a case-by-case basis.
Participants with treated brain metastases are not eligible except if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
Participants who have not recovered (CTCAE <= grade 1) from non heme adverse events due to prior treatments, except for alopecia, or stable grade 2 tinnitus (not interfering with ADL's) or baseline hearing loss by audiometry or stable grade 2 sensory neuropathy (moderate symptoms; limiting instrumental ADL) without pain or motor component, and not interfering with ADL's.
Parallel
Belinostat
Drug400mg/m\^2/24h or 600 mg/m\^2/24h IV over (48h continuous infusion) on days 1, 2 and 3 based on UGT1A1 status
Cisplatin
Drug60 mg/m\^2 IV over 60 minutes on day 2
Etoposide
Drug80 mg/m\^2 IV over 60 minutes on day 2 after infusion of cisplatin and again on days 3 and 4
To determine if pharmacogenomic intervention can normalize the area under the curve (AUC) at cycle 6 between UGT1A1*28 and UGT1A1*60 genotypes) of belinostat administered as a continuous 48 h infusion in combination with cisplatin and etoposide
Identified as the PK parameter of interest.
To determine efficacy with respect to objective response rate of belinostat administered as a continuous 48 h infusion in combination with cisplatin and etoposide
Objective response rate will be assessed by CT/MRI scans, calculated by Kaplan-Meier method, reporting the median values of each.
To determine the progression-free survival (PFS) and overall survival (OS) of belinostat administered as a continuous 48 h infusion in combination with cisplatin and etoposide
Progression free survival and overall survival calculated by Kaplan-Meier method, reporting the median values of each.
To assess duration of response of belinostat administered as a continuous 48 h infusion in combination with cisplatin and etoposide in platinum sensitive
Duration of response will be calculated by the Kaplan-Meier method, starting at date response was identified until progression or the response is declared to have ended, if the participants have a PR or CR.
To assess duration of response of belinostat maintenance
Duration of response will be calculated by the Kaplan-Meier method, starting at date response was identified until progression or the response is declared to have ended, if the participants have a PR or CR.
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