Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Relapsed Non-Small-Cell Lung Cancer, Refractory Non-Small-Cell Lung Cancer
Brief summary
The reason for this study will be to find the safest maximum tolerated dose of oral vorinostat in combination with erlotinib \[Tarceva (TM)\] that can be given to patients with lung cancer who have relapsed or failed other therapy for the disease. Once the safest maximum tolerated dose of vorinostat is determined, patients enrolled in the clinical trial will continue vorinostat and erlotinib for up to 8 months. Safety and effectiveness will also be evaluated.
Interventions
DRUGVorinostat
Vorinostat 200 mg twice a day for 3 days a week.
DRUGerlotinib
erlotinib 150 mg once a day.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females 18 years of age and older with a confirmed diagnosis of non-small-cell lung cancer (NSCLC) who have failed at least one prior treatment for NSCLC. * Patients must have proven disease by CT scan or MRI. * Patients must be at least 4 weeks from any chemotherapy for cancer or from any surgeries or from any treatment using an investigational drug. * Patients must be 2 weeks out from radiation therapy. * At screening the patient must have normal lab results and can not be pregnant. * Women and men must agree to practice adequate birth control during the study. * Patient has the ability to understand and sign the consent form.
Exclusion criteria
* Patient had prior treatment with vorinostat or erlotinib. * Patient has any of the following conditions: active infections including hepatitis B or C, unstable brain metastases, swallowing difficulties, heart problems, significant eye abnormalities, drug or alcohol abuse, mental illness or pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) Occurring in Cycle 1 of the Phase I Portion of the Study | Day 1 to 28 in the Phase I portion of the study | Adverse event(s) that determined the treatment dose level was not tolerable for that patient in Cycle 1 of the Phase I portion of the study. |
| Dose Limiting Toxicity Occurring in Cycle 1 of the Phase II Portion of the Study | Day 1 to 28 in the Phase II portion of the study | Adverse event(s) that determined the treatment dose level was not tolerable for that patient in Cycle 1 of the Phase II portion of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progressive Disease (PD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | Every 57 days beginning with Cycle 3, or more frequently if appropriate | Progressive disease is defined as a ≥20% increase in the sum of the longest diameter, the appearance of one or more new lesions and/or unequivocal progression of non-target lesions by conventional or spiral CT or MRI |
| Unconfirmed Partial Response (UPR) Based on Response Criteria in Solid Tumors (RECIST) | Every 57 days beginning with Cycle 3, or more frequently if appropriate | An unconfirmed partial response is defined as a partial response that has not been confirmed by a follow up CT scan (or MRI) at least 4 weeks after the criteria for response are first met. (A partial response is defined as an at least 30% reduction in the sum of the longest diameter of the target lesions. Non-target lesions must be at least stable) |
| Progression-free Survival | Day 1 to disease progression or death | Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). |
| Disease Progression After Week 8 Based on Response Criteria in Solid Tumors (RECIST) | Every 57 days beginning with Cycle 3 (Week 8), or more frequently if appropriate | First documentation of Progressive Disease (PD) occurring \> 8 weeks on study. |
| Stable Disease (SD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | Every 57 days beginning with Cycle 3, or more frequently if appropriate | Stable disease is defined as less than a radiographic partial response, but not progressive disease |
Participant flow
Recruitment details
This study was conducted at 12 investigative sites in the United States. The first patient's first visit was 30 March 2006. The study was terminated early on 12 Oct 2007 and the last patient's last visit was 30 Oct 2007.
Pre-assignment details
Enrolled patients were assigned to 1 of 2 dose escalating cohorts (A and B) in the Phase I portion of the study to determine the maximum tolerated dose (MTD). Once determined, new patients were assigned to the Phase II portion of the study and treated with the MTD. Active Phase I patients continued into Phase II.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk Vorinostat 200 mg twice a day for 3 days a week + erlotinib 150 mg once a day was evaluated in the Phase I portion of the study and determined to be the MTD and therefore the recommended Phase II dose. Of the 16 patients treated at this dose level, 4 were assigned to the Phase I portion of the study and 12 were assigned to the Phase II portion. | 16 |
| Vorinostat 300 mg q.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk Vorinostat 300 mg once a day for 3 days a week + erlotinib 150 mg once a day was evaluated in the Phase I portion of the amended study and exceeded the MTD. All patients treated at this dose level were assigned to the Phase I portion of the study. | 3 |
| Vorinostat 300 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk Vorinostat 300 mg twice a day for 3 days a week + erlotinib 150 mg once a day was evaluated in the Phase I portion of the study and exceeded the MTD. All patients treated at this dose level were assigned to the Phase I portion of the study. | 2 |
| Vorinostat 400 mg q.d. 21d/4wk + Erlotinib 150 mg q.d. 7d/wk Vorinostat 400 mg once a day for 21 out of 28 days + erlotinib 150 mg once a day was evaluated in the Phase I portion of the original study and exceeded MTD. This cohort was then amended (Amendment 1) to identify a more tolerable once daily vorinostat dosing regimen. All patients treated at this dose level were assigned to the Phase I portion of the study. | 2 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 | 2 | 1 |
| Overall Study | Discontinued due to progressive disease | 9 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Vorinostat 300 mg q.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Vorinostat 300 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Vorinostat 400 mg q.d. 21d/4wk + Erlotinib 150 mg q.d. 7d/wk | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.0 Years STANDARD_DEVIATION 4.36 | 66.0 Years STANDARD_DEVIATION 8.49 | 48.5 Years STANDARD_DEVIATION 20.51 | 59.1 Years STANDARD_DEVIATION 11.59 | 60.7 Years STANDARD_DEVIATION 11.41 |
| Age, Customized ≤ 65 years | 11 Participants | 3 Participants | 1 Participants | 2 Participants | 17 Participants |
| Age, Customized > 65 years | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Female | 8 Participants | 2 Participants | 1 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 1 Participants | 1 Participants | 1 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 16 | 3 / 3 | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 6 / 16 | 2 / 3 | 2 / 2 | 1 / 2 |
Outcome results
Primary
Dose Limiting Toxicity (DLT) Occurring in Cycle 1 of the Phase I Portion of the Study
Adverse event(s) that determined the treatment dose level was not tolerable for that patient in Cycle 1 of the Phase I portion of the study.
Time frame: Day 1 to 28 in the Phase I portion of the study
Population: All patients as treated population in Cycle 1 of the Phase I portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Dose Limiting Toxicity (DLT) Occurring in Cycle 1 of the Phase I Portion of the Study | 0 Participants |
| Vorinostat 300 mg q.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Dose Limiting Toxicity (DLT) Occurring in Cycle 1 of the Phase I Portion of the Study | 2 Participants |
| Vorinostat 300 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Dose Limiting Toxicity (DLT) Occurring in Cycle 1 of the Phase I Portion of the Study | 2 Participants |
| Vorinostat 400 mg q.d. 21d/4wk + Erlotinib 150 mg q.d. 7d/wk | Dose Limiting Toxicity (DLT) Occurring in Cycle 1 of the Phase I Portion of the Study | 1 Participants |
Primary
Dose Limiting Toxicity Occurring in Cycle 1 of the Phase II Portion of the Study
Adverse event(s) that determined the treatment dose level was not tolerable for that patient in Cycle 1 of the Phase II portion of the study.
Time frame: Day 1 to 28 in the Phase II portion of the study
Population: All patients as treated population in Cycle 1 of the Phase II portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Dose Limiting Toxicity Occurring in Cycle 1 of the Phase II Portion of the Study | 3 Participants |
Secondary
Disease Progression After Week 8 Based on Response Criteria in Solid Tumors (RECIST)
First documentation of Progressive Disease (PD) occurring \> 8 weeks on study.
Time frame: Every 57 days beginning with Cycle 3 (Week 8), or more frequently if appropriate
Population: All patients as treated population with post-baseline data available to determine Disease Progression After Week 8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Disease Progression After Week 8 Based on Response Criteria in Solid Tumors (RECIST) | 3 Participants |
| Vorinostat 300 mg q.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Disease Progression After Week 8 Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
| Vorinostat 300 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Disease Progression After Week 8 Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
| Vorinostat 400 mg q.d. 21d/4wk + Erlotinib 150 mg q.d. 7d/wk | Disease Progression After Week 8 Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
Secondary
Progression-free Survival
Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded).
Time frame: Day 1 to disease progression or death
Population: All patients as treated population with post-baseline data available to determine progression free survival.~Cohort A, Dose Level 1 (Amended), Cohort B, Dose Level 2 and Cohort A, Dose Level 1 (Original) are not represented in the below table as post-baseline data were not available to determine progression free survival.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Progression-free Survival | 57 Days |
Secondary
Progressive Disease (PD) as Best Response Based on Response Criteria in Solid Tumors (RECIST)
Progressive disease is defined as a ≥20% increase in the sum of the longest diameter, the appearance of one or more new lesions and/or unequivocal progression of non-target lesions by conventional or spiral CT or MRI
Time frame: Every 57 days beginning with Cycle 3, or more frequently if appropriate
Population: All patients as treated population with post-baseline data available to determine Progressive Disease as Best Response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Progressive Disease (PD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 7 Participants |
| Vorinostat 300 mg q.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Progressive Disease (PD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
| Vorinostat 300 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Progressive Disease (PD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
| Vorinostat 400 mg q.d. 21d/4wk + Erlotinib 150 mg q.d. 7d/wk | Progressive Disease (PD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
Secondary
Stable Disease (SD) as Best Response Based on Response Criteria in Solid Tumors (RECIST)
Stable disease is defined as less than a radiographic partial response, but not progressive disease
Time frame: Every 57 days beginning with Cycle 3, or more frequently if appropriate
Population: All patients treated population with post-baseline data available to determine Stable Disease as Best Response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Stable Disease (SD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 6 Participants |
| Vorinostat 300 mg q.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Stable Disease (SD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 1 Participants |
| Vorinostat 300 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Stable Disease (SD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 1 Participants |
| Vorinostat 400 mg q.d. 21d/4wk + Erlotinib 150 mg q.d. 7d/wk | Stable Disease (SD) as Best Response Based on Response Criteria in Solid Tumors (RECIST) | 1 Participants |
Secondary
Unconfirmed Partial Response (UPR) Based on Response Criteria in Solid Tumors (RECIST)
An unconfirmed partial response is defined as a partial response that has not been confirmed by a follow up CT scan (or MRI) at least 4 weeks after the criteria for response are first met. (A partial response is defined as an at least 30% reduction in the sum of the longest diameter of the target lesions. Non-target lesions must be at least stable)
Time frame: Every 57 days beginning with Cycle 3, or more frequently if appropriate
Population: All patients as treated population with post-baseline data available to determine Unconfirmed Partial Response as Best Response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Unconfirmed Partial Response (UPR) Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
| Vorinostat 300 mg q.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Unconfirmed Partial Response (UPR) Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
| Vorinostat 300 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Unconfirmed Partial Response (UPR) Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
| Vorinostat 400 mg q.d. 21d/4wk + Erlotinib 150 mg q.d. 7d/wk | Unconfirmed Partial Response (UPR) Based on Response Criteria in Solid Tumors (RECIST) | 0 Participants |
Post Hoc
Dose Limiting Toxicity Occurring in Cycles 2 and Beyond of the Phase II Portion of the Study
Adverse event(s) that determined the treatment dose level was not tolerable for that patient in Cycles 2 and beyond of the Phase II portion of the study.
Time frame: After day 28 in the Phase II portion of the study
Population: All patients as treated population in Cycles 2 and beyond of the Phase II portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat 200 mg b.i.d. 3d/wk + Erlotinib 150 mg q.d. 7d/wk | Dose Limiting Toxicity Occurring in Cycles 2 and Beyond of the Phase II Portion of the Study | 3 Participants |