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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Chandra P. Belani, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier:
NCT00702962
First received: June 19, 2008
Last updated: January 3, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Small Cell Lung Cancer
Drug: Vorinostat, Carboplatin, Etoposide
Other: Vorinostat, Carboplatin, Etoposide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Carboplatin and Etoposide in Combination With Vorinostat for Patients With Extensive Stage Small Cell Lung Cancer

Resource links provided by NLM:


Further study details as provided by Milton S. Hershey Medical Center:

Primary Outcome Measures:
  • Assess maximum tolerated dose of vorinostat combined with carboplatin + etoposide for patients with extensive disease SCLC. [ Time Frame: An expected average of 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Evaluate overall survival & objective response rate among patients with extensive disease SCLC receiving carboplatin + etoposide with vorinostat. [ Time Frame: An expected average of 2 years ] [ Designated as safety issue: No ]

Enrollment: 5
Study Start Date: September 2008
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Dose escalation scheme
Drug: Vorinostat, Carboplatin, Etoposide
Sequential cohorts of 3-6 patients will be entered to the following dose levels: Level 1 - Days 1-14: Vorinostat 200 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Level 2 - Days 1-14: Vorinostat 300 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2; Level 3: Days 1-14: Vorinostat 400 mg po QD; Day 3: Carboplatin 6 AUC; Days 1,2,3: Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each patient.
Other Name: SAHA
2
Phase 2 is to determine progression free survival among patients with extensive disease SCLC receiving carboplatin plus etoposide with vorinostat.
Other: Vorinostat, Carboplatin, Etoposide
Once the recommended phase II dose has been established and additional 15 patients will be enrolled. Days 1-4 Vorinostat recommended phase II dose po QD;Day 3 Carboplatin 6 AUC; Days 1,2,3 Etoposide 100 mg/m2. Treatment cycles will be repeated every 3 weeks. A maximum of 4 cycles will be administered to each patient. An additional 35 patients on the phase II portion of the trial will be required to achieve the outlined objectives.
Other Name: SAHA

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  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: NCT00702962

Locations
United States, Pennsylvania
Penn State College of Medicine, Penn State Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
Sponsors and Collaborators
Milton S. Hershey Medical Center
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Chandra P Belani, MD Penn State College of Medicine
  More Information

No publications provided

Responsible Party: Chandra P. Belani, Professor of Medicine, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier: NCT00702962     History of Changes
Other Study ID Numbers: PSHCI 08-005
Study First Received: June 19, 2008
Last Updated: January 3, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Milton S. Hershey Medical Center:
lung cancer
small cell lung cancer

Additional relevant MeSH terms:
Lung Neoplasms
Small Cell Lung Carcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Etoposide
Etoposide phosphate
Vorinostat
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014