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Phase II Study of Bay 43-9006 (Sorafenib) With Evaluation of RAS Signal Pathway in Patients With Relapsed Non-Small Cell Lung Cancer

Phase 2
18 Years
Not Enrolling
Non-Small-Cell Lung Carcinoma

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Trial Information

Phase II Study of Bay 43-9006 (Sorafenib) With Evaluation of RAS Signal Pathway in Patients With Relapsed Non-Small Cell Lung Cancer

Despite advances in systemic chemotherapy, patients with stage IV NSCLC will die from their
disease. The median survival of all patients is 8-16 months, with a one year-survival rate
of 33%. Chemotherapy is the mainstay of treatment of advanced disease. Based on available
data from randomized trials, current treatment recommendations are to treat with one of
several effective cisplatin-doublets which have resulted in median survival of 16 to 18
months. Second line chemotherapy is able to improve outcome in patients who have had prior
cisplatin therapy. Although these important milestones represent improvements in the care
of patients with metastatic NSCLC, outcome has not been able to be further improved by
substituting one active drug for another in a platinum-based doublet, treating patients with
more than four cycles of chemotherapy or by using cisplatin-based triplets. It is clear
that if we are to improve outcome of NSCLC patients, we will need to develop drugs with
novel mechanisms of action that perhaps will inhibit major cellular signaling pathways
affecting survival, proliferation and angiogenesis. One new compound, BAY 43-9006, was
designed to inhibit Raf and is also known to inhibit other kinases including VEGFR2, VEGFR3,
PDGFR-beta, Flt3, c-KIT, and p38(1). BAY 43-9006 has shown in vitro activity against NSCLC
cell lines NCI-H460 and A549 with tumor growth inhibition of 27% to 68%. In addition, BAY
43-9006 has shown activity in the H460 NSCLC xenograft model. In NSCLC, the proliferation
signaling of the Ras/Raf/MEK/ERK pathway is increased due to the frequent (30%) presence of
K-ras mutations in the tumor. Mutations in K-ras have been associated with malignant
transformation of normal epithelium and constitutive activation of p21 and its downstream
effects on cellular proliferation and inhibition of apoptosis. Clinical observations have
shown that tumors with K-ras mutations tended to be smaller but more poorly differentiated,
and associated with a significantly worse three-year mortality rate. As mentioned above,
other pathways significant to the malignant potential of NSCLC, particularly those involved
in angiogenesis, may also be affected by BAY 43-9006. The in vitro and in vivo data support
the clinical investigation of BAY 43-9006 as an inhibitor of the Ras/Raf/MEK/ERK downstream
proliferation effects. The goal of this phase II trial is to determinate if BAY 43-9006 is
active in NSCLC, and to measure the BAY 43-9006 biological effects on the Ras/Raf/MEK/ERK
pathway. To achieve these goals, patients with relapsed or recurrent NSCLC will be given
BAY 43-9006 (four weeks cycle of 400mg PO BID). A series of correlative studies will be
done during treatment to measure biological and clinical effects of BAY 43-9006. These
studies will include analyses of tissue and blood samples as well as correlative imaging

Inclusion Criteria


Histologically documented Non-small cell lung cancer and confirmed by the Laboratory of
Pathology at the Clinical Center/National Institutes of Health (NIH) or the Laboratory of
Pathology at National Naval Medical Center (NNMC).

Recurrent or progressed Non-Small Cell Lung Cancer (NSCLC).

Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as greater
than 20 mm with conventional techniques or as greater than 10 mm with spiral Computed
tomography (CT) scan.

Patients must have recovered from toxicity related to prior therapy to at least to grade 1
(defined by Common Terminology Criteria for Adverse Events (CTCAE) 3.0) and must not have
had prior chemotherapy within 4 weeks. Patients must be at least 28 days since any prior
radiation or major surgery.

Age greater than 18 years (males or non-pregnant females). Because no dosing or adverse
event data are currently available on the use of BAY 43-9006 in patients less than 18
years of age, children are excluded from this study but will be eligible for future
pediatric single-agent trials, if applicable.

Life expectancy of greater than 3 months.

Eastern Cooperative Oncology Group (ECOG) performance status less than 2 (Karnofsky >

Patients must have adequate organ and marrow function (as defined below). Patients must
have returned to base line or grade one from any acute toxicity related to prior therapy.

Leukocytes greater than 3,000/micro l;

Absolute neutrophil count greater than 1,200/micro l;

Platelets greater than 100,000/micro l;

International normalized ratio (INR) less than or equal to 1.2

Partial thromboplastin time (PTT) less than or equal to 36 seconds or abnormality can be
explained by the presences of lupus anticoagulant

Total bilirubin less than or equal to 1.5 times the institutional upper limits of normal;

Aspartate aminotransferase, oxaloacetic transaminase (AST,SGOT) and alanine transaminase,
serum glutamic pyruvic transaminase (ALT,SGPT) less than 2.5 times the institutional upper
limits of normal;

Creatinine or creatinine clearance less than or equal to 1.5 times the institutional upper
limits of normal or greater than 45 mL/min/1.73 m^2 for patients with creatinine levels
above institutional normal.

The effects of BAY 43-9006 on the developing human fetus at the recommended therapeutic
dose are unknown. For this reason and because kinase inhibitors are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation and continue for at least 2 months after
completion. Should a woman become pregnant or suspect she is pregnant while participating
in this study, she should inform her treating physician immediately. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to treatment of
the mother with BAY 43-9006, breastfeeding should be discontinued if the mother is treated
with BAY 43-9006.

Ability to comply with daily oral self administration schedule, and the ability to
understand and the willingness to sign a written informed consent document.


Patients with symptomatic brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.
However, patients who have had treatment for their brain metastases and whose brain
metastatic disease status has remained stable for at least 3 months without steroids may
be enrolled at the discretion of the principal investigator.

Uncontrolled medical illness including, but not limited to, ongoing or uncontrolled,
symptomatic congestive heart failure (American Heart Association (AHA) Class II or worse),
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.

Human immunodeficiency virus (HIV)positive patients receiving combination anti-retroviral
therapy are excluded from the study because of possible pharmacokinetic interactions with
BAY 43-9006. HIV positive patients not receiving antiretroviral therapy are excluded due
to the possibility that BAY 43-9006 may worsen their condition and the likelihood that the
underlying condition may obscure the attribution of adverse events with respect to BAY

Patients may not be receiving any other investigational agents.

History of another invasive malignancy in the last five years. Non-invasive, non-melanoma
skin cancers will be allowed.

Patients with conditions that would impair their ability to swallow tablets are excluded.

Patients must not have any evidence of bleeding diathesis.

Patients must not be on therapeutic anticoagulation. Prophylactic anticoagulation (i.e.
low dose warfarin) of venous or arterial access devices is allowed provided that the
requirements for prothrombin time (PT), international normalized ratio (INR) or partial
thromboplastin time (PTT) are met.

Both men and women and members of all races and ethnic groups are eligible for this trial.
Every effort will be made to recruit women and minorities in this study.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response Rate

Outcome Description:

Percentage of participants with response rate = CR + PR. Response will be evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR (complete response) is the disappearance of all target lesions; PR (partial response) is a 30% decrease in the sum of the longest diameter of target lesions; PD (progressive disease) is a 20% increase in the sum of the longest diameter of target lesions; and SD (stable disease) are small changes that do not meet the above criteria. Please see the Protocol Link module for additional information about RECIST if desired.

Outcome Time Frame:

17 months

Safety Issue:


Principal Investigator

Giuseppe Giaccone, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

December 2004

Completion Date:

January 2011

Related Keywords:

  • Non-Small-Cell Lung Carcinoma
  • Non-Small Cell
  • Molecular
  • Targeted
  • Therapies
  • Cancer
  • Non-Small Cell Lung Cancer
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



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