Non-small Cell Lung CancerPhase 2NCT01156545
BIBW 2992 Plus Simvastatin vs. BIBW 2992 in Previously Treated Patients With Advanced Non-adenocarcinomatous NSCLC
A Phase 2 study testing BIBW 2992 and simvastatin in people with Non-small Cell Lung Cancer, run by National Cancer Center, Korea at 1 site in South Korea.
Trial summary
The investigators hypothesized that simvastatin may enhance sensitivity to BIBW 2992 in non-adenocarcinoma that is relatively resistant to TKIs. Based on these data, the investigators will research the effectiveness comparing BIBW2992, an irreversible EGFR-TKI, plus simvastatin with BIBW2992 alone in the setting of a… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-small Cell Lung Cancer
- What is being tested?
- BIBW 2992 and simvastatin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 68 participants
- Where
- 1 siteSouth Korea
- Study dates
- Oct 2010to 9 Jun 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Pathologically confirmed diagnosis of Stage IIIB or Stage IV non-adenocarcinomatous non-small cell lung cancer (e.g., squamous cell or large cell carcinoma).(The 7th edition of the TNM classification for lung cancer47-See Appendix 6)
- Progressive disease following the first or second line cytotoxic chemotherapy regimen(s) including at least one platinum-containing regimen.
- Measurable disease according to RECIST 1.1.40
- Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2.41
- Age ≥ 18 years.
- Life expectancy of at least three (3) months.
- Written informed consent that is consistent with ICH-GCP guidelines.
Who cannot join
- More than three (3) prior cytotoxic chemotherapy treatment regimen for relapsed or metastatic NSCLC.
- Prior treatment with EGFR targeting small molecules or antibodies (e.g., gefitinib, erlotinib, cetuximab).
- Chemotherapy, hormonal therapy (other than megestrol acetate or steroids required for maintenance non-cancer therapy), immunotherapy or surgery (other than biopsy) within 4 weeks prior to study entry.
- Radiotherapy within 2 weeks prior to study entry. Only palliative radiotherapy to non-target lesion should be allowed for the entered cases.
- Active brain metastases with clinically significant neurological symptoms or signs. Patients with brain metastasis are allowed unless there were clinically significant neurological symptoms or signs.
- Any other current malignancy or malignancy diagnosed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer).
Show all 25Show fewer
- Known pre-existing interstitial lung disease.
- Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g. Crohn's disease, malabsorption or CTC grade ≥2 diarrhea of any etiology.
- Absolute neutrophil count (ANC) <1500 / mm3.
- Platelet count < 100,000 / mm3.
- Serum creatinine >1.5 times upper limit of normal (ULN) or creatinine clearance < 60 ml / min
- Bilirubin > 1.5 times upper limit of normal.
- Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 3 times the upper limit of normal (ULN) (if related to liver metastases > 5 times ULN).
- History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to study entrance.
- Cardiac left ventricular function with resting ejection fraction of less than 50%.
- Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
- Women of childbearing potential, or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial.
- Pregnancy or breast-feeding.
- Patients unable to comply with the protocol.
- Active hepatitis B infection, active hepatitis C infection or known HIV carrier.
- Known or suspected active drug or alcohol abuse.
- Requirement for treatment with any of the prohibited concomitant medications listed in Section 4.2.2.
- Any contraindications for therapy with simvastatin.
- Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs.
- Use of any investigational drug within 4 weeks of randomization (unless a longer time period is required by local regulations).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized Open Label Phase II Trial Comparing BIBW2992 Plus Simvastatin With BIBW2992 Plus Best Supportive Care in Previously Treated Patients With Advanced (Stage IIIB/IV) Non-adenocarcinomatous Non-small Cell Lung Cancer (NSCLC)
The investigators hypothesized that simvastatin may enhance sensitivity to BIBW 2992 in non-adenocarcinoma that is relatively resistant to TKIs. Based on these data, the investigators will research the effectiveness comparing BIBW2992, an irreversible EGFR-TKI, plus simvastatin with BIBW2992 alone in the setting of a randomized phase II study in previously treated patients with advanced non-adenocarcinomatous non-small cell lung cancer (NSCLC).
Read the detailed description
One of the main reasons of resistance to EGFR tyrosine kinase inhibitors (TKIs) is that there are alternative mechanisms for persistent activating EGFR downstream signaling, including both RAS/Erk and PI3K/Akt kinase pathways. Therefore, simultaneous inhibition of both pathways would be necessary to reduce tumor cell survival more effectively. One of the candidate combinations is concurrent use of EGFR-TKIs and statins, which are irreversible inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and have been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Beside the cholesterol lowering effect, statins have been shown to induce apoptosis in several tumor types. It affects the synthesis of other products of the mevalonate pathway such as isoprenoids, which are used as substrates for prenylation. Attachment of isoprenoids to RAS proteins facilitates their anchoring to the cell membrane where they carried out their roles. By interrupting the biosynthesis of mevalonate, statins inhibit activation of RAS and downstream signaling cascades, including the RAF/MEK/ERK and PI3K/AKT, which play critical roles in regulation of cell survival and proliferation. Therefore, it seems to be a promising therapeutic approach overcoming tumor resistance to EGFR-TKIs, which is associated with RAS activation.
According to the recent clinical result of phase II trial, a randomized phase II study of gefitinib with or without simvastatin in previously treated patients with advanced NSCLC conducted by Han et al.37 gefitinib plus simvastatin combination produced higher response rates than gefitinib alone in patients with non-adenocarcinoma (5/13 [39%] v 1/13 [8%], P=0.06). This finding suggests that simvastatin may enhance sensitivity to gefitinib in non-adenocarcinoma that is relatively resistant to gefitinib. Moreover, by Mantha et al.35 demonstrated that the combination of gefitinib and lovastatin showed significant synergic cytotoxic effects in vitro in a total of 16 squamous cell carcinomas, NSCLC, and colon carcinoma cell lines. Of special interest, these cell lines did not possess the activating mutations of EGFR, which confer increased sensitivity to gefitinib. Nevertheless, combining lovastatin with gefitinib induced more significant inhibition of AKT activation than either agent alone. Additionally, lovastatin significantly enhanced the sensitivity to gefitinib treatment regardless PTEN loss in glioblastoma cell lines. These results suggest that statins can augment EGFR inhibition.
- Conditions
- Non-small Cell Lung Cancer
- Being tested
- BIBW 2992, simvastatin
- Keywords
- BIBW 2992, Simvastatin, NSCLC, advanced stage, previously treated patients, non-adenocarcinoma
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BIBW 2992Drug
Also called afatinib
BIBW 2992 40mg, once a day, oral intake, every day
simvastatinDrug
Also called simvastar
simvastatin 40mg, once a day, oral intake, every day.
| Study group | Role | What they receive |
|---|---|---|
| Treatment arm | Experimental | BIBW 2992 plus simvastatin arm Receives: Drug: BIBW 2992; Drug: simvastatin |
| control arm | Active comparator | BIBW 2992 arm Receives: Drug: BIBW 2992 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective response rate
Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
Measured: each 8 weeks
Secondary outcomes (5)
Disease Control Rate
Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
Measured: every 8 weeks
Progression-Free Survival
Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
Measured: every 8 weeks
Overall Survival
Overall survival (OS) will be calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurs first.
Measured: every 12 weeks
Adverse event
For grading of adverse events CTC AE criteria (version 4.0) will be utilizedStatistical analysis and reporting of adverse events will concentrate on treatment-emergent adverse events. To this end, all adverse events occurring between first drug intake until 28 days (inclusive) after last treatment administration will be considered 'treatment-emergent'. Adverse events that start before first drug intake and deteriorate under treatment will also be considered as 'treatment-emergent'.
Measured: first drug intake until 28 days after last treatment administration
Pharmacogenetic and biomarkers analyses
The primary focus of predictive biomarker analyses is to investigate potential relationships of certain biomarkers with efficacy or safety endpoints. For this study, predictive efficacy analyses will be performed with such biomarkers as EGFR mutation status. EGFR mutation status will be measured in tumor samples and blood samples. In addition, plasma levels of IGFBP-3 and amphiregulin as well as gene polymorphisms related to the EGFR and IGF-1R pathways will be investigated.
Measured: every 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jul 2010 (estimated)
- Study startOct 2010
- Primary completion31 Dec 2016
- Study completion9 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-small Cell Lung CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 68 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Center, Korea
- Sponsor type
- Other government
- Collaborators
- Boehringer Ingelheim
- Responsible party
- Principal investigator, Ji-youn Han, National Cancer Center, Korea
- Investigators
- JI-YOUN HAN, M.D. PhD., Principal investigator, National Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01156545
- Sponsor's protocol ID
- NCCCTS-10-489
- Other IDs
- BIBW 2992 1200.113
- Status last verified
- Apr 2022
- First submitted
- 2 Jul 2010
- Last updated
- 6 Apr 2022
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Open Label Phase II Trial Comparing BIBW2992 Plus Simvastatin With BIBW2992 Plus Best Supportive Care in Previously Treated Patients With Advanced (Stage IIIB/IV) Non-adenocarcinomatous Non-small Cell Lung Cancer (NSCLC)
- ClinicalTrials.gov ID
- NCT01156545
- Acronym / sponsor ID
- NCCCTS-10-489
- Conditions
- Non-small Cell Lung Cancer
- Keywords
- BIBW 2992, Simvastatin, NSCLC, advanced stage, previously treated patients, non-adenocarcinoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 68 participants (actual)
- Lead sponsor
- National Cancer Center, KoreaOther government
- Collaborators
- Boehringer Ingelheim
- Study start
- Oct 2010 (actual)
- Primary completion
- 31 Dec 2016 (actual)
- Study completion
- 9 Jun 2021 (actual)
- First posted
- 5 Jul 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators hypothesized that simvastatin may enhance sensitivity to BIBW 2992 in non-adenocarcinoma that is relatively resistant to TKIs. Based on these data, the investigators will research the effectiveness comparing BIBW2992, an irreversible EGFR-TKI, plus simvastatin with BIBW2992 alone in the setting of a randomized phase II study in previously treated patients with advanced non-adenocarcinomatous non-small cell lung cancer (NSCLC).
Detailed description
One of the main reasons of resistance to EGFR tyrosine kinase inhibitors (TKIs) is that there are alternative mechanisms for persistent activating EGFR downstream signaling, including both RAS/Erk and PI3K/Akt kinase pathways. Therefore, simultaneous inhibition of both pathways would be necessary to reduce tumor cell survival more effectively. One of the candidate combinations is concurrent use of EGFR-TKIs and statins, which are irreversible inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and have been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Beside the cholesterol lowering effect, statins have been shown to induce apoptosis in several tumor types. It affects the synthesis of other products of the mevalonate pathway such as isoprenoids, which are used as substrates for prenylation. Attachment of isoprenoids to RAS proteins facilitates their anchoring to the cell membrane where they carried out their roles. By interrupting the biosynthesis of mevalonate, statins inhibit activation of RAS and downstream signaling cascades, including the RAF/MEK/ERK and PI3K/AKT, which play critical roles in regulation of cell survival and proliferation. Therefore, it seems to be a promising therapeutic approach overcoming tumor resistance to EGFR-TKIs, which is associated with RAS activation.
According to the recent clinical result of phase II trial, a randomized phase II study of gefitinib with or without simvastatin in previously treated patients with advanced NSCLC conducted by Han et al.37 gefitinib plus simvastatin combination produced higher response rates than gefitinib alone in patients with non-adenocarcinoma (5/13 [39%] v 1/13 [8%], P=0.06). This finding suggests that simvastatin may enhance sensitivity to gefitinib in non-adenocarcinoma that is relatively resistant to gefitinib. Moreover, by Mantha et al.35 demonstrated that the combination of gefitinib and lovastatin showed significant synergic cytotoxic effects in vitro in a total of 16 squamous cell carcinomas, NSCLC, and colon carcinoma cell lines. Of special interest, these cell lines did not possess the activating mutations of EGFR, which confer increased sensitivity to gefitinib. Nevertheless, combining lovastatin with gefitinib induced more significant inhibition of AKT activation than either agent alone. Additionally, lovastatin significantly enhanced the sensitivity to gefitinib treatment regardless PTEN loss in glioblastoma cell lines. These results suggest that statins can augment EGFR inhibition.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment arm | Experimental | Drug: BIBW 2992, Drug: simvastatinBIBW 2992 plus simvastatin arm |
| control arm | Active comparator | Drug: BIBW 2992BIBW 2992 arm |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Pathologically confirmed diagnosis of Stage IIIB or Stage IV non-adenocarcinomatous non-small cell lung cancer (e.g., squamous cell or large cell carcinoma).(The 7th edition of the TNM classification for lung cancer47-See Appendix 6)
- Progressive disease following the first or second line cytotoxic chemotherapy regimen(s) including at least one platinum-containing regimen.
- Measurable disease according to RECIST 1.1.40
- Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2.41
- Age ≥ 18 years.
Key exclusion criteria (25 listed)
- More than three (3) prior cytotoxic chemotherapy treatment regimen for relapsed or metastatic NSCLC.
- Prior treatment with EGFR targeting small molecules or antibodies (e.g., gefitinib, erlotinib, cetuximab).
- Chemotherapy, hormonal therapy (other than megestrol acetate or steroids required for maintenance non-cancer therapy), immunotherapy or surgery (other than biopsy) within 4 weeks prior to study entry.
- Radiotherapy within 2 weeks prior to study entry. Only palliative radiotherapy to non-target lesion should be allowed for the entered cases.
- Active brain metastases with clinically significant neurological symptoms or signs. Patients with brain metastasis are allowed unless there were clinically significant neurological symptoms or signs.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BIBW 2992Also: afatinibBIBW 2992 40mg, once a day, oral intake, every day | Drug | Treatment arm, control arm |
| simvastatinAlso: simvastarsimvastatin 40mg, once a day, oral intake, every day. | Drug | Treatment arm |
Primary outcome
Objective response rate
Time frame: each 8 weeks
Repeat tumor assessments will be performed after the completion of Week 4, Week 8, and in 8-week intervals thereafter until progression or withdrawal for another reason
5 secondary outcomes
Disease Control Rate
Time frame: every 8 weeks
Progression-Free Survival
Time frame: every 8 weeks
Overall Survival
Time frame: every 12 weeks
Adverse event
Time frame: first drug intake until 28 days after last treatment administration
Pharmacogenetic and biomarkers analyses
Time frame: every 8 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Apr 2022.
Related trials for Non-small Cell Lung Cancer
RecruitingPhase 3
A Study to Learn About the Study Medicine Called PF-08046054/SGN-PDL1V Versus Docetaxel in Adult Participants With Previously-Treated Programmed Cell Death Ligand 1 (PD-L1) Positive Non-Small-Cell Lung Cancer (NSCLC)
Non-small Cell Carcinoma, Non-Small Cell Lung Cancer Metastatic
RecruitingObservational study
Real-World Outcomes of Sevabertinib in HER2-Mutant Advanced NSCLC: A Bidirectional Cohort Study
HER2-mutant Advanced Non-Small Cell Lung Cancer
Active, not recruitingPhase 2
CAN-2409 Plus Prodrug With Standard of Care Immune Checkpoint Inhibitor for Stage III/IV NSCLC
Non Small Cell Lung Cancer
RecruitingPhase 2
Hotspot Stereotactic Ablative Radiotherapy Versus Traditional Stereotactic Ablative Radiotherapy for the Treatment of Early-Stage Non-Small Cell Lung Cancer
Early Stage Lung Non-Small Cell Carcinoma, Stage I Lung Cancer AJCC v8
RecruitingObservational study
Biospecimen Procurement for Center for Immuno-Oncology Immunotherapy Protocols
Multiple Myeloma, Lymphoma, Non-Hodgkin
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
JI-YOUN HAN, M.D. PhD. principal investigator
National Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing BIBW 2992 and simvastatin in people with Non-small Cell Lung Cancer, run by National Cancer Center, Korea at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective response rate (time frame: each 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2022.