Small Cell Lung Cancer
Conditions
Keywords
lung cancer, 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.
Interventions
DRUGVorinostat, 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.
Sponsors
Merck Sharp & Dohme LLC
University of Pennsylvania
Milton S. Hershey Medical Center
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assess Maximum Tolerated Dose of Vorinostat When Combined With Carboplatin and Etoposide of Patients With Extensive Disease SCLC | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate Overall Survival of Patients With Extensive Disease SCLC Receiving Carboplatin, Etoposide, and a Fixed Dose (300mg) of Vorinostat | 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. | 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 | 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. |
Countries
United States
Participant flow
Recruitment details
Open to accrual 09/2008 as Phase I study. Three participants treated with dose level 1. Similar NCI-CTEP Phase I trial (NCI 8703) established the maximum tolerated dose (MTD) for the study drug. This study was amended to Phase II using the NCI established dose. One participant treated on Phase II. Closed to accrual 01/2012 due to low enrollment.
Pre-assignment details
Eight patients total were consented (i.e. enrolled). Three of the 8 were determined to be ineligible upon screening. One of the 8 was eligible but subsequently declined participation soon after signing consent. Four (4) of 8 enrolled went to active treatment (started). Of these 4, 3 participated in Phase I and 1 participated in Phase II.
Participants by arm
| Arm | Count |
|---|---|
| PHASE I: Vorinostat 200mg Carbo 6 (AUC) Phase I portion: To determine MTD of Vorinostat when used in combination with other chemotherapy. Start at Vorinostat 200 mg PO QD D1-14; Carbo 6 (AUC) D3; Etoposide 100 mg/m2 D1,2,3; Vorinostat, Carboplatin, Etoposide, SAHA
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. | 3 |
| PHASE II: Vorinostat 300mg Carbo 6 (AUC) Phase II portion: To determine progression free survival among patients with extensive disease SCLC receiving carboplatin plus etoposide with fixed dose Vorinostat. (Vorinostat, Carboplatin, Etoposide, SAHA)
SAHA: 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. | 1 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Hospitalized for other health disorder | 1 | 0 |
| Overall Study | Progressive disease | 0 | 1 |
Baseline characteristics
| Characteristic | Total | PHASE I: Vorinostat 200mg Carbo 6 (AUC) | PHASE II: Vorinostat 300mg Carbo 6 (AUC) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 1 Participants |
| Age, Continuous | 65.8 years STANDARD_DEVIATION 9.7 | 64.3 years STANDARD_DEVIATION 10.8 | 70 years STANDARD_DEVIATION 0 |
| Region of Enrollment United States | 4 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 3 / 3 |
| other Total, other adverse events | 1 / 1 | 3 / 3 |
| serious Total, serious adverse events | 0 / 1 | 1 / 3 |
Outcome results
Primary
Assess Maximum Tolerated Dose of Vorinostat When Combined With Carboplatin and Etoposide of Patients With Extensive Disease SCLC
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).
Time frame: 2 years, not analyzed
Population: The first three participants enrolled were treated at dose level 1 (vorinostat 200 mg). Phase I protocol closed prematurely with no additional subjects enrolled. No analysis due to premature closure.
Secondary
Evaluate Objective Response Rate Among Patients With Extensive Disease SCLC Receiving Carboplatin and Etoposide With a Fixed Dose of Vorinostat.
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.
Time frame: 2 years, not analyzed
Population: One participant enrolled and treated in the Phase II portion. Participant rendered off treatment and off study prior to completion due to concurrent health disorders. 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.
Secondary
To Assess the Safety Profile and Define the Toxicities of Using a Fixed Dose (300mg) of Vorinostat With Carboplatin and Etoposide
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.
Time frame: 2 years, not analyzed
Population: One participant enrolled in the Phase II portion and discontinued treatment prematurely due to concurrent health issues and hospitalization. No unanticipated adverse events occurred while on study. The study closed prematurely due to low accrual. No analysis conducted.
Secondary
To Evaluate Overall Survival of Patients With Extensive Disease SCLC Receiving Carboplatin, Etoposide, and a Fixed Dose (300mg) of Vorinostat
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.
Time frame: 2 years, not analyzed
Population: One participant enrolled on Phase II. Off treatment and off study prematurely due to concurrent health disorders.