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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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)

Conditions
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Lung Cancer, Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: vandetanib induction
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Placebo
* Drug: Vandetanib maintenance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed non-small cell lung cancer Advanced disease (stage IIIB disease [malignant pleural or pericardial effusion seen on CT or Chest X-ray, any N, M0] or stage IV disease [Any T, any N, M1: distant metastases]) that is primary or recurrent Measurable disease according to the RECIST criteria ECOG Performance Status 0 or 1 Adequate organ function, as evidenced by ALL the following Absolute neutrophil count (ANC) ≥ 1500/mm³ and platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 gm/dL Total bilirubin ≤ 1 X institutional ULN; if patient has Gilbert's disease, then patient must have isolated hyperbilirubinemia (e.g. no other liver function test abnormality), with maximum bilirubin ≤ 2 X institutional ULN. AST, ALT and alkaline phosphatase (Alk Phos) must be ≤ 1.5 ULN Creatinine ≤ 1.5 X institutional ULN or calculated creatinine clearance ≥ 60 ml/min Potassium between 4 mEq/L and institutional ULN (supplementation may be used), Calcium (ionized or adjusted for albumin)within institutional normal limits Magnesium within institutional normal limits (supplementation may be used) No prior cytotoxic chemotherapy or targeted therapy for advanced or metastatic disease (Prior adjuvant therapy for lung cancer allowed if completed > 1 year prior to registration) Able to take oral medication Exclusion Criteria: Myocardial infarction, superior vena caval syndrome, NYHA classification of heart disease ≥ 2 within the 3 months prior to entry History of an uncontrolled or recurrent ventricular, supraventricular or nodal arrhythmia that requires treatment Hypertension not controlled by medication Peripheral or sensory neuropathy > grade 1 Known hypersensitivity to carboplatin or docetaxel Active infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vandetanib Maintenance<br>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. | Drug: vandetanib induction<br>* 100 mg daily by mouth<br>* Other names: ZD6474;Drug: Docetaxel<br>* (75mg/m2) IV (in the vein) on day 1 of a 21-day cycle for 4 cycles or until disease progression<br>* Other names: Taxotere;Drug: Carboplatin<br>* 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<br>Drug: Vandetanib maintenance<br>* 300 mg daily by mouth<br>* Other names: ZD6474;|
| Placebo Comparator: Placebo Maintenance<br>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. | Drug: vandetanib induction<br>* 100 mg daily by mouth<br>* Other names: ZD6474;Drug: Docetaxel<br>* (75mg/m2) IV (in the vein) on day 1 of a 21-day cycle for 4 cycles or until disease progression<br>* Other names: Taxotere;Drug: Carboplatin<br>* 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<br>Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | 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. | Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance)) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Best overall response (complete or partial response), assessed using RECIST criteria (version 1.0) | Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance)) | 
| Progression-free Survival | Time from randomization to first evidence of disease progression or death. Patients alive without progression are censored at the date of last disease evaluation. | every 2 cycles (every 6 weeks during induction, every 8 weeks during maintenance) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage IIIB Non Small Cell Lung Cancer, Stage IV Non Small Cell Lung Cancer, Vandetanib, Docetaxel plus carboplatin