Non-Small Cell Lung Cancer
Conditions
Brief summary
This single arm study in patients with advanced Stage IIIb/IV NSCLC who have progressive disease after deriving clinical benefit (defined as response or stable disease after 12 weeks) from second or third line Tarceva monotherapy will determine the proportion of patients with progression-free survival at 12 weeks following combination therapy with R1507 and Tarceva. Patients will receive R1507 (9mg/kg iv) weekly in combination with Tarceva (150mg oral daily) for up to a maximum of 24 months. 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 \<100 individuals.
Interventions
DRUGRG1507
iv 9mg/kg weekly
DRUGerlotinib [Tarceva]
150mg oral daily
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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; * currently receiving Tarceva monotherapy and having failed at least one standard chemotherapy regimens; * prior response or stable disease 12 weeks from start of Tarceva; * documented progressive disease at enrollment; * measurable disease according to the RECIST criteria; * ECOG performance status 0-2; * life expectancy \>12 weeks.
Exclusion criteria
* patients with active CNS lesions; * prior treatment with agents acting via IGF-1R inhibition or 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 |
|---|---|---|
| Percentage of Participants With Progression Free Survival (PFS) | 12 weeks | The primary efficacy endpoint is progression-free survival at 12 weeks after start of therapy. A progression-free survival rate at 12 weeks will be calculated, with patients categorized in a dichotomous manner as alive and progression-free or in progression or dead at 12 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants Achieving Objective Response | Patients were followed from start of therapy until date of first response | Objective response is defined as 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. Response is assessed using Response Evaluation Criteria in Solid Tumors (RECIST)criteria. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. |
| Time to Best Response | Patients were followed from start of therapy until date of first response | This is defined as time from the start of therapy to the date of first CR or PR. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. |
| Time to Progressive Disease (PD) | From start of therapy to the date of first documentation of PD. Pts who never progress prior to final analysis or are withdrawn from the study without documented progression will be censored at the date of the last valid tumor assessment. | The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. |
| Duration of Objective Response | from the date the complete or partial response was first recorded to the date which progressive disease is first noted or date of death. If a patient does not progress or die while being followed, the date of the last valid tumor assessment will be taken | This is defined similarly for complete and partial responders. Complete response or partial response lasts from the date the complete response or partial response was first recorded to the date on which progressive disease is first noted or date of death. If a patient does not progress or die while being followed, the date of the last valid tumor assessment will be taken. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. |
| Baseline Electrocardiogram (ECG) | baseline within 28 days of starting treatment (screening visit). | Standard safety monitoring includes baseline Electrocardiogram (ECG). The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. |
| Fasting Glucose, Highest Post-Baseline Value | Baseline, Highest Post-Baseline value within the timeframe of post-baseline collection up to when patient discontinued (up to 59 weeks) | A fasting glucose was required at baseline, and random non-fasting glucose testing was performed weekly for the first 6 weeks followed by day 1 of each 3 week treatment phase. The number of participants with the highest post-baseline fasting glucose level at any time point post baseline relative to the participant's baseline glucose level is reported. |
| Duration of Overall Survival | From start of treatment to death; up to the time that all participants ended treatment | The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. |
| Monthly Urine Pregnancy Test in Female Patients of Childbearing Potential | Within 7 days of starting treatment (baseline visit) | Standard safety monitoring includes baseline Electrocardiogram (ECG), Fasting glucose and HbA1c, monthly urine pregnancy test in female patients of childbearing potential and Human anti-human antibody (HAHA) testing. Not posted; it will be represented in the Serious Adverse Event (SAE) Adverse Event (AE) section of Protocol Registration System (PRS). |
| Number of Participants With Positive Results for Human Anti-human Antibody (HAHA) Testing | prior to dosing on week 1 (day 1), week 4 (day 22), week 10 (day 64), final visit, follow up visit and 12 weeks post last dose (up to 71 weeks) | Number of participants who tested positive for Human anti-human antibody (HAHA) testing for immunogenicity. To determine HAHA specificity, screened positive samples were tested in a confirmatory assay in the presence of 10 ug/mL R1507. Samples with \> 19.7% inhibition were considered true positives, whereas those with \< 19.7% inhibition were considered to be false positives. |
| Electrocardiogram (ECG) | baseline and thereafter as clinically indicated at the discretion of the investigator up to the time that the patient discontinued (up to 59 weeks) | 12 lead ECG is required at baseline and will be measured during the trial as clinically indicated at the discretion of the investigators. For each reading, QTcF value will be calculated as the QT value (seconds) divided by the cube root of the RR interval in seconds (Fridericia correction). A listing will be generated showing, for each patient, the visits at which ECGs were taken and the results (normal or abnormal, as well as any comments provided). |
| Population Pharmacokinetics of R1507 and Tarceva | Throughout study | Population PK of R1507 and erlotinib were planned but not analyzed due to the termination of the trial. |
| Assessment of Potential Predictive and Prognostic Biomarkers. | Throughout study | Total IGF-I, free IGF I/II and other potential biomarkers present in serum. Further putative biomarker analyses in blood and tumor samples were planned in the protocol for exploratory assessment of correlation with clinical outcome. None of these were analyzed due to the termination of the trial. |
| Hemoglobin A1c (HbA1c) | screening | Standard safety monitoring includes baseline Electrocardiogram (ECG), Fasting glucose and HbA1c, monthly urine pregnancy test in female patients of childbearing potential and Human anti-human antibody (HAHA) testing. Data will be represented in the Serious Adverse Event (SAE) Adverse Event (AE) section of Protocol Registration System (PRS). |
Countries
Canada, France, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| R1507 9 mg/kg once a week (qw) IV administered over 60-90 minutes erlotinib - 150 mg Once daily administration (qd) Oral administration(PO) | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 1 |
| Overall Study | No study dose received | 1 |
| Overall Study | Other | 2 |
| Overall Study | Progression of Disease | 23 |
Baseline characteristics
| Characteristic | R1507 |
|---|---|
| Age Continuous | 59.9 years STANDARD_DEVIATION 11.43 |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 34 |
| serious Total, serious adverse events | 12 / 34 |
Outcome results
Primary
Percentage of Participants With Progression Free Survival (PFS)
The primary efficacy endpoint is progression-free survival at 12 weeks after start of therapy. A progression-free survival rate at 12 weeks will be calculated, with patients categorized in a dichotomous manner as alive and progression-free or in progression or dead at 12 weeks.
Time frame: 12 weeks
Population: All Treated Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| R1507 | Percentage of Participants With Progression Free Survival (PFS) | Progression-Free & Alive | 32.4 Percentage of participants |
| R1507 | Percentage of Participants With Progression Free Survival (PFS) | Progressed, Died, or Unknown | 67.6 Percentage of participants |
Secondary
Assessment of Potential Predictive and Prognostic Biomarkers.
Total IGF-I, free IGF I/II and other potential biomarkers present in serum. Further putative biomarker analyses in blood and tumor samples were planned in the protocol for exploratory assessment of correlation with clinical outcome. None of these were analyzed due to the termination of the trial.
Time frame: Throughout study
Population: Responders and non-responders
Secondary
Baseline Electrocardiogram (ECG)
Standard safety monitoring includes baseline Electrocardiogram (ECG). The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed.
Time frame: baseline within 28 days of starting treatment (screening visit).
Population: Safety Population
Secondary
Duration of Objective Response
This is defined similarly for complete and partial responders. Complete response or partial response lasts from the date the complete response or partial response was first recorded to the date on which progressive disease is first noted or date of death. If a patient does not progress or die while being followed, the date of the last valid tumor assessment will be taken. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed.
Time frame: from the date the complete or partial response was first recorded to the date which progressive disease is first noted or date of death. If a patient does not progress or die while being followed, the date of the last valid tumor assessment will be taken
Population: All Treated Population
Secondary
Duration of Overall Survival
The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed.
Time frame: From start of treatment to death; up to the time that all participants ended treatment
Population: All Treated Population
Secondary
Electrocardiogram (ECG)
12 lead ECG is required at baseline and will be measured during the trial as clinically indicated at the discretion of the investigators. For each reading, QTcF value will be calculated as the QT value (seconds) divided by the cube root of the RR interval in seconds (Fridericia correction). A listing will be generated showing, for each patient, the visits at which ECGs were taken and the results (normal or abnormal, as well as any comments provided).
Time frame: baseline and thereafter as clinically indicated at the discretion of the investigator up to the time that the patient discontinued (up to 59 weeks)
Population: Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R1507 | Electrocardiogram (ECG) | Summary of QTcF Interval (n = 2) | 421.5 ms (millisecond) | Standard Deviation 3.54 |
| R1507 | Electrocardiogram (ECG) | Change from Baseline (n = 1) | 24.0 ms (millisecond) | — |
Secondary
Fasting Glucose, Highest Post-Baseline Value
A fasting glucose was required at baseline, and random non-fasting glucose testing was performed weekly for the first 6 weeks followed by day 1 of each 3 week treatment phase. The number of participants with the highest post-baseline fasting glucose level at any time point post baseline relative to the participant's baseline glucose level is reported.
Time frame: Baseline, Highest Post-Baseline value within the timeframe of post-baseline collection up to when patient discontinued (up to 59 weeks)
Population: Safety Population: based on the total number of participants n = 34
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| R1507 | Fasting Glucose, Highest Post-Baseline Value | Normal (< 140 mg/dL) | 21 participants |
| R1507 | Fasting Glucose, Highest Post-Baseline Value | Impaired Fasting Glucose (≥ 140 to ≤ 200 mg/dL) | 2 participants |
| R1507 | Fasting Glucose, Highest Post-Baseline Value | Diabetes Mellitus (> 200 mg/dL) | 0 participants |
| R1507 | Fasting Glucose, Highest Post-Baseline Value | Missing | 3 participants |
| R1507_Baseline Impaired Fasting Glucose | Fasting Glucose, Highest Post-Baseline Value | Impaired Fasting Glucose (≥ 140 to ≤ 200 mg/dL) | 1 participants |
| R1507_Baseline Impaired Fasting Glucose | Fasting Glucose, Highest Post-Baseline Value | Diabetes Mellitus (> 200 mg/dL) | 0 participants |
| R1507_Baseline Impaired Fasting Glucose | Fasting Glucose, Highest Post-Baseline Value | Missing | 0 participants |
| R1507_Baseline Impaired Fasting Glucose | Fasting Glucose, Highest Post-Baseline Value | Normal (< 140 mg/dL) | 3 participants |
| R1507_Baseline Diabetes Mellitus | Fasting Glucose, Highest Post-Baseline Value | Diabetes Mellitus (> 200 mg/dL) | 0 participants |
| R1507_Baseline Diabetes Mellitus | Fasting Glucose, Highest Post-Baseline Value | Impaired Fasting Glucose (≥ 140 to ≤ 200 mg/dL) | 1 participants |
| R1507_Baseline Diabetes Mellitus | Fasting Glucose, Highest Post-Baseline Value | Missing | 0 participants |
| R1507_Baseline Diabetes Mellitus | Fasting Glucose, Highest Post-Baseline Value | Normal (< 140 mg/dL) | 1 participants |
| R1507_Baseline Missing | Fasting Glucose, Highest Post-Baseline Value | Missing | 2 participants |
| R1507_Baseline Missing | Fasting Glucose, Highest Post-Baseline Value | Impaired Fasting Glucose (≥ 140 to ≤ 200 mg/dL) | 0 participants |
| R1507_Baseline Missing | Fasting Glucose, Highest Post-Baseline Value | Normal (< 140 mg/dL) | 0 participants |
| R1507_Baseline Missing | Fasting Glucose, Highest Post-Baseline Value | Diabetes Mellitus (> 200 mg/dL) | 0 participants |
Secondary
Hemoglobin A1c (HbA1c)
Standard safety monitoring includes baseline Electrocardiogram (ECG), Fasting glucose and HbA1c, monthly urine pregnancy test in female patients of childbearing potential and Human anti-human antibody (HAHA) testing. Data will be represented in the Serious Adverse Event (SAE) Adverse Event (AE) section of Protocol Registration System (PRS).
Time frame: screening
Population: Safety Population
Secondary
Monthly Urine Pregnancy Test in Female Patients of Childbearing Potential
Standard safety monitoring includes baseline Electrocardiogram (ECG), Fasting glucose and HbA1c, monthly urine pregnancy test in female patients of childbearing potential and Human anti-human antibody (HAHA) testing. Not posted; it will be represented in the Serious Adverse Event (SAE) Adverse Event (AE) section of Protocol Registration System (PRS).
Time frame: Within 7 days of starting treatment (baseline visit)
Population: Female patients of childbearing potential
Secondary
Number of Participants With Positive Results for Human Anti-human Antibody (HAHA) Testing
Number of participants who tested positive for Human anti-human antibody (HAHA) testing for immunogenicity. To determine HAHA specificity, screened positive samples were tested in a confirmatory assay in the presence of 10 ug/mL R1507. Samples with \> 19.7% inhibition were considered true positives, whereas those with \< 19.7% inhibition were considered to be false positives.
Time frame: prior to dosing on week 1 (day 1), week 4 (day 22), week 10 (day 64), final visit, follow up visit and 12 weeks post last dose (up to 71 weeks)
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| R1507 | Number of Participants With Positive Results for Human Anti-human Antibody (HAHA) Testing | POSITIVE | 1 participants |
| R1507 | Number of Participants With Positive Results for Human Anti-human Antibody (HAHA) Testing | FALSE POSITIVE | 5 participants |
Secondary
Participants Achieving Objective Response
Objective response is defined as 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. Response is assessed using Response Evaluation Criteria in Solid Tumors (RECIST)criteria. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed.
Time frame: Patients were followed from start of therapy until date of first response
Population: All Treated Population
Secondary
Population Pharmacokinetics of R1507 and Tarceva
Population PK of R1507 and erlotinib were planned but not analyzed due to the termination of the trial.
Time frame: Throughout study
Population: Population PK of R1507 and erlotinib
Secondary
Time to Best Response
This is defined as time from the start of therapy to the date of first CR or PR. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed.
Time frame: Patients were followed from start of therapy until date of first response
Population: All Treated Population
Secondary
Time to Progressive Disease (PD)
The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed.
Time frame: From start of therapy to the date of first documentation of PD. Pts who never progress prior to final analysis or are withdrawn from the study without documented progression will be censored at the date of the last valid tumor assessment.
Population: All Treated Population