Clinical trial NCT00271505
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer Lung Cancer Bevacizumab Carboplatin Docetaxel Avastin NSCLC Anti-VEGF monoclonal antibody rhuMAb-VEGF Paraplatin® Taxotere
Sponsor: M.D. Anderson Cancer Center
Start date: 2005-12-05; Completion date: 2017-07-27
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to evaluate the effectiveness of Avastin® in combination with docetaxel and carboplatin in the treatment of lung cancer. The safety of this combination will also be studied.

Detailed description:
Avastin® is a humanized monoclonal antibody that binds to vascular endothelial growth factor (VEGF). VEGF plays an important role in the growth of both normal and abnormal blood vessels. Avastin® is designed to prevent or slow down the growth of cancer cells by blocking the effects of VEGF.

Docetaxel and carboplatin are standard chemotherapy drugs that have been approved by the FDA for the treatment of NSCLC. Docetaxel and carboplatin are designed to work by stopping the division of cancer cells.

If you are found to be eligible, you will begin receiving Avastin®, docetaxel, and carboplatin. Avastin®, carboplatin, and docetaxel will be given by vein once every 3 weeks. The first dose of Avastin® will be given over 90 minutes. The second dose of Avastin® will be given over 60 minutes. All other doses of Avastin® will be given over 30 minutes. Carboplatin and docetaxel will always be given over 30 minutes. They will be given on the same day every 3 weeks (1 cycle). You may receive up to 6 cycles of treatment. You will receive standard premedication with dexamethasone to help decrease the risk of side effects. Dexamethasone will be taken before you receive your docetaxel infusion.

During the study, you will have blood tests (about 2 teaspoons) every 3 weeks to look at your blood counts. These samples will be used only for routine lab tests. You will be seen by a physician every 3 weeks and given a physical exam. Your blood pressure will be monitored, and you will be asked about any side effects you are experiencing. A performance status evaluation will also be done. In addition, you will have a urine test every 2 cycles of treatment.

After 2 cycles of treatment (6 weeks), you will have a chest x-ray and computerized tomography (CT) or magnetic resonance imaging (MRI) scan to evaluate the status of the disease. These will be repeated every 2 cycles. Your continued participation in this study depends on how your cancer responds to the study drugs. Your doctor may decide to take you off this study if you experience significant side effects or your medical condition worsens. You may continue receiving bevacizumab for as long as your cancer responds to study treatment.

You will be followed-up on by phone or at routine clinic visits for at least 12 months to monitor your condition and disease status.

This is an investigational study. Avastin® has been approved by the FDA for the treatment of colorectal cancer. Docetaxel and carboplatin are FDA approved and commercially available. The use of these drugs together in this study is experimental. A total of 50 patients will take part in this study. All participants will be enrolled at M. D. Anderson.

Arms: arm 1: Avastin 15 mg/kg intravenously (IV) every 3 weeks. Docetaxel 75 mg/m2 IV every 3 weeks. Carboplatin AUC 6 IV every 3 weeks.
Interventions: intervention 1: Bevacizumab (Avastin) intervention 2: Carboplatin intervention 3: Docetaxel
Intervention descriptions: intervention 1: 15 mg/kg intravenously (IV) every 3 weeks intervention 2: AUC 6 IV every 3 weeks intervention 3: 75 mg/m2 IV every 3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Protocol Abstract Page 
Protocol 2005-0224 
July 10, 2017 
Abstract Page 1 
 
 
 
 
A Phase II Evaluation of Avastin® in Combination with Docetaxel and 
Carboplatin as Chemotherapy in Patients with Metastatic Non-Small Cell 
Lung Cancer 
2005-0224 
 
 
 
Core Protocol Information 
 
 
 
 
 
 
 
 
 
Full Title: 
A Phase II Evaluation of Avastin® in Combination with Docetaxel and Carboplatin 
as Chemotherapy in Patients with Metastatic Non-Small Cell Lung Cancer 
Protocol Phase: 
Phase II 
Version Status: 
Terminated 07/27/2017 
Version: 
22 
Document Status: 
Final 
 
Abstract 
 
 
Objectives: 
 
Primary 
 
The primary endpoint of this trial is to estimate progression-free survival, defined as the time from study 
enrollment to disease progression or death as an indicator of the activity of the Avastin® regimen. 
 
Secondary 
 
• Assessment of overall survival 
• Assessment of disease control rate (complete response + partial response + stable disease) 
• Evaluation of the safety and toxicity profile of this triple-agent regimen 
• To correlate the above primary and secondary objectives with biomarkers and immunohistochemistry 
from tissue samples (optional) 
 
 
Rationale: (Be as concise as possible) 
 
In this Phase II trial, the biologic agent Avastin® is combined with cytotoxic chemotherapy, attacking 
against the factors that lead to the development of tumor blood supply and tumor cell proliferation in 
NSCLC. Avastin® directly binds to VEGF and inhibits from binding to endothelial cells and in turn blocks 
blood vessel growth. 
 
The common 21-day dosing regimen has been studied and is used for docetaxel and carboplatin. Due to 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 2 
 
 
the fact that there are not to be overlapping toxicities or pharmacodynamic interactions with the study 
drug Avastin as well as secondarily for ease of delivery and monitoring, it will be given along with the 
other two drugs. The treatments will be repeated every 21 days as another cycle with disease evaluation 
after every 2 cycles in order to monitor for need for continuation of therapy and endpoints closely. 
 
 
Eligibility: (List All Criteria) 
 
Inclusion: 
1) 
Men and women, at least 18 years old, with histologically confirmed, advanced stage IIIB or IV 
NSCLC for whom no curative options exist and for whom docetaxel and carboplatin is a reasonable 
treatment option; 
 
2) 
At least 1 target lesion that is unidimensionally measurable as defined by the Response Evaluation 
Criteria in Solid Tumors (RECIST) and has not been previously irradiated; 
 
3) 
Eastern Cooperative Oncology Group Performance Status of 0 or 1, (determined within 2 weeks 
prior to receiving study medication; 
 
4) 
Ability to understand and adhere to the protocol requirements, and give informed consent 
 
5) 
Use of effective means of contraception (men and women) in subjects of child-bearing potential. 
Child-bearing potential is defined as follows: A woman of childbearing potential is a sexually mature 
woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at 
least 12 consecutive months (i.e., who has had menses at any time in the preceding 12 consecutive 
months). 
Exclusion: 
1) 
Patients who have had docetaxel in nonradiosensitizing therapy 
 
2) 
Patients who have received prior full dose systemic chemotherapy for NSCLC (ie neoadjuvant, 
adjuvant, or metastatic) within the last 6 months. 
 
3) 
ECOG status of 2 or greater 
 
4) 
Screening clinical laboratory values:*ANC of <1,500/µL *Platelet count of <75,000/µL * INR >/= 1.5 
*T bilirubin elevation above normal (MDACC upper normal limit is 1.0 mg/dL) *Serum creatinine of >2.0 
mg/dL *Hemoglobin of <9 mg/dL (may be transfused or receive epoetin alfa [e.g., Epogen®] to maintain 
or exceed this level) *The pt is ineligible if: 1.alk phos>5xULN; 2.AST or ALT >5xULN; 3.alk phos >1xULN 
but </= 2.5xULN AND AST or ALT >1.5xULN but </=5xULN;4.alk phos >2.5xULN but </=5xULN AND 
AST or ALT > 1xULN but</= 1.5xULN; 5.alk phos >2.5xULN but</=5xULN AND AST or ALT >1.5xULN 
but </=5xULN 
 
5) 
Inability to comply with study and/or follow-up procedures 
 
6) 
History of other disease, active infection, metabolic dysfunction , physical examination finding, or 
clinical laboratory finding which is uncontrolled requiring medical intervention giving reasonable suspicion 
of a disease or condition that contraindicates the use of an investigational drug or that might affect the 
interpretation of the results of the study or render the subject at high risk from treatment complications. 
 
7) 
Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an 
experimental drug study other than a bevacizumab cancer study 
 
8) 
Prior exposure to anti-VEGF therapy 
 
9) 
Blood pressure of > 140/90 mmHg as documented in two consecutive blood pressure readings 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 3 
 
 
within 4 hours 
 
10) 
Any prior history of hypertensive crisis or hypertensive encephalopathy 
 
11) 
New York Heart Association (NYHA) Grade II or greater congestive heart failure 
 
12) 
History of myocardial infarction or unstable angina within 6 months 
 
13) 
History of stroke or transient ischemic attack within 6 months 
 
14) 
Significant vascular disease (e.g., aortic aneurysm, aortic dissection) 
 
15) 
Evidence of bleeding diathesis or coagulopathy 
 
16) 
Presence of central nervous system or brain metastases at any time 
 
17) 
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, 
anticipation of need for major surgical procedure during the course of the study 
 
18) 
Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 0 
 
19) 
Pregnant (positive pregnancy test) or lactating 
 
20) 
Proteinuria at screening as demonstrated by either: Urine protein:creatinine (UPC) ratio > 1.0 at 
screening OR Urine dipstick for proteinuria > 2+ (patients discovered to have > 2+ proteinuria on dipstick 
urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate < 1g of protein in 
24 hours to be eligible). 
 
21) 
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 
months prior to Day 0 
 
22) 
Serious, non-healing wound, ulcer, or bone fracture 
 
23) 
Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, 
cavitation. 
 
24) 
History of hemoptysis (bright red blood of 1/2 teaspoon or more) 
 
25) 
Full dose anitcoagulation, chronic use of Aspirin (>325 mg/day) or NSAIDs 
 
26) 
Inability to comply with study and/or follow-up procedures 
Is there an age limit? Yes 
 
Why? Please explain: 
A diagnosis of NSCLC is exceedingly uncommon at ages 18 and below. 
 
 
Treatment/Study Plan: 
 
This is a single center Phase II open-labeled single-arm nonrandomized study of Avastin®  in 
combination with docetaxel and carboplatin as first line systemic chemotherapy for metastatic non small 
cell lung cancer.  Patients will receive Carboplatin (AUC 6) IV with Docetaxel (75 mg/m^2) IV with 
Avastin®  (15 mg/kg) IV every 3 weeks.  (Patients will receive standard premedication with 
dexamethasone before docetaxel infusion.)  After 2 cycles, patients will be restaged. If there is evidence 
of progression, they will be taken off study.  If, however, there is either response or stable disease, they 
will be continued on the regimen just described for 2 more cycles, followed again by restaging studies to 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 4 
 
 
evaluate for progression versus stable or responsive disease. This will continue the triplet regimen for a 
maximum of up to 6 cycles.  Patients who are stable or still responding may continue Avastin® until 
progression. If 3 or more patients experience a grade >/= 3 drug-related adverse event, then dose 
modification will be considered. 
 
 
Estimated number of patients enrolled will be 50 total.  Estimated rate of accrual will be 5 patients per 
month for a total of 50 patients in 10 months, and each to be followed for 12 months minimum as 
possible. 
 
Disease Group:  Lung 
 
Treatment Agent:  Avastin, Carboplatin, Docetaxel 
 
 
Statistical Considerations: 
 
The primary objective of this single-arm, phase II clinical trial is to evaluate the efficacy of carboplatin, 
docetaxel, and Avastin® in the treatment of patients with metastatic non-small cell lung cancer who have 
not received prior systemic chemotherapy. The primary endpoint is progression-free survival.  Up to 50 
patients will be accrued in approximately 10 months; each patient will be followed for at least 12 months. 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 5 
 
 
Total study duration should be less than 24 months. Assuming a one-sided type I error rate of 10%, we 
have at least 81% power to detect an increase in median survival from a historical estimate of 4.5 months 
to 6.3 months. 
 
 
Planned Efficacy Evaluations, Variables, and Analysis 
 
The primary endpoint of this study is the estimation of progression-free survival, defined as the time from 
enrollment to disease progression or death.  Secondary endpoints include the assessment of overall 
survival, disease control rate (complete response + partial response + stable disease) and the evaluation 
of the safety profile of this triple-agent regimen.  Survival distributions will be summarized using the 
method of Kaplan and Meier.  Comparisons with historical controls of survival distributions by patient 
subgroups will be tested using the log rank test.  Multivariable models of PFS and OS will be analyzed 
using the Cox (proportional hazards) regression model. 
 
 
Continuous variables will be summarized using the mean (s.d.) and median (range). Categorical 
variables will be summarized in frequency tables.  Graphical summaries will be emphasized for 
describing the distribution of variables. The Pearson correlation, or its non-parametric analogue, the 
Spearman correlation, will be used to assess linear correlations among variables. Scatter plots and other 
powerful bi-variate plots will be used to characterize association among variables. 
 
 
Protocol Monitoring: 
 
Who is monitoring the day-to-day implementation and performance of this study, i.e., Good Clinical 
Practice? 
 
 
Data Monitoring Committee: 
 
Is this study randomized or blinded? No 
 
 
Patient/Participant Evaluation: (Pretreatment and Interim Testing) 
 
Pre-Treatment Evaluations: 
 
Unless otherwise specified, the following evaluations must be performed within four weeks prior to each 
patient's on-study (initial Avastin® treatment) date: 
• Pregnancy test (serum or urine) for women of childbearing potential (within 2 weeks of treatment). 
• Medical history and documentation of the rationale for treatment of the patient's disease with 
Avastin 
• Physical examination, including vital signs (blood pressure), performance status and tumor 
assessment. 
• Baseline staging exams (i.e. chest x-ray, CT, brain MRI) 
• Urine protein:creatinine ratio or urine dipstick (and 24 hour collection if indicated) 
• Hematology (within 2 weeks of treatment): complete blood count (CBC) with differential and platelet 
count. 
• Serum Chemistries: sodium, potassium, magnesium, calcium, glucose, BUN, creatinine, uric acid, 
total bilirubin, alkaline phosphatase, LDH, total protein, albumin, SGOT(AST), and SGPT (ALT). 
• PT, PTT, and/or INR (within 2 weeks of treatment) 
• (Optional) Tumor biopsy for biomarker analysis 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 6 
 
 
Evaluations During Treatment (See Timetable below) 
Blood pressure monitoring every 3 weeks, prior to each Avastin® dose 
Urine protein approximately every 2 cycles (with every other dose) 
 
 
 
 
 
 
Biosafety: 
 
Does this study involve the use of Recombinant DNA Technology? 
No 
 
Does this study involve the use of organisms that are infectious to humans? 
No 
 
Does this study include any products manufactured or produced at MD Anderson 
No 
Cancer Center? 
 
 
 
Radiation Safety: 
 
Does this study involve the use of radioisotopes? 
No 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 7 
 
 
Does this protocol include the administration of a radioactive drug to human research 
No 
subjects intended to obtain basic information regarding the metabolism (including 
kinetics, distribution, and localization) of the drug or regarding human physiology, 
pathophysiology, or biochemistry, but not intended for immediate therapeutic, 
diagnostic, or similar purposes or to determine the safety and effectiveness of the drug 
in humans for such purposes (i.e. to carry out a clinical trial)? 
 
 
 
Where Will Study Be Conducted: 
 
B) MDACC + Community Programs (CCOP/Network) 
 
The study will be conducted at MDACC and its affiliated County Hospital, Lyndon Baines Johnson 
General Hospital via the Clinical Trials Outreach Program (CTOP) program. 
 
 
Is this an M. D. Anderson Cancer Therapy Evaluation Program 
(CTEP) Protocol? 
No 
 
 
Estimated Accrual: 
 
Total Accrual at M.D. Anderson Cancer Center: Total accrual will be 50 participants. 
Estimated monthly accrual at M.D. Anderson: 
It is estimated that accrual will be 5 participants per month. 
Total accrual will be: 
50 participants 
 
 
 
 
Basis of Study: 
 
This protocol is performed on an Outpatient basis. 
 
 
 
Length of Stay: (What is the length & frequency of hospitalization) 
 
N/A 
 
 
Return Visits: (How often must participants come to MDACC) 
 
Patients will return to the clinic every 21 days. 
 
 
Home Care: (Specify what (if any) treatment may be given at home) 
 
N/A 
 
 
Public Display of Protocol on the Office of Protocol Research Web Site: 
 
The Office of Protocol Research maintains a website (www.clinicaltrials.org) 
listing protocols actively accruing patients. No information is given about drug 
dose or 
Yes 


 
 
 
 
 
schedule. Would you like this protocol listed on this website? 
 
If this protocol has a corporate sponsor, we also need to get the sponsor's written 
approval to post the trial on the website. Shall OPR send a letter requesting this 
permission to your sponsor? 
 
 
 
 
 
 
Yes 
Protocol 2005-0224 
July 10, 2017 
Abstract Page 8 
 
 
 
Prior protocol at M. D. Anderson: 
 
List the protocol number for the last clinical treatment/behavioral protocol on which you were the Principal 
Investigator that accrued patients at M. D. Anderson. 
2003-0424 
 
 
 
Space Requirements for Clinical Trials: 
 
Will implementing this protocol require additional space (clinical, office, departmental)? No 
 
Additional Space will not be made available in the future. 
 
 
Sponsorship and Support Information: 
 
 
Does the Study have a Sponsor?   Yes 
 
Name of Sponsor or Supporter:   Genentech, Inc. 
 
Does the Sponsor Provide Funding for 
the conduct of the study? 
 
Is this Protocol listed on any Federal 
Grant or Foundation Funding 
Application? 
 
Yes 
No 
 
Grant Number:   N/A 
 
Does the Sponsor supply drug(s) or 
device(s)? 
 
N 
 
 
 
 
Does this protocol require an IND? No 
 
Please check the items below to verify that the following information is correct: 
The data will not be provided to the FDA or to an outside source. 
The data will not be used to expand the label or change the advertising for the drug. 
There will be no substantial change in the dosage, drug, or route of administration or other factor 
that will significantly increase the risk to the patient. 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 9 
 
 
Does this protocol use a "Combination" of drugs or other therapies (Drug, Radiation or 
Surgical Therapy) or Diagnostic Procedures that pose a significant risk to the patient? 
No 
 
If this protocol includes an FDA Approved Therapy, please list the disease, dose and 
route of administration: 
 
Approved Use 
Proposed Use in this Protocol 
 
Disease: 
Avastin: Metastatic Colorectal, 
Non-small cell lung cancer 
Docetaxel:Breast Cancer, Head 
& Neck Cancer, Metastatic 
Prostate Cancer, Non-small cell 
lung cancer 
Carboplatin:Ovarian Cancer 
 
Dose: 
Avastin:15mg/kg IV infusion 
Docetaxel:75mg/m(2) 
Carboplatin: AUC of 6 
 
Route of Administration: 
 Avastin:IV 
Docetaxel:IV 
Carboplatin:IV 
 
Avastin, Docetaxel, and 
Carboplatin:Metastatic Non-small 
cell lung cancer 
 
 
 
 
 
 
Avastin:15mg/kg IV infusion 
Docetaxel:75mg/m(2) 
Carboplatin: AUC of 6 
 
Avastin:IV 
Docetaxel:IV 
Carboplatin:IV 
 
 
Rationale For Planned Therapy: 
In this Phase II trial, the biologic agent Avastin is combined with cytotoxic chemotherapy, 
attacking against the factors that lead to the development of tumor blood supply and tumor cell 
proliferation in NSCLC. Avastin directly binds to VEGF and inhibits from binding to endothelial 
cells and in turn blocks blood vessel growth. 
 
The common 21-day dosing regimen has been studied and is used for docetaxel and 
carboplatin. Due to the fact that there are not to be overlapping toxicities or pharmacodynamic 
interactions with the study drug Avastin as well as secondarily for ease of delivery and 
monitoring, it will be given along with the other two drugs. The treatments will be repeated 
every 21 days as another cycle with disease evaluation after every 2 cycles in order to monitor 
for need for continuation of therapy and endpoints closely. 
 
For FDA approved drugs 
www.fda.gov/cder/da/da.htm 
 
For the FDA Investigational New Drug (IND) Exemption Rationale 
www.access.gpo.gov/nara/cfr/waisidx_03/21cfr312_03.html 
Then select 312.2 
 
For FDA approved biological therapies 
www.fda.gov/cber/ 
 
 
Device: 


Protocol 2005-0224 
July 10, 2017 
Abstract Page 10 
 
 
Is this protocol testing a new device or a device in a new application?  No 
 
For a list of significant/non-significant risk devices 
www.fda.gov/oc/ohrt/irbs/devices.html