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

NCT ID: NCT00687297

Last Updated: 2018-05-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 162 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2011-04-30

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.

Conditions

Lung Cancer; Non Small Cell Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

vandetanib induction

Intervention Type: DRUG

100 mg daily by mouth

Docetaxel

Intervention Type: DRUG

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

Carboplatin

Intervention Type: DRUG

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

Vandetanib maintenance

Intervention Type: DRUG

300 mg daily by mouth

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.

Group Type: PLACEBO_COMPARATOR

vandetanib induction

Intervention Type: DRUG

100 mg daily by mouth

Docetaxel

Intervention Type: DRUG

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

Carboplatin

Intervention Type: DRUG

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

Intervention Type: DRUG

Interventions

vandetanib induction

100 mg daily by mouth

Intervention Type: DRUG

Docetaxel

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

Intervention Type: 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

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Vandetanib maintenance

300 mg daily by mouth

Intervention Type: DRUG

Other Intervention Names

ZD6474; Taxotere; ZD6474

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

PrECOG, LLC.

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joseph Aisner, MD

Role: STUDY_CHAIR

Rutgers Cancer Institute of New Jersey

Locations

Boca Raton Community Hospital

Boca Raton, Florida, United States

Lakeland Regional Cancer Center

Lakeland, Florida, United States

SwedishAmerican Hospital

Rockford, Illinois, United States

Cancer Center of Kansas

Wichita, Kansas, United States

Ochsner Clinic

New Orleans, Louisiana, United States

Greater Baltimore Medical Center

Baltimore, Maryland, United States

St. Joseph Mercy Hospital- Ann Arbor

Ann Arbor, Michigan, United States

West Michigan Cancer Center

Kalamazoo, Michigan, United States

Metro-Minnesota CCOP

Saint Louis Park, Minnesota, United States

Ocean Medical Center

Brick, New Jersey, United States

Morristown Memorial Hospital

Morristown, New Jersey, United States

Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

Riverview Medical Center

Red Bank, New Jersey, United States

Montefiore Medical Center

The Bronx, New York, United States

Aultman Hospital

Canton, Ohio, United States

Abington Memorial Hospital

Abington, Pennsylvania, United States

Hematology & Oncology of NEPA

Dunmore, Pennsylvania, United States

Lancaster General Hospital

Lancaster, Pennsylvania, United States

Central PA Hematology & Medical Oncology Associaties

Lemoyne, Pennsylvania, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Albert Einstein Cancer Center

Philadelphia, Pennsylvania, United States

The Reading Hospital and Medical Center

Reading, Pennsylvania, United States

Mount Nittany Medical Center

State College, Pennsylvania, United States

Sanford Clinic

Sioux Falls, South Dakota, United States

Meharry Medical College

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Charleston Area Medical Center

Charleston, West Virginia, United States

St. Vincent Hospital

Green Bay, Wisconsin, United States

Gundersen Lutheran

La Crosse, Wisconsin, United States

Regional Cancer Center

Waukesha, Wisconsin, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 23689430 (View on PubMed)

Related Links

https://www.ncbi.nlm.nih.gov/pubmed/23689430

Vandetanib in Advanced Non-Small Cell Lung Cancer

Other Identifiers

IRUSZACT0088

Identifier Type: OTHER

Identifier Source: secondary_id

PrE0501

Identifier Type: -

Identifier Source: org_study_id