Carcinoma, Non Small Cell Lung
Conditions
Keywords
non small cell lung cancer, HDAC, proteasome inhibitor
Brief summary
The purpose of this study is to evaluate the efficacy of vorinostat and bortezomib in the third line treatment of advanced NSCLC, as well as to assess toxicity (including neuropathy) and tolerability of this regimen.
Detailed description
Current treatment for non-small cell lung cancer (NSCLC) remains inadequate. Vorinostat is a novel agent that inhibits the enzymatic activity of histone deacetylases (HDACs). Bortezomib is a small molecule proteasome inhibitor. Preclinical and clinical studies have shown the advantages of combining these two agents in the treatment of NSCLC
Interventions
DRUGvorinostat
400 mg by mouth once daily for days 1-14 of each 21 day cycle
DRUGbortezomib
1.3 mg/m2 IV on days 1, 4, 8, 11 of each 21 day cycle
Sponsors
Millennium Pharmaceuticals, Inc.
Merck Sharp & Dohme LLC
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically/histologically confirmed NSCLC * Advance NSCLC (stage IIIB w/ effusion, stage IV, or recurrent disease) * Measurable disease * Two prior systemic anti-cancer (cytotoxic or biologic) regimens for advanced/metastatic disease, including one (1) platinum-based chemotherapy * Prior treatment allowed if side effects have resolved and 3 weeks has passed since last dose of treatment (1 week for palliative radiation therapy) * ECOG performance status 0, 1, or 2 * Patients with brain metastases are allowed, if clinically stable after treatment * Normal liver, kidney, and marrow function * 18 years of age or older * Negative pregnancy test for women of child-bearing potential. * Life expectancy 3 months or more * No concurrent use of other antitumor agents
Exclusion criteria
* Prior therapy with vorinostat, HDAC inhibitors, or bortezomib * Pre-existing neuropathy grade \>/= 2 * Myocardial infarction within 6 months prior to enrollment or have NY Heart Association Class III or Class IV heart failure * Have taken valproic acid \</= 4 weeks prior to enrollment * Previous or current malignancies of other histologies within the past 5 years, except cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin * Hypersensitivity to bortezomib, boron, or mannitol * Serious medical or psychiatric illness likely to interfere with participation in the clinical study * Pregnant women * HIV positive patients * Hepatitis infection (HCV or HBV) patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Three-month Progression-free Survival | Three-months post-treatment | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started or the appearance of one or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Until disease progression, up to 2 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI, CT, or chest x-ray: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR. |
| Median Overall Survival | 5 years | — |
| Toxicity | 30 days post-treatment | Graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 |
Participant flow
Recruitment details
Recruitment occurred during 2/16/2008 and 03/09/2010.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat + Bortezomib Vorinostat 400 mg + Bortezomib 1.3 mg/m2
vorinostat: 400 mg by mouth once daily for days 1-14 of each 21 day cycle
bortezomib: 1.3 mg/m2 IV on days 1, 4, 8, 11 of each 21 day cycle | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Vorinostat + Bortezomib |
|---|---|
| Age, Continuous | 57 years |
| Disease Stage Brain Metastases | 6 participants |
| Disease Stage Metastatic | 16 participants |
| Disease Stage Recurrent | 2 participants |
| Histology Adenocarcinoma | 9 participants |
| Histology NSCLC, NOS | 7 participants |
| Histology Squamous Cell | 2 participants |
| Performance Status 0 | 5 participants |
| Performance Status 1 | 12 participants |
| Performance Status 2 | 1 participants |
| Prior first-line systemic therapy Paclitaxel/Platinum | 10 participants |
| Prior first-line systemic therapy Paclitaxel/Platinum/Bevacizumab | 2 participants |
| Prior first-line systemic therapy Paclitaxel/Platinum/Investigational Drug | 2 participants |
| Prior first-line systemic therapy Pemetrexed/Platinum | 3 participants |
| Prior first-line systemic therapy Vinorelbine/Platinum | 1 participants |
| Prior second-line systemic therapy Docetaxel/Investigational drug | 1 participants |
| Prior second-line systemic therapy Erlotinib | 4 participants |
| Prior second-line systemic therapy Pemetrexed | 10 participants |
| Prior second-line systemic therapy Pemetrexed/Investigational drug | 1 participants |
| Prior second-line systemic therapy Platinum doublets | 2 participants |
| Prior thoracic radiation therapy | 6 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 18 participants |
| Response to first-line therapy Not reported | 1 participants |
| Response to first-line therapy Partial response | 7 participants |
| Response to first-line therapy Progressive disease | 6 participants |
| Response to first-line therapy Stable disease | 4 participants |
| Response to second-line therapy Not reported | 1 participants |
| Response to second-line therapy Partial response | 1 participants |
| Response to second-line therapy Progressive disease | 13 participants |
| Response to second-line therapy Stable disease | 3 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 18 |
| serious Total, serious adverse events | 8 / 18 |
Outcome results
Primary
Three-month Progression-free Survival
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time frame: Three-months post-treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat + Bortezomib | Three-month Progression-free Survival | 11.1 percentage of participants |
Secondary
Median Overall Survival
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat + Bortezomib | Median Overall Survival | 4.7 months |
Secondary
Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI, CT, or chest x-ray: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR.
Time frame: Until disease progression, up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorinostat + Bortezomib | Response Rate | Partial response | 0 participants |
| Vorinostat + Bortezomib | Response Rate | Stable disease | 5 participants |
| Vorinostat + Bortezomib | Response Rate | Progressive disease | 13 participants |
Secondary
Toxicity
Graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
Time frame: 30 days post-treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorinostat + Bortezomib | Toxicity | Hyponatremia Grade 3 | 3 participants |
| Vorinostat + Bortezomib | Toxicity | Thrombocytopenia Grade 3 | 7 participants |
| Vorinostat + Bortezomib | Toxicity | Thrombocytopenia Grade 4 | 1 participants |
| Vorinostat + Bortezomib | Toxicity | Lymphopenia Grade 3 | 3 participants |
| Vorinostat + Bortezomib | Toxicity | Fatigue Grade 3 | 4 participants |
| Vorinostat + Bortezomib | Toxicity | Fatigue Grade 4 | 1 participants |
| Vorinostat + Bortezomib | Toxicity | Vomiting Grade 3 | 2 participants |
| Vorinostat + Bortezomib | Toxicity | Dizziness Grade 3 | 2 participants |
| Vorinostat + Bortezomib | Toxicity | Syncope Grade 3 | 2 participants |
| Vorinostat + Bortezomib | Toxicity | Neuropathy Grade 3 | 2 participants |