Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer
- Conditions
- Lung CancerNon Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT00687297
- Lead Sponsor
- PrECOG, LLC.
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 162
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Maintenance vandetanib induction 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. Placebo Maintenance Placebo 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 Maintenance vandetanib induction 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. Vandetanib Maintenance Vandetanib maintenance 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. Vandetanib Maintenance Carboplatin 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. Vandetanib Maintenance Docetaxel 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. Placebo Maintenance Docetaxel 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. Placebo Maintenance Carboplatin 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.
- Primary Outcome Measures
Name Time Method Progression-free Survival Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance)) 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.
- Secondary Outcome Measures
Name Time Method Objective Response Rate Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance)) Best overall response (complete or partial response), assessed using RECIST criteria (version 1.0)
Progression-free Survival every 2 cycles (every 6 weeks during induction, every 8 weeks during maintenance) Time from randomization to first evidence of disease progression or death. Patients alive without progression are censored at the date of last disease evaluation.
Trial Locations
- Locations (30)
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Ocean Medical Center
🇺🇸Brick, New Jersey, United States
Riverview Medical Center
🇺🇸Red Bank, New Jersey, United States
Charleston Area Medical Center
🇺🇸Charleston, West Virginia, United States
SwedishAmerican Hospital
🇺🇸Rockford, Illinois, United States
Boca Raton Community Hospital
🇺🇸Boca Raton, Florida, United States
Lakeland Regional Cancer Center
🇺🇸Lakeland, Florida, United States
West Michigan Cancer Center
🇺🇸Kalamazoo, Michigan, United States
Lancaster General Hospital
🇺🇸Lancaster, Pennsylvania, United States
The Reading Hospital and Medical Center
🇺🇸Reading, Pennsylvania, United States
Regional Cancer Center
🇺🇸Waukesha, Wisconsin, United States
Meharry Medical College
🇺🇸Nashville, Tennessee, United States
Greater Baltimore Medical Center
🇺🇸Baltimore, Maryland, United States
Metro-Minnesota CCOP
🇺🇸Saint Louis Park, Minnesota, United States
Morristown Memorial Hospital
🇺🇸Morristown, New Jersey, United States
Ochsner Clinic
🇺🇸New Orleans, Louisiana, United States
Sanford Clinic
🇺🇸Sioux Falls, South Dakota, United States
Gundersen Lutheran
🇺🇸La Crosse, Wisconsin, United States
St. Vincent Hospital
🇺🇸Green Bay, Wisconsin, United States
Aultman Hospital
🇺🇸Canton, Ohio, United States
Central PA Hematology & Medical Oncology Associaties
🇺🇸Lemoyne, Pennsylvania, United States
Mount Nittany Medical Center
🇺🇸State College, Pennsylvania, United States
St. Joseph Mercy Hospital- Ann Arbor
🇺🇸Ann Arbor, Michigan, United States
Albert Einstein Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Abington Memorial Hospital
🇺🇸Abington, Pennsylvania, United States
Hematology & Oncology of NEPA
🇺🇸Dunmore, Pennsylvania, United States
Cancer Center of Kansas
🇺🇸Wichita, Kansas, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States