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

• ClinicalTrials.gov Identifier: NCT00702962
• Recruitment Status: Terminated
• First Posted: June 20, 2008
• Results First Posted: October 15, 2018
• Last Update Posted: October 22, 2018
• Sponsor: Milton S. Hershey Medical Center
• Collaborators: 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: June 19, 2008
• First Posted Date: June 20, 2008
• Results First Submitted Date: July 24, 2017
• Results First Posted Date: October 15, 2018
• Last Update Posted Date: October 22, 2018
• Actual Study Start Date: September 2008
• Actual Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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 ]

Current Secondary Outcome Measures (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 (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: Carboplatin and Etoposide in Combination With Vorinostat for Patients With Extensive Stage Small Cell Lung Cancer
• Official Title: 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Small Cell Lung Cancer

Intervention

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

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

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 11, 2018): 8
• Original Estimated Enrollment (submitted: June 19, 2008): 20
• Actual Study Completion Date: July 2012
• Actual Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00702962
• Other Study ID Numbers: PSHCI 08-005
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• 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: Milton S. Hershey Medical Center

Collaborators

• Merck Sharp & Dohme Corp.
• University of Pennsylvania

Investigators

• Principal Investigator: Chandra P Belani, MD; Penn State College of Medicine

• PRS Account: Milton S. Hershey Medical Center
• Verification Date: September 2018