Non-Squamous Non-Small Cell Lung Cancer
Conditions
Brief summary
This 4 arm study in patients with advanced Stage IIIb/IV non-small cell cancer (NSCLC) who failed at least one standard chemotherapy regimen will determine the proportion of patients with progression-free survival at 12 weeks following combination therapy with R1507 and Tarceva or placebo and Tarceva. Patients will be randomized to one of four treatment arms to receive R1507 (9mg/kg iv) or placebo weekly or R1507 (16mg/kg iv) or placebo every 3 weeks. Tarceva (150mg oral daily) will be administered in all treatment arms. Other disease-related endpoints including overall survival, objective response rate, time to response, time to progressive disease and duration of response will also be evaluated. The anticipated time on study treatment is 1-2 years, and the target sample size is \<500 individuals.
Interventions
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* male or female patients \>=18 years with histologically documented inoperable, locally advanced or metastatic (stage IIIB or IV) NSCLC; * patients must have failed at least one but no more than two standard chemotherapy regimens; * measurable disease according to the RECIST criteria; * Eastern Cooperative Oncology Group (ECOG) performance status; * life expectancy \>12 weeks.
Exclusion criteria
* patients with active central nervous system (CNS) lesions; * prior treatment with agents acting via insulin-like growth factor 1 receptor (IGF-1R) inhibition or epidermal growth factor receptor (EGFR) targeting; * administration with high doses of systemic corticosteroids; * radiotherapy in the 4 weeks prior to study start; * surgery or significant traumatic injury with in the last 2 weeks prior to study start.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression Free Survival (PFS) | 12 weeks | PFS was defined as the time at which half of the participants have progressed (progressive disease \[PD\]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants who had not died or progressed at the time of the final analysis were censored at the date of last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From baseline up to 20 months | OS was defined as the median time, in weeks, from the date of randomization to the date of death, due to any cause. Participants who have not died at the time of the final analysis will be censored at the date the participant was last known to be alive. The 90% CI was estimated using Kaplan-Meier methodology. |
| Objective Response Rate | From baseline up to 20 months | Objective response rate (ORR) was defined by RECIST criteria as the best response achieved by a patient over the course of the trial, which includes a complete response (CR) or partial response (PR) that has been confirmed by a second tumor assessment no earlier than 4 weeks after the initial documentation, stable disease (SD), or progressive disease (PD). PR was defined as ≥ 30% decrease in sum of longest diameter of all target lesions, from baseline sum. CR was defined as disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. PD = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions. SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on the study. |
| Duration of Response | From baseline up to 20 months | Duration of response was defined as the time from the first documented complete response (CR) or partial response (PR) to the first documented disease progression (PD) or death, whichever occurs first. A CR was defined as the disappearance of all target lesions (TL). A PR was defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs taking as reference the Baseline SLD. PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since treatment started or the unequivocal progression of existing non-TLs. |
| Time to Response | From baseline up to 20 months | This is defined for participants with objective response, as the date of randomization to the date of first CR or PR which will be the date the response is first radiographically documented following initiation of therapy (the date of the actual imaging modality). |
Countries
Australia, Belgium, Canada, France, Germany, Ireland, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
A screening examination was to be performed between -28 and 1 days before first day of treatment.
Pre-assignment details
Safety population was used for the participant flow. All randomized participants who received at least one treatment. Two patients randomized to placebo QW actually received R1507 9 mg/kg QW.
Participants by arm
| Arm | Count |
|---|---|
| Placebo for R1507 (9mg/kg iv) Participants received a placebo equivalent to R1507 (9mg/kg iv) intravenously every week until disease progression. | 26 |
| Placebo for R1507 (16mg/kg iv) Participants received the placebo equivalent to R1507 (16 mg/kg iv) intravenously every 3 weeks until disease progression. | 29 |
| R1507 (9mg/kg iv) Participants received R1507 (9mg/kg iv) intravenously every week until disease progression. | 59 |
| R1507 (16mg/kg iv) Participants received R1507 (16 mg/kg iv) intravenously every 3 weeks until disease progression. | 57 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 6 | 10 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 2 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Other | 2 | 0 | 2 | 1 |
| Overall Study | Progression of Disease | 21 | 26 | 38 | 42 |
| Overall Study | Violation of Selection Criteria at Entry | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 9 | 1 |
Baseline characteristics
| Characteristic | R1507 (16mg/kg iv) | Total | R1507 (9mg/kg iv) | Placebo for R1507 (16mg/kg iv) | Placebo for R1507 (9mg/kg iv) |
|---|---|---|---|---|---|
| Age, Continuous | 60.5 Years STANDARD_DEVIATION 9.82 | 61.0 Years STANDARD_DEVIATION 9.56 | 60.3 Years STANDARD_DEVIATION 10.45 | 62.3 Years STANDARD_DEVIATION 8.26 | 62.0 Years STANDARD_DEVIATION 8.01 |
| Race/Ethnicity, Customized Black | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 56 Participants | 166 Participants | 57 Participants | 27 Participants | 26 Participants |
| Sex: Female, Male Female | 19 Participants | 57 Participants | 18 Participants | 11 Participants | 9 Participants |
| Sex: Female, Male Male | 38 Participants | 114 Participants | 41 Participants | 18 Participants | 17 Participants |
| Smoking Status Current smoker | 5 Participants | 22 Participants | 8 Participants | 6 Participants | 3 Participants |
| Smoking Status Never smoked | 7 Participants | 20 Participants | 6 Participants | 4 Participants | 3 Participants |
| Smoking Status Past smoker | 45 Participants | 129 Participants | 45 Participants | 19 Participants | 20 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 | 20 / 26 | 22 / 29 | 43 / 59 | 34 / 57 |
| other Total, other adverse events | 26 / 26 | 27 / 29 | 57 / 59 | 56 / 57 |
| serious Total, serious adverse events | 5 / 26 | 3 / 29 | 18 / 59 | 14 / 57 |
Outcome results
Primary
Number of Participants With Progression Free Survival (PFS)
PFS was defined as the time at which half of the participants have progressed (progressive disease \[PD\]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Participants who had not died or progressed at the time of the final analysis were censored at the date of last contact.
Time frame: 12 weeks
Population: All-treated population: All participants enrolled in the study who had been randomly assigned to one of the four study treatments were included. For analysis, participants receiving both weekly and every 3 weeks of placebo were combined and evaluated as one group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Progression Free Survival (PFS) | Progression-Free & Alive | 18 Participants |
| Placebo | Number of Participants With Progression Free Survival (PFS) | Progressed, Died, or Unknown | 39 Participants |
| R1507 (9mg/kg iv) | Number of Participants With Progression Free Survival (PFS) | Progression-Free & Alive | 16 Participants |
| R1507 (9mg/kg iv) | Number of Participants With Progression Free Survival (PFS) | Progressed, Died, or Unknown | 41 Participants |
| R1507 (16mg/kg iv) | Number of Participants With Progression Free Survival (PFS) | Progression-Free & Alive | 21 Participants |
| R1507 (16mg/kg iv) | Number of Participants With Progression Free Survival (PFS) | Progressed, Died, or Unknown | 36 Participants |
Secondary
Duration of Response
Duration of response was defined as the time from the first documented complete response (CR) or partial response (PR) to the first documented disease progression (PD) or death, whichever occurs first. A CR was defined as the disappearance of all target lesions (TL). A PR was defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs taking as reference the Baseline SLD. PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since treatment started or the unequivocal progression of existing non-TLs.
Time frame: From baseline up to 20 months
Population: All-treated population: All participants enrolled in the study who had been randomly assigned to one of the four study treatments were included. For analysis, participants receiving both weekly and every 3 weeks of placebo were combined and evaluated as one group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Response | 260.40 days | Standard Deviation 140.56 |
| R1507 (9mg/kg iv) | Duration of Response | 215.50 days | Standard Deviation 91.7 |
| R1507 (16mg/kg iv) | Duration of Response | 257.75 days | Standard Deviation 130.07 |
Secondary
Objective Response Rate
Objective response rate (ORR) was defined by RECIST criteria as the best response achieved by a patient over the course of the trial, which includes a complete response (CR) or partial response (PR) that has been confirmed by a second tumor assessment no earlier than 4 weeks after the initial documentation, stable disease (SD), or progressive disease (PD). PR was defined as ≥ 30% decrease in sum of longest diameter of all target lesions, from baseline sum. CR was defined as disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. PD = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions. SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on the study.
Time frame: From baseline up to 20 months
Population: All-treated population: All participants enrolled in the study who had been randomly assigned to one of the four study treatments were included. For analysis, participants receiving both weekly and every 3 weeks of placebo were combined and evaluated as one group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Objective Response Rate | 8.8 Percentage of Participants |
| R1507 (9mg/kg iv) | Objective Response Rate | 7 Percentage of Participants |
| R1507 (16mg/kg iv) | Objective Response Rate | 7 Percentage of Participants |
Secondary
Overall Survival (OS)
OS was defined as the median time, in weeks, from the date of randomization to the date of death, due to any cause. Participants who have not died at the time of the final analysis will be censored at the date the participant was last known to be alive. The 90% CI was estimated using Kaplan-Meier methodology.
Time frame: From baseline up to 20 months
Population: All-treated population: All participants enrolled in the study who had been randomly assigned to one of the four study treatments were included. For analysis, participants receiving both weekly and every 3 weeks of placebo were combined and evaluated as one group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival (OS) | 35.1 Weeks |
| R1507 (9mg/kg iv) | Overall Survival (OS) | 35.1 Weeks |
| R1507 (16mg/kg iv) | Overall Survival (OS) | 52.4 Weeks |
p-value: 0.430190% CI: [0.58, 1.21]Wald Test
p-value: 0.034290% CI: [0.42, 0.9]Wald Test
Secondary
Time to Response
This is defined for participants with objective response, as the date of randomization to the date of first CR or PR which will be the date the response is first radiographically documented following initiation of therapy (the date of the actual imaging modality).
Time frame: From baseline up to 20 months
Population: All-treated population: All participants enrolled in the study who had been randomly assigned to one of the four study treatments were included. For analysis, participants receiving both weekly and every 3 weeks of placebo were combined and evaluated as one group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to Response | 42.40 days | Standard Deviation 4.34 |
| R1507 (9mg/kg iv) | Time to Response | 65.25 days | Standard Deviation 22.95 |
| R1507 (16mg/kg iv) | Time to Response | 85.25 days | Standard Deviation 34.7 |