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)

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Mouth Neoplasms

Squamous Cell Carcinoma of Head and Neck

Oropharyngeal Neoplasms

Neoplasms, Squamous Cell

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Mouth Diseases

Oral Cancer

Anticonvulsants

Central Nervous System Depressants

Psychotropic Drugs

Valproic Acid

Neurotransmitter Agents

Milena P Mak, MD

The purpose of this study is to evaluate if the addition of valproic acid to standard platinum-based chemoradiation as definitive treatment of locally advanced Head and Neck squamous cell carcinoma can improve treatment outcomes, such as response rate.

Valproic acid is a known histone deacetylase inhibitor. In addition to activating apoptosis pathways, cell differentiation and downregulating expression of growth factors, it also promotes radiosensitization.

Most patients with Head and Neck squamous cell carcinoma are diagnosed with locally advanced disease, in which long term disease control is still a challenge. The incorporation of epigenetic regulation into standard treatment could improve results of definitive platinum-based chemoradiation in such patients.

Valproic Acid and Platinum-based Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma

Efficacy Evaluation of the Combination of Valproic Acid and Standard Platinum-based Chemoradiation in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma

University of Sao Paulo

Instituto do Cancer do Estado de São Paulo

Symptoms and General Pathology

Blood and Lymph Conditions

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Azacitidine

Decitabine

Panobinostat

Antimetabolites

LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 40 mg/day three times a week on nonconsecutive days for the first 2 weeks in a 28 day cycle.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was Level 5B.

Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

LBH589

Geoffrey Uy, M.D.

This study is designed to evaluate the combination of LBH589 and decitabine in patients age ≥ 60 years with high risk Myelodysplastic Syndrome (IPSS Int-2 or High) or Acute Myeloid Leukemia.

To address the need for less toxic, more effective treatments for older patients with advanced MDS and AML, the purpose of this Phase 1-2 single institution study is to evaluate the safety and efficacy of LBH 589 and decitabine administered in combination.

Decitabine is an epigenetic modifier of gene expression that has been shown to be well-tolerated in this population at the dose schedule proposed in this study, with reasonable efficacy. Although its precise mechanism of action is incompletely understood, it is postulated to work by reactivating the expression of key tumor suppressor genes silenced in tumor cells by reversing a pattern of hypermethylation of promotor elements.

LBH389 is likewise an epigenetic modifier that inhibits the deacetylation of both histones and non-histone proteins, including HSP90 and p53. Although clinical experience with LBH589 in AML is limited, aberrant histone deacetylase activity has been previously shown to play a significant role in the pathogenesis of AML. The addition of LBH589 to a decitabine regimen of previously established efficacy and tolerability will allow us to evaluate the hypothesis that two epigenetic modifiers that are believed to work through distinct mechanisms of action may act together to improve the responses of patients treated with decitabine alone, without significant additional toxicity.

LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)

A Phase I/II Study of LBH589 Plus Decitabine for Patients Age ≥ 60 Years With High Risk MDS or AML

* Morphologic complete remission (CR). A CR designation requires that the patient achieve the morphologic leukemia-free state with less than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods or persistence of extramedullary disease. Patients must also have an absolute neutrophil count of more than 1,000/μLand platelets of 100,000/μL.
* Cytogenetic complete remission (CRc). A CRc will be defined by the achievement of a CR with reversion to a normal karyotype in a minimum of 20 metaphases analyzed by cytogenetics.
* Morphologic complete remission with incomplete blood count recovery (CRi): Achievement of all of the criteria for CR except for residual neutropenia (\< 1,000/μL) or thrombocytopenia (\< 100,000/μL).

Cytogenetic complete remission (CRc). A CRc will be defined by the achievement of a CR with reversion to a normal karyotype in a minimum of 20 metaphases analyzed by cytogenetics.

-The FACT-Leu consists of a 27-item compilation of general questions divided into four primary quality of life domains: physical well-being, social/family well being, emotional well-being, and functional well-being along with a 17 item subscale developed specifically for patients with leukemia.

Time to response is defined as the date of the first dose of study drug to the date that all criteria for CR or CRi are fulfilled.

Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0.

Defined as the first date that all criteria for CR, CRi or HI are fulfilled to the date of treatment failure, relapse from CR, or death due to any cause.

Event-free survival is defined as the interval from the date of first dose of study drug to date of treatment failure, relapse from CR, or death due to any cause.

Overall survival is defined as the date of first dose of study drug to the date of death from any cause.

Morphologic complete remission with incomplete blood count recovery (CRi): Achievement of all of the criteria for CR except for residual neutropenia (\< 1,000/μL) or thrombocytopenia (\< 100,000/μL).

-Hematologic improvement (HI). Includes the following categories:

* Erythroid response: Hemoglobin increase by ≥ 1.5 g/dL over baseline in which the pretreatment hemoglobin is \< 11 g/dL or reduction of RBC transfusions of at least 4 RBC transfusions / 8 wk compared with the pretreatment transfusion number in the previous 8 weeks.
* Platelet response. Absolute increase of \> 30 x 10\^9/L for patients starting with 20 x 10\^9/L or increase from \< 20 x 10\^9/L to \> 20 x 109/L and by at least 100%
* Neutrophil response. At least 100% increase and an absolute increase \> 0.5 x 109/L for patients with pretreatment neutrophils \< 1.0 x 109/L)

Washington University School of Medicine

LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 1

LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 2

LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 3

LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 4

LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 5

LBH589 40 mg/day three times a week on nonconsecutive days for the first 2 weeks in a 28 day cycle.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Level 5B

LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was dose from Level 5B.

Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Phase II

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Phase I (Includes Levels 1-5)

After enrolling all Phase I patients in Dose Levels 1-5b, the maximum tolerated dose was not determined. The Phase II portion of the study used the 5b dose level.

Phase I: Maximum Tolerated Dose (MTD) of LBH589 When Given in Combination With Decitabine

* Level 1:LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 2:LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 3: LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 4:LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 5:LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.
* Level 5B/Phase II:LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was dose from Level 5B. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

Level 1-Phase II (All Patients Enrolled)

Phase II: Overall Rate of Morphologic Complete Remission (CR) + Cytogenetic Complete Remission (CRc) + Morphologic Complete Remission With Incomplete Blood Count Recovery (CRi)

Rate of Cytogenetic Complete Remission (CRc)

Data was not collected for this outcome measure.

Changes in Quality of Life Scores as Measured by the Function Assessment of Cancer Therapy-Leukemia (FACT-Leu) Version 4

Number of participants analyzed are participants that met the criteria for CR or CRi.

Time to Response

Fatigue

Febrile neutropenia

Diarrhea

Nausea

Safety and Tolerability of Regimen as Measured by the Rate of the Most Common Adverse Events Experienced

Number of participants analyzed include those participants who met the criteria for CR, CRi, or HI.

Remission Duration

Data was not collected for this outcome measure. Progression is very hard to define for MDS and AML and including it as a pre-specified secondary outcome measure in the protocol was an oversight.

Progression-free Survival

Event-free Survival

Overall Survival

Rates of Morphologic Complete Remission With Incomplete Count Recovery (CRi)

Rate of Hematologic Improvement.

Overall Study

Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Temazolomide, Valproic Acid and Whole Brain Radiation Therapy

Cohort 1: 20 mg/kg/day Cohort 2: 30 mg/kg/day Cohort 3: 40 mg/kg/day Cohort 4: 50 mg/kg/day

Whole Brain Radiation Therapy

Sajeel Chowdhary, MD

Jade Homsi, MD

This type of study is called a "Phase I study". Its purpose is to determine the side effects of the two medicines listed in this study when given together with whole brain radiation, and the highest dose of valproic acid that can be given together with temozolomide and whole brain radiation. We will also study the drug combination's effectiveness in treating cancer. While both of these drugs and whole brain radiation have been used in people for many years, they have never been combined for the purpose of treating patients with cancer.

At the start of the study, patients will be informed which dose level they will be treated with. On day 1, patients will have a physical exam and several blood draws including draws to measure the level of valproic acid in their body. Patients will start your whole brain radiation and also at the same time start the valproic acid and temozolomide pills. Patients will be asked to take the valproic acid pills every 12 hours and the temozolomide pills once daily. Patients will not need to come to the center for that but will need to come to the center to receive you whole brain radiation for 3 weeks (on weekdays, excluding holidays). Radiation therapy will not be administered on weekends but patients will still take their pills for the whole 3 weeks from starting the radiation.

Patients will have to come back for a study visit weekly for the 6 months. Two more visits are also required: approximately 6 weeks and 10 weeks from starting the treatment. Patients will be asked about any old or new symptoms to determine if adjustment in the pill dose is required.

Every study visit except the last one will include blood draws. These will evaluate blood counts, blood chemistry and also measure the level of valproic acid in your body. The Mini Mental Status examination described above will be repeated in every visit.

Phase I Study of Temozolomide, Valproic Acid and Radiation Therapy in Patients With Brain Metastases

Phase I Trial Of Temozolomide Combined With The Histone Deacetylase Inhibitor Valproic Acid (VPA) And Whole Brain Radiation Therapy (WBR) For Brain Metastases From Solid Tumors In Adults

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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)
Valproic Acid and Platinum-based Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma	NCT01695122	Head and Neck C... Oral Cavity Can... Oropharyngeal C...	Valproic Acid	- 65 Years	Instituto do Cancer do Estado de São Paulo
LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)	NCT00691938	Leukemia, Myelo... Myelodysplastic...	LBH589 Decitabine	60 Years -	Washington University School of Medicine
LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)	NCT00691938	Leukemia, Myelo... Myelodysplastic...	LBH589 Decitabine	60 Years -	Washington University School of Medicine
Valproic Acid and Platinum-based Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma	NCT01695122	Head and Neck C... Oral Cavity Can... Oropharyngeal C...	Valproic Acid	- 65 Years	Instituto do Cancer do Estado de São Paulo
Phase I Study of Temozolomide, Valproic Acid and Radiation Therapy in Patients With Brain Metastases	NCT00437957	Brain Metastase...	Temozolomide Valproic Acid Whole Brain Rad...	18 Years -	H. Lee Moffitt Cancer Center and Research Institute

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