- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00926640
A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers
October 18, 2018 updated by: National Cancer Institute (NCI)
A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With a Focus on Small Cell Lung Cancer and Other Cancers of Neuroendocrine Origin
BACKGROUND:
- The histone deacetylase (HDAC) inhibitors are a novel class of anticancer agent. These agents lead to the increased acetylation of both histone and non-histone proteins, which leads to rapid cell death in many tumor models. It is thought that the cell death observed with this class of agents may be mediated, in part, through the selective acetylation of histone proteins resulting in increased expression of specific genes.
- For solid tumors in general, cell death in preclinical models has not translated to activity in patients. For this reason, studies increasingly have combined chemotherapy with HDAC inhibitors to achieve additive and potentially synergistic effects on cancer cells.
- This protocol will study a continuous infusion of the HDAC inhibitor belinostat in combination with cisplatin and etoposide for patients with advanced cancer.
OBJECTIVES:
- To determine a safe and tolerable phase 2 dose for the combination of belinostat with cisplatin and etoposide.
- Evaluate molecular markers of HDAC inhibition.
ELIGIBILITY:
- The protocol will be open to all patients with recurrent or advanced cancer (small-cell lung cancer and other advanced cancers) for whom standard therapy offers no curative potential.
- Age greater than or equal to 18 years
- ECOG Performance Status 0-2
DESIGN:
- The study will begin with belinostat 400 mg/m (2)/24h administered by continuous IV infusion on days 1 and 2, cisplatin at 80 mg/m (2) IV on day 2, and etoposide at 100 mg/m (2) IV daily times 3 on days 2 - 4. Dose escalation of belinostat will follow according to traditional 3 patient cohorts.
- Treatment schedule and dose escalation schemata.
Study Overview
Status
Completed
Intervention / Treatment
Detailed Description
BACKGROUND:
- The histone deacetylase (HDAC) inhibitors are a novel class of anticancer agent. These agents lead to the increased acetylation of both histone and non-histone proteins, which leads to rapid cell death in many tumor models. It is thought that the cell death observed with this class of agents may be mediated, in part, through the selective acetylation of histone proteins resulting in increased expression of specific genes.
- For solid tumors in general, cell death in preclinical models has not translated to activity in patients. For this reason, studies increasingly have combined chemotherapy with HDAC inhibitors to achieve additive and potentially synergistic effects on cancer cells.
- This protocol will study a continuous infusion of the HDAC inhibitor belinostat in combination with cisplatin and etoposide for patients with advanced cancer.
OBJECTIVES:
- To determine a safe and tolerable phase 2 dose for the combination of belinostat with cisplatin and etoposide.
- Evaluate molecular markers of HDAC inhibition.
- To explore the results of administering the dose of belinostat based on the patients' UGT1A1 *28 or *60 genotype, which is a characteristic that may be associated with toxicity.
ELIGIBILITY:
- The protocol will be open to all patients with recurrent or advanced cancer (small-cell lung cancer and other advanced cancers) for whom standard therapy offers no curative potential.
- Age greater than or equal to 18 years
- ECOG Performance Status 0-2
DESIGN:
- The study will begin with belinostat 400 mg/m (2)/24h administered by continuous IV infusion on days 1 and 2, cisplatin at 60 mg/m(2) IV on day 2, and etoposide at 80 mg/ (2) IV daily times 3 on days 2 - 4. Dose escalation of belinostat will follow according to traditional 3 patient cohorts.
With Amendment M, dosing will be based on UGT1A1 status, at either 400 mg/m(2) or
600 mg/m(2)
Study Type
Interventional
Enrollment (Actual)
28
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center, 9000 Rockville Pike
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 99 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
-INCLUSION CRITERIA:
- Patients must have histologic or cytologic confirmation of cancer for which there is no known standard therapy capable of extending life expectancy.
- Patients must be greater than or equal to 4 weeks from cytotoxic chemotherapy, except greater than or equal to 6 weeks for mitomycin C or nitrosoureas, and greater than or equal to 8 weeks from prior UCN01; greater than or equal to 4 weeks from monoclonal antibody therapy (cetuximab, bevacizumab); greater than or equal to 4 weeks from prior experimental therapy; greater than or equal 2 weeks from radiation or hormonal therapy; greater than or equal to 2 weeks from sorafenib, sunitinib or temsirolimus treatment. Patients with prostate cancer may continue ongoing LhRH agonist therapy. Patients with bone metastases or hypercalcemia who began intravenous bisphosphonate treatment prior to study entry may continue this treatment while on study.
- ECOG performance status 0-2.
- Life expectancy of 3 months or greater.
Patients must have acceptable organ and marrow function as defined below:
- absolute neutrophil count greater than or equal to 1,500/ mm(3)
- platelets greater than or equal to 100,000/ mm(3)
- total bilirubin less than or equal to 1.2 mg/dL (except patients with Gilbert's Syndrome)
- AST (SGOT) and ALT(SGPT) less than or equal to 2.5 times institutional upper limit of normal
- creatinine less than or equal to 1.5 times institutional upper limit of normal
OR
- creatinine clearance >50 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.
- Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study, and for 3 months after study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- Age greater than or equal to 18 years.
- Ability to understand and the willingness to sign a written informed consent document.
- Willing to comply with study procedures and follow-up.
EXCLUSION CRITERIA:
- Patients who have not recovered (CTCAE less than or equal to grade 1) from adverse events due to prior treatments, except for alopecia or base stable grade 2 tinnitus (not interfering with ADL s) or stable grade 2 sensory neuropathy without pain or motor component, and not interfering with ADL s.
- Patients may not have received more than 2 prior cytotoxic regimens.
- Patients may not be receiving any other investigational agent with therapeutic anticancer intent.
- Patients may not have taken another histone deacetylase inhibitor (i.e. valproic acid, vorinostat) for at least 2 weeks prior to enrollment.
- Patients with history of CNS metastasis may not be enrolled on the study, unless control has been achieved with either radiation or surgical resection at least 3 months prior to enrollment on study.
- Patients 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).
- Uncontrolled medical illness including, but not limited to ongoing or active infection, chronic or acute hepatitis, renal failure, symptomatic congestive heart failure, myocardial infarction unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- HIV-positive patients.
- Patients with acute or chronic hepatitis.
- Pregnant patients may not receive this experimental therapy.
- Significant cardiovascular 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 patients with atrial fibrillation is allowed, if stable medication for at least last month prior to randomization and medication not listed as causing Torsade de Points), or evidence of acute ischemia on ECG.
- Baseline prolongation of QT/QTc interval, i.e., defined as an average QTc interval > 450 msec; Long QT Syndrome; or the required use of concomitant medication that may cause Torsade de Pointes.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1
Belinostat dose escalation
|
6 cycles of belinostat 400 mg/m2/24h X2 administered by CIV
6 cycles at 60mg/m2 IV on day 2
6 cycles 80 mg/m2 IV daily X3 beginning day 2.
|
Experimental: 2
Belinostat UGT1A1 wild type/*28 variant
|
6 cycles of belinostat 400 mg/m2/24h X2 administered by CIV
6 cycles at 60mg/m2 IV on day 2
6 cycles 80 mg/m2 IV daily X3 beginning day 2.
|
Experimental: 3
Belinostat UGT1A1*60 or 2/3/4 variant
|
6 cycles of belinostat 400 mg/m2/24h X2 administered by CIV
6 cycles at 60mg/m2 IV on day 2
6 cycles 80 mg/m2 IV daily X3 beginning day 2.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Safety and tolerability
Time Frame: Dose Limiiting Toxicity
|
Dose Limiiting Toxicity
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Markers of HDAC
Time Frame: End of treatment
|
End of treatment
|
Tumor response
Time Frame: Disease Progression
|
Disease Progression
|
miRNA and CGH
Time Frame: End of treatment
|
End of treatment
|
Increased acetylation in PBMCs
Time Frame: End of treatment
|
End of treatment
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Akerley W, McCoy J, Hesketh PJ, Goodwin JW, Bearden JD, Atkins JN, Chansky K, Crowley JJ, Gandara DR; SWOG. Gemcitabine and irinotecan for patients with untreated extensive stage small cell lung cancer: SWOG 0119. J Thorac Oncol. 2007 Jun;2(6):526-30. doi: 10.1097/JTO.0b013e318060d2dc.
- Bevins RL, Zimmer SG. It's about time: scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells. Cancer Res. 2005 Aug 1;65(15):6957-66. doi: 10.1158/0008-5472.CAN-05-0836.
- Camphausen K, Scott T, Sproull M, Tofilon PJ. Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation. Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6066-71. doi: 10.1158/1078-0432.CCR-04-0537.
- Peer CJ, Hall OM, Sissung TM, Piekarz R, Balasubramaniam S, Bates SE, Figg WD. A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat. Cancer Chemother Pharmacol. 2018 Sep;82(3):565-570. doi: 10.1007/s00280-018-3631-7. Epub 2018 Jun 27.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
July 1, 2009
Primary Completion (Actual)
June 16, 2017
Study Completion (Actual)
April 20, 2018
Study Registration Dates
First Submitted
June 20, 2009
First Submitted That Met QC Criteria
June 20, 2009
First Posted (Estimate)
June 23, 2009
Study Record Updates
Last Update Posted (Actual)
October 19, 2018
Last Update Submitted That Met QC Criteria
October 18, 2018
Last Verified
April 20, 2018
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Respiratory Tract Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lung Diseases
- Neoplasms by Site
- Adenocarcinoma
- Respiratory Tract Neoplasms
- Thoracic Neoplasms
- Carcinoma, Bronchogenic
- Bronchial Neoplasms
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroendocrine Tumors
- Lung Neoplasms
- Carcinoma
- Small Cell Lung Carcinoma
- Carcinoma, Neuroendocrine
- Neoplasms, Glandular and Epithelial
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Histone Deacetylase Inhibitors
- Etoposide
- Cisplatin
- Belinostat
Other Study ID Numbers
- 090173
- 09-C-0173
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Small Cell Lung Carcinoma
-
National Cancer Institute (NCI)RecruitingExtensive Stage Lung Small Cell Carcinoma | Limited Stage Lung Small Cell Carcinoma | Platinum-Resistant Lung Small Cell Carcinoma | Platinum-Sensitive Lung Small Cell Carcinoma | Recurrent Lung Small Cell CarcinomaUnited States
-
National Cancer Institute (NCI)Active, not recruitingExtensive Stage Lung Small Cell Carcinoma | Limited Stage Lung Small Cell Carcinoma | Platinum-Resistant Lung Small Cell Carcinoma | Platinum-Sensitive Lung Small Cell Carcinoma | Bladder Small Cell Neuroendocrine Carcinoma | Extrapulmonary Small Cell Neuroendocrine Carcinoma | Recurrent Lung... and other conditionsUnited States
-
Ohio State University Comprehensive Cancer CenterNational Institute on Aging (NIA)RecruitingStage IVA Lung Cancer AJCC v8 | Stage IVB Lung Cancer AJCC v8 | Stage IV Lung Cancer AJCC v8 | Stage IIIA Lung Cancer AJCC v8 | Stage IIIB Lung Cancer AJCC v8 | Extensive Stage Lung Small Cell Carcinoma | Unresectable Lung Non-Small Cell Carcinoma | Advanced Lung Non-Small Cell Carcinoma | Advanced... and other conditionsUnited States
-
National Cancer Institute (NCI)CompletedCarcinoma, Non-Small Cell Lung | Carcinoma, Small-Cell LungUnited States
-
Mayo ClinicNational Cancer Institute (NCI)RecruitingPlatinum-Resistant Lung Small Cell Carcinoma | Platinum-Sensitive Lung Small Cell Carcinoma | Recurrent Extensive Stage Lung Small Cell Carcinoma | Refractory Extensive Stage Lung Small Cell CarcinomaUnited States
-
National Cancer Institute (NCI)Active, not recruitingExtensive Stage Lung Small Cell CarcinomaUnited States
-
National Cancer Institute (NCI)TerminatedExtensive Stage Lung Small Cell CarcinomaUnited States
-
University of WashingtonNational Cancer Institute (NCI); Imago BioSciences, Inc., a subsidiary of Merck...SuspendedExtensive Stage Lung Small Cell Carcinoma | Limited Stage Lung Small Cell CarcinomaUnited States
-
SWOG Cancer Research NetworkNational Cancer Institute (NCI)RecruitingExtensive Stage Lung Small Cell Carcinoma | Limited Stage Lung Small Cell Carcinoma | Lung Small Cell CarcinomaUnited States, Canada, Korea, Republic of, Mexico
-
Sidney Kimmel Cancer Center at Thomas Jefferson...Bristol-Myers SquibbCompletedStage IIIA Non-Small Cell Lung Cancer | Stage IIA Non-Small Cell Lung Carcinoma | Stage IIB Non-Small Cell Lung Carcinoma | Stage I Non-Small Cell Lung Cancer | Stage II Non-Small Cell Lung Cancer | Stage IA Non-Small Cell Lung Carcinoma | Stage IB Non-Small Cell Lung Carcinoma | Non-Squamous Non-Small...United States
Clinical Trials on Belinostat
-
Yale UniversitySidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Massey Cancer CenterWithdrawnLymphoma | Relapsed and Refractory Aggressive B- and T-cell LymphomasUnited States
-
National Cancer Institute (NCI)CompletedPreviously Treated Myelodysplastic Syndromes | Secondary Myelodysplastic Syndromes | de Novo Myelodysplastic SyndromesUnited States
-
National Cancer Institute (NCI)CompletedRecurrent Adult Burkitt Lymphoma | Recurrent Adult Diffuse Large Cell LymphomaUnited States
-
OnxeoTerminatedNon-Hodgkin's Lymphoma | Cutaneous T-Cell Lymphoma | Peripheral T-Cell LymphomaUnited States, Germany, Israel, France, Thailand
-
Acrotech Biopharma Inc.Axis Clinicals LimitedCompletedSolid Tumors | Hematological MalignanciesUnited States
-
National Cancer Institute (NCI)CompletedAdvanced Adult Primary Liver Cancer | Localized Unresectable Adult Primary Liver Cancer | Recurrent Adult Primary Liver Cancer | Adult Primary Hepatocellular CarcinomaUnited States, Singapore
-
National Cancer Institute (NCI)CompletedThymic Carcinoma | ThymomaUnited States
-
National Cancer Institute (NCI)CompletedRecurrent Malignant Mesothelioma | Advanced Malignant Mesothelioma | Epithelial Mesothelioma | Sarcomatous MesotheliomaUnited States
-
National Cancer Institute (NCI)CompletedRecurrent Adult Acute Myeloid Leukemia | Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities | Adult Acute Myeloid Leukemia With Del(5q) | Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) | Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) | Adult Acute Myeloid Leukemia With t(8... and other conditionsUnited States
-
OnxeoSpectrum Pharmaceuticals, IncCompletedLymphoma | Solid TumorUnited States, Denmark, United Kingdom