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A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00926640
First Posted: June 23, 2009
Last Update Posted: October 19, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
  Purpose

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.

Condition Intervention Phase
Carcinoma Neuroendocrine Small Cell Lung Carcinoma Malignant Epithelial Neoplasms Drug: Belinostat Drug: Cisplatin Drug: Etoposide Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Primary Outcome Measures:
  • Safety and tolerability [ Time Frame: Dose Limiiting Toxicity ]

Secondary Outcome Measures:
  • Markers of HDAC [ Time Frame: End of treatment ]
  • Tumor response [ Time Frame: Disease Progression ]
  • miRNA and CGH [ Time Frame: End of treatment ]
  • Increased acetylation in PBMCs [ Time Frame: End of treatment ]

Enrollment: 28
Study Start Date: July 1, 2009
Study Completion Date: June 16, 2017
Primary Completion Date: June 16, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Belinostat dose escalation
Drug: Belinostat
6 cycles of belinostat 400 mg/m2/24h X2 administered by CIV
Drug: Cisplatin
6 cycles at 60mg/m2 IV on day 2
Drug: Etoposide
6 cycles 80 mg/m2 IV daily X3 beginning day 2.
Experimental: 2
Belinostat UGT1A1 wild type/*28 variant
Drug: Belinostat
6 cycles of belinostat 400 mg/m2/24h X2 administered by CIV
Drug: Cisplatin
6 cycles at 60mg/m2 IV on day 2
Drug: Etoposide
6 cycles 80 mg/m2 IV daily X3 beginning day 2.
Experimental: 3
Belinostat UGT1A1*60 or 2/3/4 variant
Drug: Belinostat
6 cycles of belinostat 400 mg/m2/24h X2 administered by CIV
Drug: Cisplatin
6 cycles at 60mg/m2 IV on day 2
Drug: Etoposide
6 cycles 80 mg/m2 IV daily X3 beginning day 2.

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)

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Patients must have histologic or cytologic confirmation of cancer for which there is no known standard therapy capable of extending life expectancy.
  2. 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.
  3. ECOG performance status 0-2.
  4. Life expectancy of 3 months or greater.
  5. 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.

  6. 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.
  7. Age greater than or equal to 18 years.
  8. Ability to understand and the willingness to sign a written informed consent document.
  9. Willing to comply with study procedures and follow-up.

EXCLUSION CRITERIA:

  1. 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.
  2. Patients may not have received more than 2 prior cytotoxic regimens.
  3. Patients may not be receiving any other investigational agent with therapeutic anticancer intent.
  4. Patients may not have taken another histone deacetylase inhibitor (i.e. valproic acid, vorinostat) for at least 2 weeks prior to enrollment.
  5. 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.
  6. 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).
  7. 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.
  8. HIV-positive patients.
  9. Patients with acute or chronic hepatitis.
  10. Pregnant patients may not receive this experimental therapy.
  11. 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.
  12. 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00926640


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00926640     History of Changes
Other Study ID Numbers: 090173
09-C-0173
First Submitted: June 20, 2009
First Posted: June 23, 2009
Last Update Posted: October 19, 2017
Last Verified: July 10, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Solid Tumors
Histone deacetylase inhibitors
EP & Belinostat
Phase I
SCLC
Small Cell Lung Cancer

Additional relevant MeSH terms:
Carcinoma
Small Cell Lung Carcinoma
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Carcinoma, Neuroendocrine
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Etoposide phosphate
Belinostat
Cisplatin
Etoposide
Histone Deacetylase Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action