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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)

Phase 2
18 Years
Open (Enrolling)
Non-small Cell Lung Cancer

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Trial Information

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)

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.

Inclusion Criteria:

1. 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)

2. Progressive disease following the first or second line cytotoxic chemotherapy
regimen(s) including at least one platinum-containing regimen.

3. Measurable disease according to RECIST 1.1.40

4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2.41

5. Age ≥ 18 years.

6. Life expectancy of at least three (3) months.

7. Written informed consent that is consistent with ICH-GCP guidelines.

Exclusion Criteria:

1. More than three (3) prior cytotoxic chemotherapy treatment regimen for relapsed or
metastatic NSCLC.

2. Prior treatment with EGFR targeting small molecules or antibodies (e.g., gefitinib,
erlotinib, cetuximab).

3. 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.

4. Radiotherapy within 2 weeks prior to study entry. Only palliative radiotherapy to
non-target lesion should be allowed for the entered cases.

5. 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.

6. Any other current malignancy or malignancy diagnosed within the past five (5) years
(other than non-melanomatous skin cancer and in situ cervical cancer).

7. Known pre-existing interstitial lung disease.

8. 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.

9. Absolute neutrophil count (ANC) <1500 / mm3.

10. Platelet count < 100,000 / mm3.

11. Serum creatinine >1.5 times upper limit of normal (ULN) or creatinine clearance < 60
ml / min

12. Bilirubin > 1.5 times upper limit of normal.

13. 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).

14. 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.

15. Cardiac left ventricular function with resting ejection fraction of less than 50%.

16. 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.

17. 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.

18. Pregnancy or breast-feeding.

19. Patients unable to comply with the protocol.

20. Active hepatitis B infection, active hepatitis C infection or known HIV carrier.

21. Known or suspected active drug or alcohol abuse.

22. Requirement for treatment with any of the prohibited concomitant medications listed
in Section 4.2.2.

23. Any contraindications for therapy with simvastatin.

24. Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs.

25. Use of any investigational drug within 4 weeks of randomization (unless a longer time
period is required by local regulations).

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response rate

Outcome Description:

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

Outcome Time Frame:

each 8 weeks

Safety Issue:


Principal Investigator


Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Center


Korea: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

December 2015

Related Keywords:

  • Non-Small Cell Lung Cancer
  • BIBW 2992
  • Simvastatin
  • advanced stage
  • previously treated patients
  • non-adenocarcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms