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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)

Phase 2
18 Years
Not Enrolling
Lung Cancer, Non Small Cell Lung Cancer

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Trial Information

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)

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

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.

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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Progression-free Survival

Outcome Description:

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.

Outcome Time Frame:

Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance))

Safety Issue:


Principal Investigator

Joseph Aisner, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Cancer Institute of New Jersey


United States: Food and Drug Administration

Study ID:




Start Date:

April 2008

Completion Date:

April 2011

Related Keywords:

  • Lung Cancer
  • Non Small Cell Lung Cancer
  • Stage IIIB Non Small Cell Lung Cancer
  • Stage IV Non Small Cell Lung Cancer
  • Vandetanib
  • Docetaxel plus carboplatin
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



Abington Memorial Hospital Abington, Pennsylvania  19001
West Michigan Cancer Center Kalamazoo, Michigan  49007-3731
Morristown Memorial Hospital Morristown, New Jersey  07962-1956
Albert Einstein Cancer Center Philadelphia, Pennsylvania  19141
St. Vincent Hospital Green Bay, Wisconsin  54307-3508
Cancer Institute of New Jersey New Brunswick, New Jersey  08901
Riverview Medical Center Red Bank, New Jersey  07701
Ochsner Clinic New Orleans, Louisiana  70121
Montefiore Medical Center Bronx, New York  10467-2490
Mount Nittany Medical Center State College, Pennsylvania  16803
Charleston Area Medical Center Charleston, West Virginia  25304
Lancaster General Hospital Lancaster, Pennsylvania  17604-3555
Greater Baltimore Medical Center Baltimore, Maryland  21204
University of Pennsylvania Philadelphia, Pennsylvania  19104
Meharry Medical College Nashville, Tennessee  37208-3599
Lakeland Regional Cancer Center Lakeland, Florida  33805
University of Texas Southwestern Medical Center Dallas, Texas  
Metro-Minnesota CCOP St. Louis Park, Minnesota  
Regional Cancer Center Eau Claire, Wisconsin  54701
Boca Raton Community Hospital Boca Raton, Florida  33486
Ocean Medical Center Brick, New Jersey  08724
Cancer Center of Kansas Wichita, Kansas  67214
Aultman Hospital Canton, Ohio  44710
St. Joseph Mercy Hospital- Ann Arbor Ann Arbor, Michigan  48106
Gundersen Lutheran La Crosse, Wisconsin  54601
Sanford Clinic Sioux Falls, South Dakota  57104
SwedishAmerican Hospital Rockford, Illinois  61104
Hematology & Oncology of NEPA Dunmore, Pennsylvania  18512
Central PA Hematology & Medical Oncology Associaties Leymone, Pennsylvania  17043
The Reading Hospital and Medical Center Reading, Pennsylvania  19610