Lung Cancer, Non Small Cell Lung Cancer
Conditions
Keywords
NSCLC, Non Small Cell Lung Cancer
Brief summary
Non-small cell lung cancer (NSCLC) can be treated with drugs that kill tumour cells, stop them from dividing, or stop the growth of the blood supply that cancers need to grow and spread. Clinical research has shown that drugs that inhibit vascular endothelial growth factor receptor (VEGFR) or epidermal growth factor receptor (EGFR) signalling can increase overall survival in patients with advanced non-small cell lung cancer (NSCLC). Preclinical studies have shown that vandetanib (ZD6474) is an inhibitor of both VEGFR and EGFR signalling. Giving vandetanib may therefore inhibit the growth of cancer cells by blocking their blood supply and by stopping them from dividing. This lung cancer study is to investigate if adding vandetanib to Alimta (pemetrexed) is more effective than Alimta (pemetrexed) alone.
Detailed description
This randomized phase III non-small cell lung cancer clinical trial is studying the effect of Alimta (pemetrexed) plus vandetanib to see how well the combination works compared to Alimta (pemetrexed) alone in patients who have previously been treated for non-small cell lung cancer (NSCLC).
Interventions
DRUGVandetanib
oral once daily tablet
DRUGPemetrexed
intravenous infusion
Sponsors
Genzyme, a Sanofi Company
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
* Provision of informed consent * Female or male aged 18 years or above * Histologic or cytologic confirmation of locally advanced or metastatic NSCLC (stage IIIB or IV) on entry into study * Failure of 1st line anti-cancer therapy (either radiological documentation of disease progression or due to toxicity) or subsequent relapse of disease following 1st line therapy * WHO Performance status 0 - 2 * One or more measurable lesions at least 10 mm in the longest diameter (LD) by spiral CT scan or 20 mm with conventional techniques according to RECIST criteria. Previously irradiated lesions will not be considered measurable. * Life expectancy of 12 weeks or longer * Negative pregnancy test for women of childbearing potential only
Exclusion criteria
* Mixed small cell and non-small cell lung cancer histology * Patients have received 2nd-line or subsequent anti-cancer therapy * Prior treatment with pemetrexed * Prior treatment with VEGFR TKIs (previous treatment with bevacizumab \[Avastin\] is permitted) * Known or suspected brain metastases or spinal cord compression, unless treated at least 4 weeks before entry, and stable without steroid treatment for 10 days * The last radiation therapy within 4 weeks before the start of study therapy, not including local palliative radiation * The last dose of prior chemotherapy or other anti-cancer therapy is discontinued less than 3 weeks before the start of study therapy (6 weeks for nitrosoureas, mitomycin, and suramin) * Major surgery within 4 weeks before entry, or incompletely healed surgical incision * Neutrophils \<1.5 x 109/L or platelets \<100 x 109/L * Serum bilirubin \>1.5 x the upper limit of reference range (ULRR) * Creatinine clearance \<50 ml/min calculated by either Cockcroft -Gault, 24 hours urine collection, EDTA scan or other validated methods * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 x ULRR in the absence of liver metastases, or \> 5 x ULRR in the presence of liver metastases * Alkaline phosphatase (ALP) \>2.5 x ULRR in the absence of liver metastases, or \>5 x ULRR in the presence of liver metastases * Current active gastrointestinal disease that may affect the ability of the patient to absorb ZD6474 or tolerate diarrhoea * Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol * Any unresolved toxicity greater than CTCAE Grade 2 from previous anti-cancer therapy * Significant cardiovascular event (e.g., myocardial infarction, superior vena cava \[SVC\] syndrome), New York Heart Association \[NYHA\] classification of heart disease ≥2 within 3 months before entry, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia * History of arrhythmia (multifocal premature ventricular contractions \[PVCs\], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded * Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age * QT prolongation with other medications that required discontinuation of that medication * Presence of left bundle branch block (LBBB) * QTc with Bazett's correction unmeasurable or ≥ 480 msec on screening ECG (Note: If a patient has QTc interval ≥480 msec on screening ECG, the screen ECG may be repeated twice \[at least 24 hours apart\]. The average QTc from the three screening ECGs must be \<480 msec in order for the patient to be eligible for the study) Patients who are receiving a drug that has a risk of QTc prolongation are eligible if QTc is \<460 msec. * Potassium \<4.0 mmol/L despite supplementation; serum calcium (or ionized or adjusted for albumin), or magnesium out of normal range despite supplementation * Women who are pregnant or breast-feeding * Any concomitant medications that may cause QTc prolongation or induce Torsades de Pointes or induce CYP3A4 function. Drugs that have a risk of QTc prolongation, that in the investigator's opinion cannot be discontinued, are allowed, but only of the QTc is \<460 msec * Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 millimetre of mercury \[mmHg\] or diastolic blood pressure greater than 100 mmHg) * Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix and adequately treated basal cell or squamous cell carcinoma of the skin * Treatment with a non-approved or investigational drug within 30 days before Day 1 of study treatment * Concomitant use of yellow fever vaccine or any live attenuated vaccines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) in the Overall Population | RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression | Median time (in weeks) from randomization until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable Response Evaluation Criteria in Solid Tumors (RECIST) assessment. |
| Progression-Free Survival in the Female Population | RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression | Median time (in weeks) from randomization until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression | The DCR is defined as the number of patients who achieved disease control at 6 weeks following randomization. Disease control at 6 weeks is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) \>= 6 weeks. |
| Duration of Response (DoR) | RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression | Response is defined as a confirmed best objective response of CR or PR. Duration of response is defined as time from the date of first documented response until date of documented progression or death in the absence of disease progression (provided death is within 3 months of last RECIST assessment). |
| Time to Deterioration of Disease-Related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score | LCSS questionnaires are to be administered every 3 weeks after randomization | TDS is the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 21 days. The LCSS scale measures changes in symptoms associated with lung cancer. |
| Overall Survival (OS) | Time to death in months | The OS is defined as the time from date of randomization until death. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive (i.e, their status must be known at the censored date and should not be lost to follow up or unknown). |
| Longitudinal Analysis of Lung Cancer Symptom Scale Total Score | LCSS questionnaires are to be administered every 3 weeks after randomization | The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. LCSS total score is an average of all 9 visual analogue participant scales from none \[0 millimeter (mm)\] to as much as it could be (100 mm). |
| Longitudinal Analysis of Average Symptom Burden Index Score | ASBI is a score taken from the LCSS questionnaires administered every 3 weeks after randomization | The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. ASBI is an average of the 6 symptom visual analogue patient scales from none (0 mm) to as much as it could be (100 mm). |
| Time to Deterioration of Disease-Related Symptoms by Average Symptom Burden Index (ASBI) Score | ASBI is a score taken from the LCSS questionnaires which are to be administered every 3 weeks after randomization | Time to deterioration is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 21 days. The ASBI is derived from 6 of LCSS's 9 items. |
| Objective Response Rate (ORR) | Each participant was assessed for objective response from the sequence of RECIST scan data up to data cut off. RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression | The ORR is the number of participants that are responders i.e, those participants with a confirmed best objective response of complete response (CR) or partial response (PR) as defined by RECIST criteria. The categories for best objective response are CR, PR, stable disease (SD)\>= 6 weeks, progressive disease (PD) or NE. |
Countries
Argentina, Australia, Belgium, Colombia, France, Germany, Greece, Hong Kong, India, Israel, Italy, Mexico, Philippines, Portugal, South Africa, Spain, Sweden, Taiwan, United Kingdom, United States, Venezuela
Participant flow
Recruitment details
First participant enrolled 09 January 2007, last participant enrolled 29 February 2008, cut off date 05 September 2008.
Pre-assignment details
A total of 534 participants were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Vandetanib Plus Pemetrexed Vandetanib (100 mg daily) plus pemetrexed (500 mg/m\^2 given on Day 1 of each 21-day cycle). | 256 |
| Placebo Plus Pemetrexed Placebo plus pemetrexed (500 mg/m\^2 given on Day 1 of each 21-day cycle). | 278 |
| Total | 534 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomized Period | Death | 122 | 147 |
| Randomized Period | discontinue treatment survival follow-up | 90 | 91 |
| Randomized Period | Lost to Follow-up | 4 | 6 |
| Randomized Period | randomised but no treatment received | 0 | 1 |
| Randomized Period | Withdrawal by Subject | 9 | 10 |
| Randomized Period | withdrawn due to other reason | 1 | 0 |
Baseline characteristics
| Characteristic | Vandetanib Plus Pemetrexed | Placebo Plus Pemetrexed | Total |
|---|---|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 9.95 | 60.2 years STANDARD_DEVIATION 9.5 | 59.4 years STANDARD_DEVIATION 9.73 |
| Sex/Gender, Customized Female | 97 Participants | 107 Participants | 204 Participants |
| Sex/Gender, Customized Male | 159 Participants | 171 Participants | 330 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 122 / 260 | 147 / 273 | 63 / 124 | 58 / 110 |
| other Total, other adverse events | 234 / 260 | 242 / 273 | 22 / 124 | 19 / 110 |
| serious Total, serious adverse events | 84 / 260 | 94 / 273 | 7 / 124 | 3 / 110 |
Outcome results
Primary
Progression-Free Survival in the Female Population
Median time (in weeks) from randomization until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment.
Time frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
Population: The female analysis set included all randomized female participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Progression-Free Survival in the Female Population | 17.9 weeks |
| Placebo Plus Pemetrexed | Progression-Free Survival in the Female Population | 13.0 weeks |
Primary
Progression-Free Survival (PFS) in the Overall Population
Median time (in weeks) from randomization until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable Response Evaluation Criteria in Solid Tumors (RECIST) assessment.
Time frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Progression-Free Survival (PFS) in the Overall Population | 17.6 weeks |
| Placebo Plus Pemetrexed | Progression-Free Survival (PFS) in the Overall Population | 11.9 weeks |
Secondary
Disease Control Rate (DCR)
The DCR is defined as the number of patients who achieved disease control at 6 weeks following randomization. Disease control at 6 weeks is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) \>= 6 weeks.
Time frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Disease Control Rate (DCR) | 56.6 percentage of participants |
| Placebo Plus Pemetrexed | Disease Control Rate (DCR) | 45.7 percentage of participants |
Secondary
Duration of Response (DoR)
Response is defined as a confirmed best objective response of CR or PR. Duration of response is defined as time from the date of first documented response until date of documented progression or death in the absence of disease progression (provided death is within 3 months of last RECIST assessment).
Time frame: RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
Population: The full analysis set included all randomized participants. Only participants with response are analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Duration of Response (DoR) | 24.1 weeks |
| Placebo Plus Pemetrexed | Duration of Response (DoR) | 24.4 weeks |
Secondary
Longitudinal Analysis of Average Symptom Burden Index Score
The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. ASBI is an average of the 6 symptom visual analogue patient scales from none (0 mm) to as much as it could be (100 mm).
Time frame: ASBI is a score taken from the LCSS questionnaires administered every 3 weeks after randomization
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vandetanib Plus Pemetrexed | Longitudinal Analysis of Average Symptom Burden Index Score | 21.7 mms on a visual analogue scale | Standard Error 2.75 |
| Placebo Plus Pemetrexed | Longitudinal Analysis of Average Symptom Burden Index Score | 24.3 mms on a visual analogue scale | Standard Error 2.67 |
Secondary
Longitudinal Analysis of Lung Cancer Symptom Scale Total Score
The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. LCSS total score is an average of all 9 visual analogue participant scales from none \[0 millimeter (mm)\] to as much as it could be (100 mm).
Time frame: LCSS questionnaires are to be administered every 3 weeks after randomization
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vandetanib Plus Pemetrexed | Longitudinal Analysis of Lung Cancer Symptom Scale Total Score | 25.7 mms on a visual analogue scale | Standard Error 2.85 |
| Placebo Plus Pemetrexed | Longitudinal Analysis of Lung Cancer Symptom Scale Total Score | 28.3 mms on a visual analogue scale | Standard Error 2.77 |
Secondary
Objective Response Rate (ORR)
The ORR is the number of participants that are responders i.e, those participants with a confirmed best objective response of complete response (CR) or partial response (PR) as defined by RECIST criteria. The categories for best objective response are CR, PR, stable disease (SD)\>= 6 weeks, progressive disease (PD) or NE.
Time frame: Each participant was assessed for objective response from the sequence of RECIST scan data up to data cut off. RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Objective Response Rate (ORR) | 19.1 percentage of participants |
| Placebo Plus Pemetrexed | Objective Response Rate (ORR) | 7.9 percentage of participants |
Secondary
Overall Survival (OS)
The OS is defined as the time from date of randomization until death. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive (i.e, their status must be known at the censored date and should not be lost to follow up or unknown).
Time frame: Time to death in months
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Overall Survival (OS) | 10.5 months |
| Placebo Plus Pemetrexed | Overall Survival (OS) | 9.2 months |
Secondary
Time to Deterioration of Disease-Related Symptoms by Average Symptom Burden Index (ASBI) Score
Time to deterioration is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 21 days. The ASBI is derived from 6 of LCSS's 9 items.
Time frame: ASBI is a score taken from the LCSS questionnaires which are to be administered every 3 weeks after randomization
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Time to Deterioration of Disease-Related Symptoms by Average Symptom Burden Index (ASBI) Score | 16.0 weeks |
| Placebo Plus Pemetrexed | Time to Deterioration of Disease-Related Symptoms by Average Symptom Burden Index (ASBI) Score | 13.4 weeks |
Secondary
Time to Deterioration of Disease-Related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score
TDS is the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of 'worsened' with no visit assessment of 'improved' within the next 21 days. The LCSS scale measures changes in symptoms associated with lung cancer.
Time frame: LCSS questionnaires are to be administered every 3 weeks after randomization
Population: The full analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib Plus Pemetrexed | Time to Deterioration of Disease-Related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score | 18.1 weeks |
| Placebo Plus Pemetrexed | Time to Deterioration of Disease-Related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score | 12.1 weeks |