Lung Cancer, Non-Small Cell
Conditions
Keywords
GW786034, pazopanib, pemetrexed, cisplatin, non-small cell lung cancer, NSCLC
Brief summary
The main purpose of this study is to determine whether the combination of pazopanib and pemetrexed is safe and effective in the treatment of advanced non-small cell lung cancer (NSCLC).
Interventions
DRUGpazopanib and pemetrexed
oral pazopanib 600 mg once daily and pemetrexed intravenous (IV) 500mg/m\^2 once every 3 weeks, then pazopanib 800 mg once daily
pemetrexed IV 500 mg/m\^2 and cisplatin IV 75 mg/m\^2 once every 3 weeks
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent * At least 18 years old * Histologically- or cytologically-confirmed diagnosis of predominantly nonsquamous cell Stage IIIBwet (with confirmed malignant pleural effusion) or Stage IV NSCLC * No prior systemic first-line therapy for advanced NSCLC * Measurable disease * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Life expectancy of at least 12 weeks * Able to swallow and retain oral medication * Adequate organ system function (hematological, hepatic, and renal) * Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) OR childbearing potential, and agrees to use adequate contraception. A male with a female partner of childbearing potential is eligible if he uses a barrier method of contraception or abstinence during the study
Exclusion criteria
* Active malignancy or any malignancy in the 3 years prior to first dose of study drug other than NSCLC * Central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for asymptomatic, previously treated CNS metastases * Clinically significant gastrointestinal abnormalities * Prolongation of corrected QT interval (QTc) \> 480 msecs * History of any one or more cardiovascular conditions within the past 6 months prior to randomization * Poorly controlled hypertension * History of cerebrovascular accident (including transient ischemic attacks), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months * Major surgery or trauma within 28 days or any non-healing wound, fracture, or ulcer * Evidence of active bleeding or bleeding diathesis * Recent hemoptysis * Endobronchial lesions and/or lesions infiltrating major pulmonary vessels * Serious and/or unstable pre-existing medical (e.g., uncontrolled infection), psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures * Use of any prohibited medication * Use of an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug * Ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity except alopecia * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib, pemetrexed, and/or cisplatin * Inability to interrupt aspirin or other non-steroidal anti-inflammatory drugs during the study * Inability or unwillingness to take folic acid, vitamin B12 supplementation, or dexamethasone * Clinically significant third-space fluid collections (e.g., ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior to study start * Recent or concurrent yellow fever vaccination
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Randomization until progression or death (up to 85 weeks) | PFS is defined as the interval between the date of randomization (date on which the investigator evaluated the participant and first determined he/she had disease progression) and the first occurrence of progressive disease (PD) or death from any cause. Per Response Evaluation Criteria in Solid Tumors (RECIST), version 1, PD is defined as a \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of \>=1 new lesion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization until death (up to 85 weeks) | OS was determined from the date of randomization to the date of death from any cause. Participants who had not died at the time of the cut-off for the final analysis were censored at the date the participants were last known to be alive. Because enrollment in the study was halted prematurely, the ability to achieve an estimate of OS was compromised. Consequently, OS was not estimated. |
| Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Randomization until response or progressive disease (up to 85 weeks) | Tumor response was assessed by the Investigator according to the RECIST, version 1.0. A participant was defined as a responder if he/she sustained a complete response (CR; the disappearance of all target lesions) or partial response (PR; \>=30% decrease in the sum of the longest diameter of target lesions) for at least 4 weeks at any time during randomized treatment. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. |
| Percentage of Participants With a Complete Response or a Partial Response | Randomization until response or progressive disease (up to 85 weeks) | The percentage of participants with a complete response or a partial response was evaluated. |
Countries
Denmark, United Kingdom
Participant flow
Pre-assignment details
Per protocol, the study had 2 treatment arms: Arm 1, investigational (pazopanib+pemetrexed); and Arm 2, standard of care (cisplatin+pemetrexed). Protocol amendment 1 lowered the pazopanib starting dose (SD) for new Arm 1 participants from 800 to 600 milligrams. For clarity, safety/demography data for these different SDs are presented separately.
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib 600 mg Plus Pemetrexed 500 mg/m^2 Oral pazopanib 600 milligrams (mg) once daily plus intravenous pemetrexed 500 mg/meters squared (m\^2) once every 3 weeks for 4 or 6 cycles during the Combination Treatment Phase. | 9 |
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 Oral pazopanib 800 mg once daily plus intravenous (IV) pemetrexed 500 mg/ m\^2 once every 3 weeks for 4 or 6 cycles during the Combination Treatment Phase. If participants experienced no disease progression, unacceptable toxicities, or death during the Combination Treatment Phase, they continued on pazopanib 800 mg monotherapy until disease progression, unacceptable toxicities, or death. | 62 |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 IV cisplatin 75 mg/m\^2 plus intravenous pemetrexed 500 mg/m\^2 once daily every 3 weeks for 4 or 6 cycles during the Combination Treatment Phase. Until Protocol Amendment 2, upon disease progression participants had the opportunity to receive pazopanib 800 mg monotherapy if the investigator considered it an appropriate treatment option after considering alternative options for second-line treatment. | 35 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Combination Treatment Phase | Adverse Event | 0 | 17 | 2 |
| Combination Treatment Phase | Disease Progression | 0 | 8 | 5 |
| Combination Treatment Phase | Physician Decision | 0 | 1 | 3 |
| Combination Treatment Phase | Randomized but Not Treated | 1 | 1 | 1 |
| Combination Treatment Phase | Treatment Stopped; Protocol Amendment | 8 | 19 | 0 |
| Combination Treatment Phase | Withdrawal by Subject | 0 | 3 | 1 |
| Monotherapy Treatment Phase | Adverse Event | 0 | 4 | 0 |
| Monotherapy Treatment Phase | Disease Progression | 0 | 9 | 1 |
Baseline characteristics
| Characteristic | Pazopanib 600 mg Plus Pemetrexed 500 mg/m^2 | Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Total |
|---|---|---|---|---|
| Age Continuous | 60.4 Years STANDARD_DEVIATION 14.32 | 60.8 Years STANDARD_DEVIATION 8.27 | 61.8 Years STANDARD_DEVIATION 9.35 | 61.1 Years STANDARD_DEVIATION 9.16 |
| Race/Ethnicity, Customized African American/African Heritage | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 0 participants | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 8 participants | 59 participants | 33 participants | 100 participants |
| Sex: Female, Male Female | 2 Participants | 23 Participants | 12 Participants | 37 Participants |
| Sex: Female, Male Male | 7 Participants | 39 Participants | 23 Participants | 69 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 | 7 / 8 | 59 / 61 | 32 / 34 |
| serious Total, serious adverse events | 3 / 8 | 34 / 61 | 12 / 34 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS is defined as the interval between the date of randomization (date on which the investigator evaluated the participant and first determined he/she had disease progression) and the first occurrence of progressive disease (PD) or death from any cause. Per Response Evaluation Criteria in Solid Tumors (RECIST), version 1, PD is defined as a \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of \>=1 new lesion).
Time frame: Randomization until progression or death (up to 85 weeks)
Population: Intent-to-Treat (ITT) Population: all participants randomized to receive treatment and who were analyzed based on the assigned randomized treatment and not based on actual treatment received/not received. Participants who had neither progressed nor died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Progression-free Survival (PFS) | 25.0 weeks |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Progression-free Survival (PFS) | 22.9 weeks |
p-value: 0.264795% CI: [0.43, 1.28]Log Rank
Secondary
Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only
Tumor response was assessed by the Investigator according to the RECIST, version 1.0. A participant was defined as a responder if he/she sustained a complete response (CR; the disappearance of all target lesions) or partial response (PR; \>=30% decrease in the sum of the longest diameter of target lesions) for at least 4 weeks at any time during randomized treatment. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.
Time frame: Randomization until response or progressive disease (up to 85 weeks)
Population: ITT Population. A participant without a post-baseline assessment of response was considered to be a non-responder; i.e., all randomized participants are included in the denominator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Partial response | 14 participants |
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Progressive disease | 6 participants |
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Stable disease | 13 participants |
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Unknown | 29 participants |
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Complete response | 0 participants |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Unknown | 4 participants |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Complete response | 0 participants |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Partial response | 12 participants |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Stable disease | 14 participants |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Best Overall Response, Assessed as the Number of Participants With the Indicated Tumor Response: Investigator Assessed Only | Progressive disease | 5 participants |
Secondary
Overall Survival (OS)
OS was determined from the date of randomization to the date of death from any cause. Participants who had not died at the time of the cut-off for the final analysis were censored at the date the participants were last known to be alive. Because enrollment in the study was halted prematurely, the ability to achieve an estimate of OS was compromised. Consequently, OS was not estimated.
Time frame: Randomization until death (up to 85 weeks)
Population: ITT Population
Secondary
Percentage of Participants With a Complete Response or a Partial Response
The percentage of participants with a complete response or a partial response was evaluated.
Time frame: Randomization until response or progressive disease (up to 85 weeks)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pazopanib 800 mg Plus Pemetrexed 500 mg/m^2 | Percentage of Participants With a Complete Response or a Partial Response | 14 percentage of participants |
| Cisplatin 75 mg/m^2 Plus Pemetrexed 500 mg/m^2 | Percentage of Participants With a Complete Response or a Partial Response | 12 percentage of participants |
p-value: 0.211395% CI: [-30.6, 7.2]Binomial asymptotic