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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 is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00926640
First received: June 20, 2009
Last updated: October 4, 2014
Last verified: September 2014
  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
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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):

Primary Outcome Measures:
  • Safety and tolerability [ Time Frame: Dose Limiiting Toxicity ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Markers of HDAC [ Time Frame: End of treatment ] [ Designated as safety issue: No ]
  • Tumor response [ Time Frame: Disease Progression ] [ Designated as safety issue: No ]
  • miRNA and CGH [ Time Frame: End of treatment ] [ Designated as safety issue: No ]
  • Increased acetylation in PBMCs [ Time Frame: End of treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 39
Study Start Date: June 2009
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Belinostat
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.

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/m (2) IV daily times 3 on days 2 - 4. Dose escalation of belinostat will follow according to traditional 3 patient cohorts.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00926640

Contacts
Contact: Robin R. Eisch, R.N. (301) 402-5958 eischar@mail.nih.gov
Contact: Susan E Bates, M.D. (301) 402-0984 batess@helix.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Susan E Bates, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00926640     History of Changes
Other Study ID Numbers: 090173, 09-C-0173
Study First Received: June 20, 2009
Last Updated: October 4, 2014
Health Authority: United States: Federal Government

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

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

ClinicalTrials.gov processed this record on November 20, 2014