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Carboplatin and Etoposide in Combination With Vorinostat for Patients With Extensive Stage Small Cell Lung Cancer

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. Identifier: NCT00702962
Recruitment Status : Terminated (Poor accrual)
First Posted : June 20, 2008
Results First Posted : October 15, 2018
Last Update Posted : October 22, 2018
Merck Sharp & Dohme Corp.
University of Pennsylvania
Information provided by (Responsible Party):
Chandra P. Belani, Milton S. Hershey Medical Center

Tracking Information
First Submitted Date  ICMJE June 19, 2008
First Posted Date  ICMJE June 20, 2008
Results First Submitted Date  ICMJE July 24, 2017
Results First Posted Date  ICMJE October 15, 2018
Last Update Posted Date October 22, 2018
Actual Study Start Date  ICMJE September 2008
Actual Primary Completion Date July 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 11, 2018)
Assess Maximum Tolerated Dose of Vorinostat When Combined With Carboplatin and Etoposide of Patients With Extensive Disease SCLC [ Time Frame: 2 years, not analyzed ]
To estimate the maximum tolerated dose of vorinostat using a traditional dose escalation schedule ("3 + 3 design). MTD is determined by assessing for specific predefined dose limiting toxicities. A starting dose of vorinostat 200mg was combined with carboplatin and etoposide. Dose escalation went in increments of 100mg (i.e. 300mg, 400mg).
Original Primary Outcome Measures  ICMJE
 (submitted: June 19, 2008)
Assess maximum tolerated dose of vorinostat combined with carboplatin + etoposide for patients with extensive disease SCLC. [ Time Frame: End of study ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 11, 2018)
  • To Evaluate Overall Survival of Patients With Extensive Disease SCLC Receiving Carboplatin, Etoposide, and a Fixed Dose (300mg) of Vorinostat [ Time Frame: 2 years, not analyzed ]
    For the purpose of this study, overall survival is defined as the percentage of participants who are alive at two years post initiation of study treatment.
  • Evaluate Objective Response Rate Among Patients With Extensive Disease SCLC Receiving Carboplatin and Etoposide With a Fixed Dose of Vorinostat. [ Time Frame: 2 years, not analyzed ]
    Eligibility limits the study population to those who have measurable disease pre-treatment. This secondary outcome measure was intended to objectively evaluate disease response and survival rate in recipients of the investigational medication regimen. Disease response was performed using standard diagnostic imaging. Tumor markers and cytology may be used to support the imaging results. Objective response rate was defined as progression-free survival (PFS) among treatment recipients. PFS, is defined as time (in months) from entry to clinical evidence of disease progression or death without progression. The clinical trial closed prematurely due to low accrual. For this reason, an analysis of this secondary objective would not be meaningful. No analysis done.
  • To Assess the Safety Profile and Define the Toxicities of Using a Fixed Dose (300mg) of Vorinostat With Carboplatin and Etoposide [ Time Frame: 2 years, not analyzed ]
    Evaluation of resultant adverse events that occurred with participants with extensive disease SCLC after initiating treatment using a fixed dose of vorinostat in combination with carboplatin and etoposide.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2008)
Evaluate overall survival & objective response rate among patients with extensive disease SCLC receiving carboplatin + etoposide with vorinostat. [ Time Frame: End of study ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Carboplatin and Etoposide in Combination With Vorinostat for Patients With Extensive Stage Small Cell Lung Cancer
Official Title  ICMJE Phase I/II Study of Carboplatin and Etoposide in Combination With Vorinostat for Patients With Extensive Stage Small Cell Lung Cancer
Brief Summary The Phase I portion of the study is to assess the maximum tolerated dose of vorinostat when combined with carboplatin plus etoposide. The Phase II portion is to determine progression-free survival among patients with extensive disease small cell lung cancer receiving carboplatin plus etoposide with vorinostat.
Detailed Description

Vorinostat inhibits growth and induces apoptosis in various human carcinoma cells. Furthermore, it affects the expression of various genes that are necessary for proliferation of cancer cells. Vorinostat also appears to block angiogenic signaling. Pre-treating four human cancer cell lines (including a brain tumor line) with vorinostat increased the killing efficiency of etoposide, ellipticine, doxorubicin, or cisplatin, but not of the topoisomerase I inhibitor camptothecin 13. Topoisomerase II is a ubiquitous nuclear enzyme that is involved in DNA replication, transcription, chromosome segregation, and apoptosis. It is the target for several anti-cancer drugs including etoposide. Treatment with HDAC inhibitors induces expression of topoisomerase II in cancer cells and enhances the sensitivity to etoposide 14.

Early phase clinical trials have demonstrated single agent anti-cancer activity with vorinostat. In our study, combination of vorinostat with carboplatin and paclitaxel, demonstrated promising anticancer activity against NSCLC, including histological subsets of patients whose tumors demonstrated neuroendocrine differentiation 8. For all these reasons, vorinostat is a rational choice to combine with the regimen of carboplatin and etoposide for evaluation in patients with SCLC-ED.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Small Cell Lung Cancer
Intervention  ICMJE Drug: Vorinostat, Carboplatin, Etoposide
Study originally a Phase I standard dose escalation of the study medication Vorinostat with sequential cohorts of 3-6 participants entered to 3 dose levels (200mg, 300mg, 400mg). Dose escalation stopped after participant 1 on dose level 2 due to recently published research identifying an appropriate dosing regimen. A set dose was then to be administered to all subsequent participants. This regimen (a "cycle") consisted of Vorinostat on Day 1 through Day 4, Carboplatin AUC 6 on Day 3, and Etoposide 100 mg/m2 on Day 3 through Day 5. Treatment cycles were repeated every 21 days (3 weeks) for 4 cycles total.
Other Name: Suberoyl anilide hydroxamic acid (SAHA)
Study Arms  ICMJE Experimental: Phase I: Vorinostat 200 mg
Vorinostat 200 mg PO QD D1-14; Administer with Carbo 6 (AUC) D3; Etoposide 100 mg/m2 D1,2,3 "Vorinostat", "Carboplatin", "Etoposide"
Intervention: Drug: Vorinostat, Carboplatin, Etoposide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 11, 2018)
Original Estimated Enrollment  ICMJE
 (submitted: June 19, 2008)
Actual Study Completion Date  ICMJE July 2012
Actual Primary Completion Date July 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically confirmed small cell lung cancer.
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with CT scan.
  • Patients must be chemotherapy naive.
  • Previous radiotherapy is allowed only if < 30% of marrow bearing bones were irradiated and if radiotherapy was completed at least 2 weeks prior to enrollment and the patient has recovered from all adverse effects of prior radiotherapy.
  • Age >18 years.
  • Life expectancy of greater than 3 months.
  • ECOG performance status <2 (Karnofsky >60%).
  • Adequate organ and marrow function.
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or double barrier method of birth control) prior to study entry and for the duration of study participation.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Both men and women of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

  • Patients who have had chemotherapy or any other investigational agent for any indication within 30 days of study enrollment.
  • Patients who have had radiotherapy within 2 weeks, prior to entering the study or those who have not recovered from adverse events due to these therapies.
  • Patients with known brain metastases are excluded.
  • Patients who have been previously treated with an HDAC inhibitor (use of valproic acid is allowed with a 30-day washout).
  • Patients with peripheral neuropathy CTC grade >2 are excluded.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Any major surgery within 2 weeks prior to enrollment. Minimally invasive procedures for the purpose of diagnosis or staging of the disease are permitted.
  • History of another malignancy in the last 5 years. Patients with prior history of in situ cancer, basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they were cured by surgery alone and have been continuously disease free for at least 5 years.
  • Pregnant women are excluded from this study because irinotecan and paclitaxel are antineoplastic agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with agents used in this trial, breastfeeding should be discontinued if the mother is treated with these agents.
  • Patients with known HIV, Hepatitis B, Hepatitis C or active Hepatitis A are excluded.
  • Patients on any systemic steroids for any indication, with doses that have not been stabilized to the equivalent of < 10 mg/day prednisone during the 30 days prior to study enrollment. This does not include short courses of steroids administered at high doses.
  • Patients with the inability to absorb oral vorinostat.
  • Patients with known allergy or hypersensitivity to any component of any of the study therapies.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00702962
Other Study ID Numbers  ICMJE PSHCI 08-005
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: To determine if data is valuable
Responsible Party Chandra P. Belani, Milton S. Hershey Medical Center
Study Sponsor  ICMJE Milton S. Hershey Medical Center
Collaborators  ICMJE
  • Merck Sharp & Dohme Corp.
  • University of Pennsylvania
Investigators  ICMJE
Principal Investigator: Chandra P Belani, MD Penn State College of Medicine
PRS Account Milton S. Hershey Medical Center
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP