Trial Title:
A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity
NCT ID:
NCT06406465
Condition:
Carcinoma, Neuroendocrine
Tumor, Neuroendocrine
Tumors, Neuroendocrine
Neuroendocrine; Carcinoma
Small Cell; Receptors
Conditions: Official terms:
Carcinoma
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Etoposide
Belinostat
Conditions: Keywords:
High-grade carcinomas
Resemble small cell carcinoma
Large cell NEC
Histone Deacetylase
Genotypes
Neuroendocrine malignancies
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Belinostat
Description:
400mg/m^2/24h or 600 mg/m^2/24h IV over (48h continuous infusion) on days 1, 2 and 3
based on UGT1A1 status
Arm group label:
Arm 1
Arm group label:
Arm 2
Intervention type:
Drug
Intervention name:
Cisplatin
Description:
60 mg/m^2 IV over 60 minutes on day 2
Arm group label:
Arm 1
Arm group label:
Arm 2
Intervention type:
Drug
Intervention name:
Etoposide
Description:
80 mg/m^2 IV over 60 minutes on day 2 after infusion of cisplatin and again on days 3 and
4
Arm group label:
Arm 1
Arm group label:
Arm 2
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.
Criteria for eligibility:
Criteria:
-INCLUSION CRITERIA:
1. Participants must have histologically confirmed diagnosis of Extrapulmonary
High-Grade Neuroendocrine Carcinomas (HGNECs) for which there is no known standard
therapy capable of extending life expectancy.
2. Age >= 18 years.
3. Participants with neuroendocrine prostate cancer may continue ongoing LHRH agonist
therapy.
4. Participants with bone metastases or hypercalcemia who began intravenous
bisphosphonate treatment prior to study entry may continue this treatment while on
study.
5. Evaluable (measurable or non-measurable) disease, per RECIST 1.1.
6. ECOG performance status <=2 at screening
7. Participants must have adequate organ and marrow function as defined below:
- Leukocytes >=3,000/mcL
- Hemoglobin >= 10 g/dL
- Absolute neutrophil count (ANC) >=1,500/mcL
- Platelets >=100,000/mcL
- Aspartate aminotransferase (AST) or serum glutamic-oxaloacetic transaminase
(SGOT) / Alanine aminotransferase (ALT) or serum glutamic-pyruvic transaminase
(SGPT): <=3 X institutional upper limit of normal
- Total bilirubin <= 1.5 x institutional upper limit of normal (ULN).
NOTE: In participants with Gilbert s syndrome, a total bilirubin <= 3.0 X ULN is
allowed
- Serum Creatinine <= 1.5 X institutional ULN OR
- An estimated Creatinine clearance (CrCL) >=60 mL/min/1.73 m^2 based on the
Cockcroft Gault equation
- Prothrombin time (PT) / International normalized ratio (INR) and Partial
thromboplastin time (PTT) <= 1 X institutional ULN
8. Hepatitis B virus (HBV)-infected participants can be enrolled if HBV DNA is
undetectable. Hepatitis C virus (HCV)-infected participants can be enrolled if HCV
RNA level is undetectable
9. Women of child-bearing potential (WOCBP) must agree to use effective contraception
(hormonal, intrauterine device (IUD), tube ligation, a partner has had a previous
vasectomy, abstinence) prior to study entry, during the study, and for 14 months for
women after the last dose of the study drug(s). Men with partners of childbearing
potential must agree to use effective contraception (abstinence, condoms, previous
vasectomy) or request partners to use effective contraception (per above) during the
study and for 11 months after the last dose of study therapy.
10. Breastfeeding participants must be willing to discontinue breastfeeding starting
with prior to study entry, during the study, and for 3 months after the last dose of
the study drug(s).
11. Willing to comply with study procedures and follow-up.
12. Participants must be able to understand and be willing to sign a written informed
consent document.
EXCLUSION CRITERIA:
1. 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.
2. 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.
3. 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.
4. 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.
5. Participants taking strong UGT1A1 inhibitors or CYP3A4 inhibitors or inducers must
discontinue their use a minimum of 5 half-lives prior to starting treatment on this
trial
6. Participants with platinum-refractory disease.
7. Participants who have had another histone deacetylase inhibitor (e.g., valproic
acid, vorinostat) for at least 2 weeks prior to enrollment.
8. Participants who have had radiation to the pelvis or other bone marrow-bearing sites
will be considered on a case-by-case basis and may be excluded if the bone marrow
reserve is not considered adequate (>25% of bone marrow).
9. Pregnancy (confirmed with beta-Human chorionic gonadotropin (HCG) serum or urine
pregnancy test performed in WOCBP at screening)
10. Significant cardiovascular disease (New York Heart Association Class III or IV
cardiac disease), myocardial infarction within the past 6 months, unstable angina,
unstable arrhythmia, or a need for anti-arrhythmic therapy (use of medication to
control heart rate in participants with atrial fibrillation is allowed, if stable
medication for at least last month prior to enrollment and medication not listed as
causing Torsade de Points), or evidence of acute ischemia on ECG.
11. Participants who have had more than one prior systemic therapy are not eligible
12. Baseline prolongation of QT/QTc interval, i.e., defined as an average QTc interval >
450 msec calculated using the Fridericia formula for QT correction; Long QT
Syndrome; or the required use of concomitant medication that may cause Torsade de
Pointes.
13. Participants with HIV infection if CD4 count <200 cells per cubic millimeter before
treatment initiation
14. Uncontrolled intercurrent illness that would limit compliance with study
requirements.
Gender:
All
Minimum age:
18 Years
Maximum age:
120 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Contact:
Last name:
Kimberley Cooper
Phone:
240-858-7989
Email:
kimberley.cooper@nih.gov
Contact backup:
Last name:
NCI Medical Oncology Referral Office
Phone:
(240) 760-6050
Email:
ncimo_referrals@mail.nih.gov
Start date:
November 17, 2024
Completion date:
July 30, 2028
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Institutes of Health Clinical Center (CC)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06406465
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_001601-C.html
