A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers
Condition: Carcinoma Neuroendocrine; Small Cell Lung Carcinoma; Malignant Epithelial Neoplasms
MeSH terms: Carcinoma; Lung Neoplasms; Small Cell Lung Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Neuroendocrine
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

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)
    

Intervention name(s): Belinostat; Cisplatin; Etoposide
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.
Intervention MeSH terms: Etoposide; Belinostat
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Solid Tumors; Histone deacetylase inhibitors; EP &amp; Belinostat; Phase I; SCLC; Small Cell Lung Cancer