Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Sorafenib

Erlotinib Hydrochloride

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Erlotinib 150 mg by mouth each day of a 28 day cycle.

Erlotinib 150 mg by mouth each day of a 28 day cycle.

MK-2206 135 mg by mouth every week of a 28 day cycle.

AZD6244 100 mg by mouth daily of a 28 day cycle. MK-2206 100 mg by mouth every week of a 28 day cycle.

Sorafenib 400 mg by mouth twice a day for a 28 day cycle.

150 mg by mouth each day of a 28 day cycle.

Erlotinib

AZD6244

100 mg by mouth every week of a 28 day cycle.

MK-2206

400 mg by mouth twice a day for a 28 day cycle.

135 mg by mouth every week of a 28 day cycle.

Marcelo V. Negrao, MD

Different people have different biomarkers (chemical "markers" in the blood that may be related to your reaction to study drugs). If researchers know about your biomarkers before you receive treatment, they may be able to prescribe a treatment that is better suited to your body's specific needs.

The goal of this clinical research study is to learn if drug or drug combinations based on your biomarkers can help to control NSCLC. The safety of these drug combinations will also be studied.

The Study Drugs:

Erlotinib hydrochloride, MK-2206, AZD6244, and Sorafenib are targeted therapies. Targeted therapy is a type of drug that blocks the growth of cancer cells by interfering with specific targeted molecules needed for tumor growth, rather than by simply interfering with rapidly dividing cells (for example with traditional chemotherapy).

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 4 groups:

* If you are in Group 1, you will take erlotinib alone.
* If you are in Group 2, you will take erlotinib and MK-2206.
* If you are in Group 3, you will take AZD6244 and MK-2206.
* If you are in Group 4, you will take sorafenib alone.

The group you are in will be assigned by a computer. The results of your screening tests will be used to determine (and may limit) which of the 4 groups you may be eligible to be assigned to. Your likelihood of being in any 1 group over another may also be affected by how well that treatment has done in earlier study participants. Your study doctor will tell you which group you have been assigned.

Study Drug Administration:

Each cycle is 28 days.

* If you are in Group 1, you will take erlotinib hydrochloride by mouth 1 time every day.
* If you are in Group 2, you will take MK-2206 by mouth 1 time every week. You will take erlotinib hydrochloride by mouth 1 time every day.
* If you are in Group 3, you will take MK-2206 by mouth 1 time per week. You will take AZD6244 by mouth 1 time every day.
* If you are in Group 4, you will take sorafenib by mouth 2 times every day.

If you will take erlotinib hydrochloride (Groups 1 and 2), you should take the tablets in the morning. You should take the drug 1 hour before or 2 hours after a meal, with no more than 7 ounces of water. If you forget to take a dose, the last missed dose should be taken as soon as you remember, as long as it is at least 12 hours before the next dose. The next day, you should take the scheduled dose at the usual time. You should try not to vomit for at least 30 minutes after taking the drug. If you feel nauseated before or after taking the erlotinib, you should take an anti-nausea drug. You may take an extra dose of erlotinib if you vomit within 30 minutes after taking the tablet.

If you are in Group 2, you should take MK-2206 at about the same time each week with about 1 cup (8 ounces) of water. You must take MK-2206 at least 2 hours before or at least 2 hours after any food or a meal. You should not make up any missed doses.

If you are in Group 3, you should take MK-2206 at about the same time each week with about 1 cup (8 ounces) of water. You must take MK-2206 at least 2 hours before or at least 2 hours after eating. You should not make up any missed doses.

If you will take AZD6244 (Group 3), you should take the study drug in the morning before you eat or drink anything. You can eat breakfast 1 hour after you take the dose.

If you will take sorafenib, you must take your doses 12 hours apart. You will take 2 tablets each morning, and again each evening. 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). If you feel nauseated before or after taking the medication, anti-nausea medications should be used. If you miss a dose, you should skip it and take the next scheduled dose at the right time.

Your medication should be stored at room temperature.

Study Visits:

The study visit schedule is described below. In certain cases, with the permission of your doctor, the study visits may occur up to 7 days earlier or later than described below.

On Day 1 of each cycle:

* You will have a complete physical exam, including measurement of your weight and vital signs.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) will be drawn for routine tests. If your doctor thinks it is needed, you may have to have these blood tests more often.

On Day 1 of every odd-numbered cycle (Cycles 3, 5, 7, and so on):

* You will have a CT scan and/or MRI of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
* You will have a chest x-ray.
* MRI of the brain (if the doctor thinks it is needed)

Additional Tests for Group 2:

* During screening, on Day 1 of Cycle 2, and at the end-of study visit, you will have an eye exam.
* On Day 1 of Cycle 1 you will have an ECG before taking your study medication and then again about 4 hours after you take your study medication.

Additional Tests for Group 3:

* During screening, on Day 1 of Cycle 2, and at the end-of study visit, you will have an eye exam.
* During Cycle 2 (Week 6 of being on study drug), on Day 1 of Cycle 4, and then every 3 months, you will have a multigated acquisition (MUGA) scan and/or echocardiogram to check your heart function. You will have these tests more often if the doctor thinks it is needed.
* On Day 1 of Cycle 1 you will have an ECG before taking your study medication and then again about 4 hours after you take your study medication.

Length of Study:

You may continue to take the study drug(s) for as long as you are benefitting. You will be taken off study if the disease gets worse or if you have intolerable side effects.

End-of-Study Visit:

When you go off study for any reason, you will have an end-of-study. This visit may occur up to 7 days earlier or later. The following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a complete physical exam, including measurement of your weight and vital signs.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Your performance status will be recorded.
* Blood (about 3 teaspoons) and urine will be collected for routine tests.
* You will have a CT scan and/or MRI of the chest (and abdomen if the doctor thinks it is needed) to check the status of the disease.
* You will have a chest x-ray.
* You will have an ECG (Group 3).

Follow-Up:

You will have a follow-up evaluation performed 4 weeks ± 7 days after therapy is discontinued. This evaluation may be a visit or contact by phone by the research personnel. If you are in Group 3, you will have a MUGA scan and/or echocardiogram to check your heart function.

You will be called every 3 months for up to 3 years and asked about any cancer treatments you may be receiving. This phone call will take about 10 minutes.

This is an investigational study. Erlotinib is FDA approved and commercially available for treatment of NSCLC that has gotten worse. Sorafenib is approved in renal cell cancer and hepatocellular carcinoma. Sorafenib has also has also been evaluated in unselected advanced patients with NSCLC both alone or with chemotherapy in the first-time treatment of patients . MK-2206, and AZD6244 are not FDA-approved or commercially available. At this time, they are only being used in research.

Up to 450 patients will take part in this multicenter study. Approximately 350 will be enrolled at MD Anderson.

BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Progression-free survival was estimated by Kaplan-Meier method

Merck Sharp & Dohme LLC

National Cancer Institute (NCI)

GlaxoSmithKline

Novartis

M.D. Anderson Cancer Center

Arm 1 - Erlotinib

Erlotinib 150 mg by mouth each day of a 28 day cycle. MK-2206 135 mg by mouth every week of a 28 day cycle.

Arm 2 - Erlotinib + MK-2206

Arm 3 - AZD6244 + MK-2206

Arm 4 - Sorafenib

Total

Age, Continuous

<=49 years

Between 50 and 59 years

Between 60 and 69 years

>=70 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

KRAS mut+

Dr. Marcelo Vailati Negrao, MD, Assistant Professor, Thoracic-Head & Neck Med Onc

Partial Response

Stable Disease

Progressive Disease

12 participants were inevaluable and 2 participants were not applicable.

8-Week Disease Control Rate (DCR)

Median Progression-free Survival

Overall Study

Symptoms and General Pathology

Recurrence

Docetaxel

Carboplatin

Tubulin Modulators

Antimitotic Agents

Docetaxel day 1, carboplatin day 1 + vandetanib induction days 1 through 21 (daily) of a 28-day cycle for 4 cycles. If free of disease progression after 4 cycles, vandetanib maintenance daily until progression.

Docetaxel day 1, carboplatin day 1 + vandetanib induction days 1 through 21 (daily) of a 28-day cycle for 4 cycles. If free of disease progression after 4 cycles, placebo maintenance daily until progression.

vandetanib induction

(75mg/m2) IV (in the vein) on day 1 of a 21-day cycle for 4 cycles or until disease progression

IV (in the vein) to area under the curve (AUC) of 6 on day 1 of a 21 day cycle, for 4 cycles or until disease progression

Placebo

Vandetanib maintenance

Joseph Aisner, MD

It has been shown in previous studies that the ability to treat lung cancer could be significantly improved by not only targeting the tumor cells directly with chemotherapy, but also by cutting off the blood supply to the cancer cells. Blood vessels that supply the tumor are formed through a process called angiogenesis. Vandetanib is an investigational drug that acts by producing what is called an anti-angiogenic effect. An Anti-angiogenic effect is able to inhibit the development of new blood vessels required by tumors to survive by blocking the growth factors needed to form new blood vessels.

The purpose of this study is to determine if the addition of vandetanib to a standard chemotherapy regimen will slow or stop the growth of the cancer for a longer period of time compared to the time period generally gained from the use of standard chemotherapy alone

Lung cancer is the number one cause of cancer-related mortality in the United States, with an estimated 160,390 deaths in 2007. Over 80% of these patients will have non-small cell lung cancer (NSCLC), and the majority of these patients have advanced disease at the time of diagnosis.

Patients with advanced disease who have an adequate performance status clearly benefit from systemic chemotherapy, and many clinical trials have been carried out to determine the most effective regimen. Comorbidities associated with NSCLC preclude the use of cisplatin in doublet therapies, and, a meta-analysis comparing platinum-based doublet regimens to non-platinum based, third generation regimens revealed that survival outcomes between these regimens were equivalent. Despite poor response and overall survival benefits in this patient population with accepted treatment doublets, the addition of a third cytotoxic agent did not improve survival and demonstrated increased toxicity. Therefore, it appears a threshold maximum response can be gained with cytotoxic chemotherapy alone. However, the poor outcomes still associated with advanced NSCLC clearly demanded the need for continued improvements in treatment. It was postulated that anticancer therapy could be significantly improved by not only targeting the tumor cells directly, but also by targeting neo-angiogenesis. A randomized phase II trial demonstrated a significant improvement in time to progression (TTP) in patients receiving carboplatin, paclitaxel and bevacizumab compared to chemotherapy alone. Due to life-threatening and fatal hemorrhage patients with squamous cell histology, as well as those with a prior history of hemoptysis and brain metastases were excluded from all further clinical trials using bevacizumab. The definitive study of bevacizumab in NSCLC was a randomized phase III clinical trial conducted by ECOG (E4599) in which patients with advanced non-squamous NSCLC received carboplatin + paclitaxel with or without bevacizumab which met the clinical endpoint of improvement in survival and led to the approval of bevacizumab in first line treatment in patients with advanced NSCLC with non-squamous histology.

The epidermal growth factor receptor (EGFR) protein activation leads to TK activation and results in cell proliferation, motility, adhesion, invasion, survival, and angiogenesis. The EGFR is over expressed in many solid tumors, including non-small cell lung cancer (NSCLC), and multiple studies have suggested a shortened survival in NSCLC patients whose tumor over expresses EGFR . Although studies using small-molecule TK inhibitors (TKIs) in NSCLC did not meet efficacy endpoints, a phase III trial demonstrated the benefit of EGFR TKI monotherapy. Patients with advanced NSCLC who have received 2 or 3 prior therapies were randomized to erlotinib or placebo, and those receiving erlotinib demonstrated a survival benefit that led to FDA approval of this drug in 2004.

The studies above clearly demonstrated a benefit to combining anti-angiogenic factors with chemotherapy, and as a monotherapy using anti-EGFR agents, in patients with advanced NSCLC. The potential benefit to simultaneously targeting these 2 pathways has been addressed in the recurrent disease setting.

Vandetanib is a novel oral molecule (anilinoquinazoline) that has dual activity against both the VEGFR and EGFR pathways. Specifically, this compound has potent and reversible inhibitory activity against VEGFR-2 (KDR), VEGFR-3 (Flt-4), EGFR and RET . Vandetanib is a TKI and thus acts through inhibition of ATP binding to the tyrosine kinase domains of these receptors. Recombinant enzyme assays have demonstrated that vandetanib is highly selective for both VEGFR-2 (IC50=40 nm) with only slightly lower affinity for VEGFR-3 (2.7 fold). EGFR tyrosine kinase activity is inhibited with an IC50=500 nm. The results of a second-line setting phase II trial were presented by Heymach et al at the ASCO meeting in 2006. In this trial, patients were randomized to receive either docetaxel alone, or docetaxel with either 100mg or 300mg of vandetanib. Patients with squamous cell histology, controlled brain metastases and prior history of hemoptysis were allowed on study. The primary endpoint of prolongation of progression-free survival (PFS) was met in the 100mg arm (Hazard Ratio(HR) 0.64, p=0.07). There was no increased incidence of hemoptysis in patients receiving vandetanib, and no CNS hemorrhage events were observed, and side effects commonly attributed to EGFR inhibition (rash, diarrhea) were higher on the 300mg arm. Early combination studies suggest that in patients with NSCLC, vandetanib is safe in combination with chemotherapy, may improve the outcomes of chemotherapy when used at the 100 mg dose, and has activity as monotherapy at the 300mg dose. In addition, none of the observed hemorrhagic complications seen with bevacizumab were observed, even in patients at high risk for this complication.

In this study, our main goal is to study the combination of docetaxel + carboplatin and vandetanib, followed by a double-blind randomized assignment to maintenance therapy with vandetanib 300 milligrams (mg) or placebo by mouth daily until disease progression to determine if maintenance therapy can prolong progression-free survival. In addition to clinical efficacy outcomes we will monitor for safety and tolerability, as well as explore any differences in outcome based on age and gender.

Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer

A Randomized Phase II Study Evaluating Vandetanib (ZD6474) in Combination With Docetaxel and Carboplatin Followed by Placebo or Maintenance Therapy With Vandetanib in Patients With IIIb, IV or Recurrent Non-Small Cell Lung Cancer (NSCLC)

Time from randomization (prior to induction) to first evidence of disease progression or death without progression. Participants alive without progression were censored at the date of last disease evaluation.

Best overall response (complete or partial response), assessed using RECIST criteria (version 1.0)

Time from randomization to first evidence of disease progression or death. Patients alive without progression are censored at the date of last disease evaluation.

AstraZeneca

PrECOG, LLC.

Serious adverse events are defined as events of grade 3 or higher that were considered possibly, probably, or definitely treatment-related. Other adverse events include grade 1 or 2 events possibly, probably or definitely treatment-related occurring at a rate of 5% or higher.

Adverse events among patients receiving Vandetanib using the maintenance phase of the study

Treated on Vandetanib Maintenance

Adverse events among patients receiving placebo during the maintenance phase of the study

Treated on Placebo Maintenance

Adverse events occurring during induction among all treated patients

All Treated Patients - Induction

Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --\> Maintenance treatment: vandetanib (300mg) daily until progression \[1 Cycle= 28 days\]

Randomized to Vandetanib Maintenance

Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --\> Maintenance treatment: Placebo 3 tablets daily until progression \[1 Cycle= 28 days\]

Randomized to Placebo Maintenance

Study Statistician

All Randomized Patients

Progression-free Survival

Fisher's exact test with two-sided Type I error of 5% was used to test the null hypothesis of no difference in response rate between arms.

Objective Response Rate

There was 80% power to detect a 50% improvement in median progression-free survival, using a stratified log-rank test with one-sided Type I error of 10%.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer	NCT01248247	Lung Cancer	Erlotinib AZD6244 MK-2206 Sorafenib Erlotinib MK-2206	18 Years -	M.D. Anderson Cancer Center
Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer	NCT00687297	Lung Cancer Non Small Cell ...	vandetanib indu... Docetaxel Carboplatin Placebo Vandetanib main...	18 Years -	PrECOG, LLC.

Spots Global Cancer Trial Database for stage iv non small cell lung cancer