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

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ClinicalTrials.gov Identifier: NCT00687297
Recruitment Status : Completed
First Posted : May 30, 2008
Results First Posted : July 10, 2012
Last Update Posted : May 30, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
PrECOG, LLC.

Tracking Information
First Submitted Date  ICMJE May 27, 2008
First Posted Date  ICMJE May 30, 2008
Results First Submitted Date  ICMJE June 6, 2012
Results First Posted Date  ICMJE July 10, 2012
Last Update Posted Date May 30, 2018
Study Start Date  ICMJE April 2008
Actual Primary Completion Date January 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2012)
Progression-free Survival [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 27, 2008)
To determine the progression-free survival after treatment with the combination of docetaxel, carboplatin in patients with IIIb or IV non-small cell lung cancer. [ Time Frame: first evidence of disease progression ]
Change History Complete list of historical versions of study NCT00687297 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2012)
  • Objective Response Rate [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 27, 2008)
  • To evaluate the safety and tolerability of the two regimens [ Time Frame: Three months ]
  • To determine the objective response rate in each arm [ Time Frame: Three months ]
  • If both arms demonstrate benefit over historical control, to explore whether vandetanib as maintenance therapy confers added PFS benefit [ Time Frame: Twelve months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer
Official Title  ICMJE 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)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Lung Cancer
  • Non Small Cell Lung Cancer
Intervention  ICMJE
  • Drug: vandetanib induction
    100 mg daily by mouth
    Other Name: ZD6474
  • Drug: Docetaxel
    (75mg/m2) IV (in the vein) on day 1 of a 21-day cycle for 4 cycles or until disease progression
    Other Name: Taxotere
  • Drug: Carboplatin
    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
  • Drug: Placebo
  • Drug: Vandetanib maintenance
    300 mg daily by mouth
    Other Name: ZD6474
Study Arms  ICMJE
  • Active Comparator: 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.
    Interventions:
    • Drug: vandetanib induction
    • Drug: Docetaxel
    • Drug: Carboplatin
    • Drug: Vandetanib maintenance
  • Placebo Comparator: Placebo 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, placebo maintenance daily until progression.
    Interventions:
    • Drug: vandetanib induction
    • Drug: Docetaxel
    • Drug: Carboplatin
    • Drug: Placebo
Publications * Aisner J, Manola JB, Dakhil SR, Stella PJ, Sovak MA, Schiller JH. Vandetanib plus chemotherapy for induction followed by vandetanib or placebo as maintenance for patients with advanced non-small-cell lung cancer: a randomized phase 2 PrECOG study (PrE0501). J Thorac Oncol. 2013 Aug;8(8):1075-83. doi: 10.1097/JTO.0b013e3182937317.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 6, 2012)
162
Original Estimated Enrollment  ICMJE
 (submitted: May 27, 2008)
160
Actual Study Completion Date  ICMJE April 2011
Actual Primary Completion Date January 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00687297
Other Study ID Numbers  ICMJE PrE0501
IRUSZACT0088 ( Other Identifier: AstraZeneca )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party PrECOG, LLC.
Study Sponsor  ICMJE PrECOG, LLC.
Collaborators  ICMJE AstraZeneca
Investigators  ICMJE
Study Chair: Joseph Aisner, MD Rutgers Cancer Institute of New Jersey
PRS Account PrECOG, LLC.
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP