Lung Cancer, Non Small Cell Lung Cancer
Conditions
Keywords
Stage IIIB Non Small Cell Lung Cancer, Stage IV Non Small Cell Lung Cancer, Vandetanib, Docetaxel plus carboplatin
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.
Interventions
DRUGvandetanib induction
100 mg daily by mouth
DRUGDocetaxel
(75mg/m2) IV (in the vein) on day 1 of a 21-day cycle for 4 cycles or until disease progression
DRUGCarboplatin
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
DRUGPlacebo
DRUGVandetanib maintenance
300 mg daily by mouth
Sponsors
AstraZeneca
PrECOG, LLC.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Randomized to Vandetanib Maintenance Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --\> Maintenance treatment: vandetanib (300mg) daily until progression \[1 Cycle= 28 days\] | 80 |
| Randomized to Placebo Maintenance Docetaxel (75mg/m2)IV (in the vein) + Carboplatin IV (AUC=6) day 1 of 21 day cycle + vandetanib (100mg) days 1 through 21 (daily) x 4 cycles. If SD, PR CR after 4 cycles --\> Maintenance treatment: Placebo 3 tablets daily until progression \[1 Cycle= 28 days\] | 82 |
| Total | 162 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Induction | Adverse Event | 16 | 15 |
| Induction | Death | 7 | 11 |
| Induction | Ineligible | 0 | 1 |
| Induction | Lack of Efficacy | 17 | 21 |
| Induction | Other | 0 | 1 |
| Induction | Patient Noncompliance | 1 | 0 |
| Induction | Physician Decision | 0 | 2 |
| Induction | Withdrawal by Subject | 4 | 4 |
| Randomization | Withdrawal by Subject | 2 | 0 |
| Randomization | Withdrew before treatment, ineligible | 1 | 1 |
Baseline characteristics
| Characteristic | Randomized to Vandetanib Maintenance | Randomized to Placebo Maintenance | Total |
|---|---|---|---|
| Age, Continuous | 63.5 years | 63 years | 63 years |
| Region of Enrollment United States | 80 participants | 82 participants | 162 participants |
| Sex: Female, Male Female | 38 Participants | 40 Participants | 78 Participants |
| Sex: Female, Male Male | 42 Participants | 42 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 32 | 22 / 26 | 145 / 157 |
| serious Total, serious adverse events | 22 / 32 | 11 / 26 | 111 / 157 |
Outcome results
Primary
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.
Time frame: Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance))
Population: All randomized patients were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Randomized Patients | Progression-free Survival | 4.5 Months |
Secondary
Objective Response Rate
Best overall response (complete or partial response), assessed using RECIST criteria (version 1.0)
Time frame: Assessed every 2 cycles (1 cycle = 3 weeks during induction and 4 weeks during maintenance))
Population: All randomized patients were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Randomized Patients | Objective Response Rate | 18.8 percentage of participants |
| Randomized to Placebo Maintenance | Objective Response Rate | 18.3 percentage of participants |
Comparison: Fisher's exact test with two-sided Type I error of 5% was used to test the null hypothesis of no difference in response rate between arms.p-value: 1Fisher Exact
Secondary
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.
Time frame: every 2 cycles (every 6 weeks during induction, every 8 weeks during maintenance)
Population: All randomized patients were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Randomized Patients | Progression-free Survival | 4.5 months |
| Randomized to Placebo Maintenance | Progression-free Survival | 4.2 months |
Comparison: There was 80% power to detect a 50% improvement in median progression-free survival, using a stratified log-rank test with one-sided Type I error of 10%.p-value: 0.0295% CI: [1.07, 2.07]Regression, Cox