Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Neuroendocrine

Carcinoma, Small Cell

Neuroendocrine Tumors

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Adenocarcinoma

Neoplasms, Nerve Tissue

Small Cell Lung Cancer

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Etoposide

Cisplatin

Belinostat

Etoposide phosphate

Enzyme Inhibitors

Histone Deacetylase Inhibitors

Belinostat at 400 mg/m\^2/day plus Cisplatin plus Etoposide

Belinostat at 600 mg/m\^2/day plus Cisplatin plus Etoposide

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

80 mg/m\^2 IV over 60 minutes on day 2 after infusion of cisplatin and again on days 3 and 4

Kimberley J Cooper

Jaydira Del Rivero, M.D.

Kimberley Cooper

NCI Medical Oncology Referral Office

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.

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.

A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity

.This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic data sharing. @@@@@@@@@@@@This study will comply with the NIH Genomic Data Sharing (GDS) Policy, which applies to all new and ongoing NIH IRP-funded research, as of January 25, 2015, that generates large-scale human or non-human genomic data, as well as the use of these data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene expression data.

Identified as the PK parameter of interest.

Objective response rate will be assessed by CT/MRI scans, calculated by Kaplan-Meier method, reporting the median values of each.

Progression free survival and overall survival calculated by Kaplan-Meier method, reporting the median values of each.

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.

National Cancer Institute (NCI)

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Carcinoid Tumor

Pancreatic Neuroendocrine Tumor

Proteasome Inhibitors

Carfilzomib will be administered as intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle.

Cycle 1: First two doses of Carfilzomib 20 mg/m2 IV; subsequent doses at 56 mg/m2 IV

Cycle 2 onwards: Carfilzomib 56 mg/m2 IV

Carfilzomib

David Spigel, M.D.

The purpose of this study is to determine if carfilzomib is safe and effective in the treatment of patients with advanced neuroendocrine tumors.

Neuroendocrine malignancies such as pancreatic neuroendocrine tumors (PNETs) and gastrointestinal (GI) carcinoids, are generally rare but their incidences are increasing. In vitro and in vivo studies have shown that proteasome inhibitors have activity against a variety of tumor types. Carfilzomib (Kyprolis®) is an irreversible proteasome inhibitor with a favorable safety profile that has been studied in a variety of hematologic and solid tumors. Carfilzomib received accelerated approval from the U.S. FDA in 2012, based on a favorable response rate, for the treatment of patients with multiple myeloma who received at least two prior therapies, and demonstrated disease progression within 60 days of completing the last therapy. In this multi-center study, the investigators propose to evaluate carfilzomib for the treatment of patients with advanced neuroendocrine cancers.

Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers

Phase II Study of Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers

Percentage of participants with confirmed complete response (CR) or partial response (PR) (i.e. 2 CRs or PRs at least 4 weeks apart) to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) CR=disappearance of all target lesions. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) (≥ 6 cycles) according to RECIST v1.1 criteria. Complete Response is defined per RECIST as the disappearance of all target/non-target lesions and normalization of tumor markers. Partial Response is defined per RECIST as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease is defined per RECIST as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest (nadir) sum LD since the treatment started.

Measured from Day 1 of study drug administration to disease progression as defined by RECIST v1.1, or death on the study. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or unequivocal progression of non-target lesions or the appearance of one or more new lesions. Patients who did not have disease progression or death documented were censored on the date of the last visit with adequate assessment.

The number of treatment-emergent adverse events will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03

Amgen

SCRI Development Innovations, LLC

All patients who received at least one dose of protocol treatment were followed for safety. Adverse events and serious adverse events were collected from the day of the first dose to 30 days after the last dose of the study medication and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.

Cycle 1: First two doses of Carfilzomib 20 mg/m\^2 IV; subsequent doses at 56 mg/m2 IV

Cycle 2 onwards: Carfilzomib 56 mg/m\^2 IV

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Full analysis set - all enrolled patients who receive at least one full or partial dose of the study group and who have measurable disease at baseline

Sarah Cannon Development Innovations, LLC

All enrolled patients who received at least one full or partial dose of the study drug and who had measurable disease at baseline were included in the analysis.

Overall Response Rate (ORR)

Disease Control Rate (DCR)

Progression Free Survival (PFS)

All enrolled patients who received at least one full or partial dose of the study drug.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity	NCT06406465	Carcinoma, Neur... Tumor, Neuroend... Tumors, Neuroen... Neuroendocrine;... Small Cell; Rec...	Belinostat Cisplatin Etoposide	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers	NCT02318784	Neuroendocrine ...	Carfilzomib	18 Years -	SCRI Development Innovations, LLC

Spots Global Cancer Trial Database for neuroendocrine malignancies