Stage IIIB or IV Non-Small Cell Lung Cancer
Conditions
Brief summary
This Phase III clinical trial which incorporates an initial Phase II component will determine the survival of advanced Non-small cell lung cancer patients when treated with MK0683 and paclitaxel plus carboplatin
Interventions
DRUGvorinostat
vorinostat 400 mg capsules once daily. Up to 6 months of treatment
DRUGComparator: paclitaxel
intravenous (IV) paclitaxel 200 mg/m2. Up to 6 months of treatment
DRUGComparator: carboplatin
intravenous (IV) carboplatin AUC 6mg/min/ml. Up to 6 months of treatment.
DRUGComparator: placebo
vorinostat 400 mg placebo capsules once daily. Up to 6 months of treatment
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females at least 18 years of age who have confirmed diagnosis of Non-small Cell Lung Cancer * Patients with no systemic prior systemic treatment for lung cancer except patients at least 12 months from prior adjuvant therapy * Adequate bone marrow,kidney and liver function * Must be recovered and at least 4 weeks from major surgery or radiation * ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1 * Men and women must agree to use birth control during the study * Women able to have children must have a negative pregnancy test 14 days before study enrollment
Exclusion criteria
* Patients with prior treatment with other investigational agents less than 4 weeks before study enrollment * Pregnant or nursing female patients * Patients who are HIV positive * Patients who have Hepatitis A, B, or C * Patients unable to take study medication by mouth * Patients with untreated brain cancer * Patient eligible for treatment with bevacizumab and for whom bevacizumab is available
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Start of treatment to death | Defined as the time from date of randomization to death due to any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Start of treatment to disease progression or death | Defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in sum of the longest diameter of all target lesions, the appearance of a new lesion, or an increase in non-target lesions. |
| Number of Participants Who Had a Disease Response to Treatment | Every 42 days from start of treatment until disease response | Response to treatment is defined as a complete response (CR) or partial response (PR) to treatment. Confirmation of response required a second assessment performed at least 4 weeks after the initial assessment. (PR is defined as at least a 30% reduction in sum of the longest diameter of all target lesions and no increase in non-target lesions). |
Participant flow
Recruitment details
This study was conducted at 99 investigative sites worldwide. The first patient's first visit was 16 May 07 and the last patient's last visit was 12 Dec 2008.
Pre-assignment details
Randomized participants were stratified by Stage (IIIB versus IV), geographic region and eligibility for treatment with bevacizumab prior to treatment assignment.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat + Paclitaxel + Carboplatin Experimental arm: Vorinostat capsules (400 mg) once daily on Days -4 through 10 of Cycle 1 (25 day treatment cycle) and Days 1 through 14 of each subsequent 21 day treatment cycle; paclitaxel (200 mg/m2) and carboplatin (area under concentration/time curve of 6 mg/min/mL) administered by intravenous (IV) infusion on Day 1 of each treatment cycle. | 126 |
| Placebo + Paclitaxel + Carboplatin Placebo Comparator arm: Placebo capsules once daily on Days -4 through 10 of Cycle 1 (25 day treatment cycle) and Days 1 through 14 of each subsequent 21 day treatment cycle; paclitaxel (200 mg/m2) and carboplatin (area under concentration/time curve of 6 mg/min/mL) administered by intravenous (IV) infusion on Day 1 of each treatment cycle. | 127 |
| Total | 253 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 30 | 17 |
| Overall Study | Did not receive study medication | 1 | 4 |
| Overall Study | Lack of Efficacy | 28 | 29 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Physician Decision | 10 | 5 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Trial Terminated | 3 | 6 |
| Overall Study | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Vorinostat + Paclitaxel + Carboplatin | Placebo + Paclitaxel + Carboplatin | Total |
|---|---|---|---|
| Age, Customized 65 years or Older | 56 participants | 38 participants | 94 participants |
| Age, Customized Less Than 65 years | 70 participants | 89 participants | 159 participants |
| Cancer Stage IIIB | 14 Participants | 15 Participants | 29 Participants |
| Cancer Stage IV | 112 Participants | 112 Participants | 224 Participants |
| Eligibility to receive treatment with Bevacizumab Eligible | 70 Participants | 63 Participants | 133 Participants |
| Eligibility to receive treatment with Bevacizumab Ineligible | 55 Participants | 60 Participants | 115 Participants |
| Eligibility to receive treatment with Bevacizumab Unknown | 1 Participants | 4 Participants | 5 Participants |
| Geographic region where the participant lived Asia | 22 Participants | 24 Participants | 46 Participants |
| Geographic region where the participant lived Europe (United Kingdom, Italy, Germany, and Spain) | 41 Participants | 40 Participants | 81 Participants |
| Geographic region where the participant lived North America | 25 Participants | 27 Participants | 52 Participants |
| Geographic region where the participant lived Rest of the World | 38 Participants | 36 Participants | 74 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native mix | 13 participants | 12 participants | 25 participants |
| Race/Ethnicity, Customized Asian | 31 participants | 32 participants | 63 participants |
| Race/Ethnicity, Customized Black | 3 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized White | 79 participants | 79 participants | 158 participants |
| Sex: Female, Male Female | 34 Participants | 56 Participants | 90 Participants |
| Sex: Female, Male Male | 92 Participants | 71 Participants | 163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 114 / 124 | 117 / 124 |
| serious Total, serious adverse events | 63 / 124 | 45 / 124 |
Outcome results
Primary
Overall Survival
Defined as the time from date of randomization to death due to any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up.
Time frame: Start of treatment to death
Population: Intention-to-treat (ITT) population is defined as all randomized participants. Participants are counted in the group to which they are randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Paclitaxel + Carboplatin | Overall Survival | 11.0 Months |
| Placebo + Paclitaxel + Carboplatin | Overall Survival | 14.0 Months |
p-value: 0.992Stratified Log Rank
Secondary
Number of Participants Who Had a Disease Response to Treatment
Response to treatment is defined as a complete response (CR) or partial response (PR) to treatment. Confirmation of response required a second assessment performed at least 4 weeks after the initial assessment. (PR is defined as at least a 30% reduction in sum of the longest diameter of all target lesions and no increase in non-target lesions).
Time frame: Every 42 days from start of treatment until disease response
Population: Full analysis set~(FAS) population is defined as all randomized participants who have received at least one dose of study medication. There are 253 participants randomized in the study. Five (5) didn't take any study medication. Therefore, 248 participants are included in this analysis population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorinostat + Paclitaxel + Carboplatin | Number of Participants Who Had a Disease Response to Treatment | Responder | 28 Participants |
| Vorinostat + Paclitaxel + Carboplatin | Number of Participants Who Had a Disease Response to Treatment | Non-Responder | 97 Participants |
| Placebo + Paclitaxel + Carboplatin | Number of Participants Who Had a Disease Response to Treatment | Responder | 36 Participants |
| Placebo + Paclitaxel + Carboplatin | Number of Participants Who Had a Disease Response to Treatment | Non-Responder | 87 Participants |
p-value: 0.899Stratified Miettinen and Nurminen
Secondary
Progression Free Survival
Defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in sum of the longest diameter of all target lesions, the appearance of a new lesion, or an increase in non-target lesions.
Time frame: Start of treatment to disease progression or death
Population: Full analysis set~(FAS) population defined as all randomized participants who have received at least one dose of study medication. There are 253 participants randomized in the study 5 didn't take any study medication. Therefore, 248 participants are included in this analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Paclitaxel + Carboplatin | Progression Free Survival | 4.3 Months |
| Placebo + Paclitaxel + Carboplatin | Progression Free Survival | 5.5 Months |
p-value: 0.862Finkelstein's Interval Censored Method