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Phase I Dose-Escalating, Open-Label, Non-Placebo Controlled Study of BAY 43-9006 (Sorafenib) in Combination With Carboplatin, Paclitaxel and Bevacizumab in Previously Untreated Patients With Stage IIIB (With Malignant Pleural Effusions) or Stage IV Non-Small Cell Lung Cancer (NSCLC)


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Lung Cancer

Thank you

Trial Information

Phase I Dose-Escalating, Open-Label, Non-Placebo Controlled Study of BAY 43-9006 (Sorafenib) in Combination With Carboplatin, Paclitaxel and Bevacizumab in Previously Untreated Patients With Stage IIIB (With Malignant Pleural Effusions) or Stage IV Non-Small Cell Lung Cancer (NSCLC)


Sorafenib is designed to stop the growth of cells that are caused by genetic changes often
associated with cancer. Paclitaxel is designed to work by blocking the mechanisms of cell
division in cancer cells, which may cause them to die. Carboplatin is designed to work by
interfering with the growth of cancer cells by stopping cell division. Bevacizumab is
designed to prevent or slow down the growth of cancer cells by blocking the effects of a
blood-vessel stimulating agent that plays an important role in the growth of both normal and
abnormal blood vessels.

If you are found to be eligible to take part in this study, you will receive 4 different
drugs during the study. This study will follow a 3-week schedule known as a study "cycle."

In the first part of the study, researchers are trying to find out the highest dose of the
study drugs that can be safely given together. The first group of 6 participants will
receive lower doses of sorafenib and bevacizumab. The doses of paclitaxel and carboplatin
will stay the same for up to 6 cycles for the study for all participants who complete 6
cycles. If the first 6 participants do not have intolerable side effects, the next group of
patients will get higher doses of bevacizumab. The doses of sorafenib will be increased
until at least some participants have unacceptable side effects. The dose that you get will
not increase during the study, but if you have bad side effects, your dose of sorafenib,
bevacizumab, paclitaxel, or carboplatin may be lowered at future visits.

On Day 1 of each cycle, you will be given bevacizumab, paclitaxel, and carboplatin in your
vein as an infusion. Paclitaxel will be infused over 3 hours, followed by carboplatin over
30 minutes, followed by bevacizumab over 90 minutes for the first 2 cycles. Your
bevacizumab infusion may be given over a shorter time period in later cycles. You will stay
in the clinic for at least 30 minutes after your bevacizumab infusion for all cycles after 1
and 2. You will take sorafenib by mouth twice a day, once in the morning before 11:00 am
and once in the evening before 11:00 p.m. Sorafenib should be taken with about 1 cup of
water on an empty stomach (either 1 hour before a meal or 2 hours after a meal) or with a
moderate fat diet (about 30% of calories from fat). Sorafenib must be swallowed whole
without chewing.

On Day 1 of Cycles 1 and 2, your complete medical history will be recorded, and you will
have a physical exam including measurement of your vital signs and weight. You will be
asked questions to find out how the disease is progressing and how the disease affects the
quality of life. You will be asked about any side effects you may be experiencing. If
possible, you should not change your medications between Cycle 1 Day 1 until all procedures
are completed on Cycle 2 Day 3. Blood (about 5 teaspoons) and urine will be collected for
routine tests. You will receive infusions of paclitaxel, carboplatin, and bevacizumab into
a vein.

On Cycle 1 Day 2, blood (about 1 tablespoon) will be drawn for routine tests.

On Cycle 1 Day 3, blood (about 1 tablespoon) will be collected for routine tests. After
your blood samples have been collected, you will be given your morning dose of sorafenib.
You will be given sorafenib to take at home that night.

On Cycle 2 Day 2, blood (about 1 tablespoon) will be drawn for routine tests. Once your
blood samples has been collected, your morning dose of sorafenib will be given to you in the
clinic. You will be given sorafenib to take at home that night.

On Cycle 2 Day 3, blood (about 1 tablespoon) will be drawn for routine tests. Once your
blood sample has been collected, your morning dose of sorafenib will be given to you in the
clinic. Before you leave the clinic, you will be given enough sorafenib tablets to last
until your next cycle visit.

On Cycles 1-2 Days 8 and 15, your complete medical history will be recorded, and you will
have a physical exam including measurement of your vital signs and weight. You will have a
performance status evaluation. You will be asked about any side effects you may be
experiencing. Blood (about 5 teaspoons) and urine will be collected for routine tests.

On Day 1 of Cycle 3 and remaining cycles, you will return all study medication and/or the
empty bottle. Your complete medical history will be recorded, and you will have a physical
exam including measurement of your vital signs and weight. You will be asked questions to
determine how the disease is progressing, and how the disease affects your quality of life.
You will be asked about any side effects you may be experiencing. Blood (about 5 teaspoons)
and urine will be collected for routine tests. You will receive infusions of paclitaxel,
carboplatin, and bevacizumab. You will stay in the clinic for at least 30 minutes after
your bevacizumab infusion. Before you leave the clinic, you will be given enough sorafenib
to last until the next cycle.

On Days 8 and 15 of Cycle 3 and remaining cycles, blood (about 5 teaspoons) and urine will
be collected for routine tests.

On Day 1 of all odd-numbered cycles (starting with Cycle 3, 5, 7, 9...), you will have CT
scans, MRI scans, and/or other x-rays to check the status of the disease.

Modified Dose Levels 4 and 5:

To find out if interrupted dosing of sorafenib will result in fewer or less severe side
effects, 2 additional dose levels, where the dose of sorafenib will be changed (modified),
will be performed. For Modified Dose Level 4, sorafenib will be interrupted for 2 days
after every 4-5 days . For Modified Dose Level 5, sorafenib will be interrupted for 1 week
after 2 weeks of continuous therapy.

For these 2 additional dose levels, the sorafenib dosing schedule will be changed. There
will be 6 patients enrolled at each dose level. Participants in Dose Level 4 may continue
treatment for 4 to 6 cycles. This is done to accurately evaluate the dose level.
Researchers will evaluate any side effects related to this new dosing schedule of sorafenib.
After all 6 patients have been enrolled in Dose level 4, then 6 additional patients will be
enrolled in Dose Level 5. If no intolerable side effects are seen at Dose Level 5, then 6
additional patients can be enrolled in that dose level. This is done so additional PK
testing can be done.

For Modified Dose Level 4 and 5, "on Day 1 of Cycle 1 and 2, you will be given bevacizumab,
paclitaxel, and carboplatin in your vein as an infusion. Paclitaxel will be infused over 3
hours, followed by carboplatin over 30 minutes, followed by bevacizumab over 90 minutes for
the first 2 cycles. Your bevacizumab infusion may be given over a shorter time period in
later cycles. You will stay in the clinic for at least 30 minutes after your bevacizumab
infusion for all cycles after 1 and 2. "

Modified Dose level 4:

For Modified Dose level 4, on Day 3 through Day 19 of Cycle 1, you will receive sorafenib by
mouth in the morning, after the morning PK tests have been collected (on Day 3 only).
Participants will take the evening dose of sorafenib on their own. After that, participants
will take sorafenib on their own twice a day for 5 days on and 2 days off. This will
continue through Day 19 on an outpatient basis.

On Day 2 through Day 19 of Cycle 2, you will receive sorafenib by mouth in the morning,
after the morning PK tests have been collected on Day 2 (Cycle 2 only). Participants will
take the evening dose of sorafenib on their own. After that, participants will take
sorafenib on their own twice a day for 5 days on and 2 days off. This will continue through
Day 19 on an outpatient basis. The modified dose level 4 and 5 patients will not take
sorafenib on Days 1, 2, 6, 7, 13, 14, 20 and 21 of Cycle 1.

Modified Dose level 5:

For Modified Dose Level 5, on Day 3 through Day 15 of Cycle 1, you will receive sorafenib by
mouth in the morning, after the morning PK tests have been collected (on Day 3 only).
Participants will take the evening dose of sorafenib on their own. After that, participants
will take sorafenib on their own twice a day for 14 days through Day 15 on an outpatient
basis. Participants will not take sorafenib on Days 1, 2 and Days 16-21.

On Day 2 through Day 15 of Cycle 2, you will receive sorafenib by mouth in the morning,
after the morning PK tests have been collected (on Day 2 Cycle 2 only). Participants will
take the evening dose of sorafenib on their own. After that, participants will take
sorafenib on their own twice a day for 14 days through Day 15 on an outpatient
basis.Participants will not take sorafenib on Days 1, 2 and Days 16-21.

You may stay on study as long as the disease does not get worse, and intolerable side
effects do not develop.

Once you are off study, you will have an end-of-study visit 21-35 days after your last dose
of the study drug. You will need to return all unused study medication and/or the empty
bottles. You will have a physical exam, including measurement of your vital signs, height,
and weight. You will have a performance status evaluation and an ECG. You will be asked
about any side effects you may be experiencing. CT scans, MRIs, and/or x-rays will be taken
to check the status of the disease. Blood (about 5 teaspoons) and urine will be collected
for routine blood tests. Women who are able to have children must have a negative blood
(about 1-2 teaspoons ) pregnancy test.

This is an investigational study. Sorafenib, paclitaxel, carboplatin, and bevacizumab are
all FDA approved and commercially available. The combination of these 4 drugs is not FDA
approved, and it has been authorized for use in research only. Up to 60 patients will take
part in this multicenter study. Up to 30 patients will be enrolled at M.D. Anderson.


Inclusion Criteria:



1. Ability to understand and the willingness to sign a written informed consent. A
signed informed consent must be obtained prior to any study specific procedures.

2. Patients must have Stage IIIB (with malignant pleural effusions) or Stage IV
histological or cytological confirmation of non-small cell carcinoma (excluding
squamous).

3. Age >/= 18 years old

4. Patients must have at least 1 measurable lesion. Lesions must be evaluated by
computed tomography (CT) scan or magnetic resonance imagining (MRI)

5. ECOG Performance Status of 0 - 1

6. Controlled blood pressure (defined as systolic BP mmHg)

7. Adequate bone marrow, liver and renal function as assessed by the following
laboratory requirements to be conducted within 7 days prior to start of first dose:
Hemoglobin >/= 9.0 g/dL; White blood cell (WBC) count >/= 2,500/mm3, Absolute
neutrophil count (ANC) >/= 1,500/mm3, Platelet count >/= 100,000/mm3, Total bilirubin
for patients with liver involvement), INR
8. Inclusion Criteria #7: Serum creatinine /= 45
mL/min (CrCl = Wt (kg) x (140 - age)/72 x Cr level, female x 0.85) for patients with
creatinine levels above institutional normal. Urinalysis (UA) must show less than 1+
protein urine, or the patient will require a repeat UA. If repeat UA shows 1+ protein
or more, a 24 hour collection will be required and must show total protein mg/24 hour to be eligible

9. Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to start of treatment.

10. Women of childbearing potential and men must agree to use adequate contraception
prior to study entry and for the duration of study participation, including the 30
day period after last study drug dosing. The investigator should advise the patient
what is considered adequate contraception.

Exclusion Criteria:

1. Patients with squamous histology.

2. Cardiac disease: Congestive heart failure (CHF) > Class II NYHA; active coronary
artery disease (myocardial infarction) [MI] more than 6 months prior to study entry
is allowed); or serious cardiac ventricular arrhythmias requiring anti-arrhythmic
therapy (beta-blockers or digoxin are permitted)

3. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg despite optimal medical management

4. Human Immunodeficiency Virus (HIV) infection or chronic hepatitis B or C

5. Active clinically serious infections (> Grade 2 NCI-CTC Version 3.0)

6. History of brain metastases. Patients with history of brain metastases are eligible
as long as the metastasis has been treated with either stereotactic whole brain
radiation or neurosurgery, patient does not require ongoing treatment with
dexamethasone and patient's radiographic imaging is stable >/= 4 weeks from start of
treatment. Time from brain metastasis treatment to first study treatment must meet
the following criteria: Stereotactic whole brain radiation >/= 4 weeks from first
study treatment, Neurosurgery >/= 24 weeks from first study treatment, continued in
exclusion # 7

7. Continued from exclusion criterion # 6: Brain biopsy >/= 12 weeks from first study
treatment.

8. Uncontrolled seizure disorder. Use of cytochrome P450 enzyme-inducing antiepileptic
drugs (phenytoin, carbamazepine or phenobarbital) is not allowed

9. Thrombotic or embolic events such as cerebrovascular accident, transient ischemic
attacks, deep vein thrombosis or pulmonary embolism

10. Organ allograft

11. Evidence or history of bleeding diathesis or coagulopathy

12. History of/or current evidence of hemoptysis (bright red blood of 1/2 teaspoon or
more)

13. Peripheral neuropathy >/= Grade 2

14. Anticancer chemotherapy or immunotherapy: Anticancer therapy is defined as any agent
or combination of agents with clinically proven anticancer activity administered by
any route with the purpose of affecting the cancer, either directly or indirectly,
including palliative and therapeutic endpoints (except patients who have received
adjuvant chemotherapy > 52 weeks from Cycle 1 Day 1)

15. Radiotherapy to the target lesions within 3 weeks of start of first dose. Toxicities
from radiotherapy must have resolved prior to start of first dose.

16. No major surgery, open biopsy or significant traumatic injury within 4 weeks of start
of first dose

17. Serious, non-healing wound, ulcer, or bone fracture

18. Granulocyte growth factors (G-CSF), within 3 weeks of study entry.

19. Patients taking chronic erythropoietin are permitted provided no dose adjustment is
made within 2 months prior to start of first dose

20. Pregnant or breast feeding patients

21. Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

22. Known or suspected allergy to any recombinant human antibodies, or compounds of
similar chemical or biologic composition to sorafenib or any of the drugs in this
study

23. Any condition that is unstable or could jeopardize the safety or compliance of the
patient in the study

24. Previous or concurrent cancer that is distinct in primary site or histology from the
cancer being evaluated in the study EXCEPT cervical cancer in situ, treated basal
cell carcinoma, superficial bladder tumors (Ta, Tis, and T1) or any cancer curatively
treated > 3 years prior to study entry

25. Any condition that impairs the patient's ability to swallow pills as a whole

26. Any malabsorption conditions

27. Therapeutic anticoagulation with warfarin, heparins, or heparinoids

28. Patients takin phenytoin, carbamazepine, and Phenobarbital

29. Patients taking rifampin, St. John's Wort

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Time Frame:

First day of every 21 day cycle

Safety Issue:

Yes

Principal Investigator

George Blumenschein, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2005-0818

NCT ID:

NCT00533585

Start Date:

May 2006

Completion Date:

Related Keywords:

  • Lung Cancer
  • Non-Small Cell Lung Cancer
  • Lung Cancer
  • NSCLC
  • malignant pleural effusions
  • Sorafenib
  • Paclitaxel
  • Taxol
  • Carboplatin
  • Paraplatin
  • Bevacizumab
  • Avastin
  • BAY 43-9006
  • Anti-VEGF monoclonal antibody
  • rhuMAb-VEGF
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Pleural Effusion
  • Pleural Effusion, Malignant

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030