A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity
- Conditions
- Carcinoma, NeuroendocrineTumor, NeuroendocrineTumors, NeuroendocrineNeuroendocrine; CarcinomaSmall Cell; Receptors
- Interventions
- Registration Number
- NCT06406465
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
Background:
* Poorly differentiated neuroendocrine carcinomas (NECs) are all high-grade carcinomas that resemble small cell carcinoma or large cell NEC of the lung. Poorly differentiated NECs are often associated with a rapidly progressive disease and a proliferative rate (Ki67%) \>20%.
* As a general rule, poorly differentiated NECs are treated with platinum-based regimens according to small cell carcinoma guidelines.
* This protocol will study a continuous infusion of the histone deacetylase (HDAC) inhibitor belinostat in combination with cisplatin and etoposide for patients with advanced neuroendocrine carcinomas.
Objective:
-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 in participants with neuroendocrine malignancies based on UGT1A1\*28 and UGT1A1\*60 genotypes.
Eligibility:
* The protocol will be open to participants with Extrapulmonary High-Grade Neuroendocrine Carcinomas (HGNECs)
* Participants must not have received more than one prior systemic therapy
* Participants will be recruited based on genotype, with n=9 carrying UGT1A1\*1/\*1 or UGT1A1\*1/\*28 and n=30 carrying any other combination of variant alleles at UGT1A1\*28 or UGT1A1\*60.
* Age \>=18 years
* ECOG Performance Status 0-2
Design:
* Parallel design in which the starting dose of belinostat is administered as a 48-hour continuous infusion at two possible doses based on genotype: 1) 400mg/m\^2/day for UGT1A1\*28/\*28 or at least one UGT1A1\*60 allele UGT1A1\*28 and UGT1A1\*60 genotypes or 2) 600 mg/m\^2/day for wild-type participants and those carrying UGT1A1\*1/\*28 in the absence of other variant alleles.
* To define pharmacokinetics, toxicities of belinostat provided to participants who carry the above genotype groups.
* All participants will also receive cisplatin at 60 mg/m2 IV on day 2, and etoposide at 80 mg/m\^2 IV daily x3 on days 2 - 4.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 60
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1 Belinostat Belinostat at 400 mg/m\^2/day plus Cisplatin plus Etoposide Arm 1 Cisplatin Belinostat at 400 mg/m\^2/day plus Cisplatin plus Etoposide Arm 1 Etoposide Belinostat at 400 mg/m\^2/day plus Cisplatin plus Etoposide Arm 2 Belinostat Belinostat at 600 mg/m\^2/day plus Cisplatin plus Etoposide Arm 2 Cisplatin Belinostat at 600 mg/m\^2/day plus Cisplatin plus Etoposide Arm 2 Etoposide Belinostat at 600 mg/m\^2/day plus Cisplatin plus Etoposide
- Primary Outcome Measures
Name Time Method 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 ... Cycles 1-6 pre- and post- treatment with belinostat with all doses Identified as the PK parameter of interest.
- Secondary Outcome Measures
Name Time Method To assess duration of response of belinostat maintenance Every 9 weeks while on monotherapy. Total study therapy will not exceed 5 years. 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 administered as a continuous 48 h infusion in combination with cisplatin and etoposide in platinum sensitive Until progression or the response is declared to have ended , if the participants have a PR or CR. Until 3 years after last participant enrolled. 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 determine efficacy with respect to objective response rate of belinostat administered as a continuous 48 h infusion in combination with cisplatin and etoposide Every 9 weeks while on study therapy 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 PFS will be assessed from on-study date until date of progression or death without progression. Overall survival (OS) will be calculated from the on-study date until date of death. Until 3 years after last participant enrolled. Progression free survival and overall survival calculated by Kaplan-Meier method, reporting the median values of each.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States