Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Squamous
Brief summary
This study will assess the safety and tolerability, and make a preliminary assessment of activity, of a combination of pertuzumab and erlotinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have failed on at least one prior chemotherapy regimen. The anticipated time on study treatment is until disease progression or unacceptable toxicity, and the target sample size is less than 100 individuals.
Interventions
DRUGErlotinib
Erlotinib will be administered as oral tablets.
DRUGPertuzumab
Pertuzumab will be administered as intravenous (IV) infusion.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients greater than or equal to 18 years of age * Histological confirmation of non-small cell lung cancer (NSCLC) * Locally advanced or metastatic disease * Failure of at least one prior regimen of standard chemotherapy for locally advanced or metastatic disease * Life expectancy of more than or equal to 12 weeks * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Baseline Left Ventricular Ejection Fraction (LVEF) of greater than or equal to 50% * A negative pregnancy test one week prior to treatment and willingness to use contraception among women of childbearing potential * Availability of histological Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissue
Exclusion criteria
* Prior chemotherapy, radiotherapy or immunotherapy within 4 weeks of study Day -8 * Prior treatment with any agent which targets growth factors or their receptors * Patients who have not recovered from the acute reversible effects of chemotherapy and radiotherapy * History of clinically significant cardiovascular disease * History or evidence of central nervous system metastases * Treatment with any investigational drug within 28 days of the start of the study (day -8) * Prior cumulative doxorubicin dose of more than 360 mg/m2 or the equivalent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Dose Limiting Toxicities (DLTs) | From baseline to end of the study (up to 42 weeks) | A DLT was defined as: Any non-hematological toxicity ≥ Grade 3 according to the Common Terminology Criteria for Adverse Events, version 3.0, except for fever, chills, and flu-like symptoms, which occurred despite adequate participant management. The following Grade 1-3 toxicities were exempt: Grade 1-3 skin and/or epithelial toxicities consistent with erlotinib single agent therapy, unless they did not respond to treatment or dose reduction or interruption (Grade 4 skin and/or epithelial toxicities were considered to be a DLT); Grade 4 neutropenia occurring for \> 7 days; febrile neutropenia which occurred despite adequate participant management; Grade 4 thrombocytopenia or any thrombocytopenia requiring platelet transfusion; and any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | From baseline to the end of the study (up to 42 weeks) | Complete and partial responses were determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A complete response was defined as the disappearance of all target and non-target lesions. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. |
| Peak Plasma Concentration (Cmax) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion | Maximum Observed Plasma Concentration (Cmax), which is the maximum (peak) concentration (amount of drug) measurable in blood plasma after a dose is administered, typically measured in nanograms/milliliter (ng/mL), reported as mg/L. |
| Time of Cmax (Tmax) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion | The time at which maximum concentration (Cmax), which is the maximum (peak) concentration (amount of drug) measurable in blood plasma after a dose is administered, is reached (Tmax). |
| Percentage of Participants Classified as Responders | within 18 weeks | Responders are participants who achieved either a complete response or a partial response according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. |
| Area Under the Plasma Concentration Versus Time Curve (AUC) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With Non-small Cell Lung Cancer (NSCLC) | on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion | Bioavailability \[AUC(0-t)\] is a measure of how much of the drug reaches the person's bloodstream from time 0 (pre-dose) to a given time point (t) for the body to use. The extent of product bioavailability is estimated by the area under the blood concentration vs time curve. The Area Under the Curve (AUC) is calculated by plotting the drug's blood levels on a graph at different times during the set period. The area under this curve reflects the amount of drug exposure in the set time period, calculated as hour \* nanograms (ng) per milliliter (mL), which equates to mg.day/L. Bioavailability Extrapolated to Infinity \[AUC (0-inf)\] is a calculated measure of how much of the drug will ever reach the person's bloodstream for the body to use. AUC (0-inf) stands for the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (forever). It is obtained from calculating AUC (0-t) plus AUC (t-inf). |
| Clearance (CL) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion | A fundamental concept in pharmacokinetics is drug clearance (CL), that is, elimination of drugs from the body. The clearance is simply the ratio of the dose to the area under the curve (AUC), so that the higher the AUC for a given dose, the lower the clearance. If a drug is administered by continuous infusion and a steady state is achieved, the clearance can be estimated from a single measurement of the plasma drug concentration. |
| Volume of Distribution at Steady-state (Vss) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion | Steady-state volume of distribution of a drug is an estimate of drug distribution independent of elimination processes. It is most useful for predicting the plasma concentrations following multiple dosing to a steady-state or pseudo-equilibrium. Vss is proportional to the amount of drug in the body versus the plasma concentration of the drug at steady state (pseudo-equilibrium). It is a calculated measure. |
| Terminal Phase Plasma Half-life (t ½) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion | Terminal phase plasma half-life (t ½) is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, rather than the time required to eliminate half the administered dose. |
Countries
Belgium, Spain, United Kingdom
Participant flow
Recruitment details
Seventeen patients enrolled in 3 centers. Three patients from cohort 1 and 1 patient from cohort 2 completed the 6 cycles of study therapy, as planned.
Pre-assignment details
Two participants in cohort 2 did not begin experimental study drug treatment in Cycle 1, so were not included in the analysis set.The resulting participant flow includes only participants who received pertuzumab.
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg Participants received erlotinib 100 mg orally once daily plus pertuzumab 420 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or the participant withdrew from the study. The first dose of pertuzumab was a loading dose of 840 mg intravenously | 6 |
| Erlotinib 150 mg + Pertuzumab 420 mg Participants received erlotinib 150 mg orally once daily plus pertuzumab 420 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or the participant withdrew from the study. The first dose of pertuzumab was a loading dose of 840 mg intravenously. | 9 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Progressive Disease | 4 | 5 |
| Overall Study | Refused treatment | 0 | 1 |
Baseline characteristics
| Characteristic | Erlotinib 100 mg + Pertuzumab 420 mg | Erlotinib 150 mg + Pertuzumab 420 mg | Total |
|---|---|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 5.89 | 56.0 years STANDARD_DEVIATION 10.28 | 60.2 years STANDARD_DEVIATION 10.06 |
| Region of Enrollment Belgium | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Spain | 4 participants | 8 participants | 12 participants |
| Region of Enrollment United Kingdom | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 9 / 9 |
| serious Total, serious adverse events | 0 / 6 | 4 / 9 |
Outcome results
Primary
Percentage of Participants With Dose Limiting Toxicities (DLTs)
A DLT was defined as: Any non-hematological toxicity ≥ Grade 3 according to the Common Terminology Criteria for Adverse Events, version 3.0, except for fever, chills, and flu-like symptoms, which occurred despite adequate participant management. The following Grade 1-3 toxicities were exempt: Grade 1-3 skin and/or epithelial toxicities consistent with erlotinib single agent therapy, unless they did not respond to treatment or dose reduction or interruption (Grade 4 skin and/or epithelial toxicities were considered to be a DLT); Grade 4 neutropenia occurring for \> 7 days; febrile neutropenia which occurred despite adequate participant management; Grade 4 thrombocytopenia or any thrombocytopenia requiring platelet transfusion; and any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds.
Time frame: From baseline to end of the study (up to 42 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Percentage of Participants With Dose Limiting Toxicities (DLTs) | 0 Percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants With Dose Limiting Toxicities (DLTs) | 0 Percentage of participants |
Secondary
Area Under the Plasma Concentration Versus Time Curve (AUC) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With Non-small Cell Lung Cancer (NSCLC)
Bioavailability \[AUC(0-t)\] is a measure of how much of the drug reaches the person's bloodstream from time 0 (pre-dose) to a given time point (t) for the body to use. The extent of product bioavailability is estimated by the area under the blood concentration vs time curve. The Area Under the Curve (AUC) is calculated by plotting the drug's blood levels on a graph at different times during the set period. The area under this curve reflects the amount of drug exposure in the set time period, calculated as hour \* nanograms (ng) per milliliter (mL), which equates to mg.day/L. Bioavailability Extrapolated to Infinity \[AUC (0-inf)\] is a calculated measure of how much of the drug will ever reach the person's bloodstream for the body to use. AUC (0-inf) stands for the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (forever). It is obtained from calculating AUC (0-t) plus AUC (t-inf).
Time frame: on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion
Population: Pharmacokinetic analysis subset with appropriate data available
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Area Under the Plasma Concentration Versus Time Curve (AUC) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With Non-small Cell Lung Cancer (NSCLC) | AUC(0-21 days) n=8 | 1780 mg*day/L | Standard Deviation 340 |
| Erlotinib 100 mg + Pertuzumab 420 mg | Area Under the Plasma Concentration Versus Time Curve (AUC) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With Non-small Cell Lung Cancer (NSCLC) | AUC(0-inf) n=7 | 3000 mg*day/L | Standard Deviation 815 |
Secondary
Clearance (CL) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC
A fundamental concept in pharmacokinetics is drug clearance (CL), that is, elimination of drugs from the body. The clearance is simply the ratio of the dose to the area under the curve (AUC), so that the higher the AUC for a given dose, the lower the clearance. If a drug is administered by continuous infusion and a steady state is achieved, the clearance can be estimated from a single measurement of the plasma drug concentration.
Time frame: on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion
Population: PK subset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Clearance (CL) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | 0.24 L/day | Standard Deviation 0.05 |
Secondary
Peak Plasma Concentration (Cmax) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC
Maximum Observed Plasma Concentration (Cmax), which is the maximum (peak) concentration (amount of drug) measurable in blood plasma after a dose is administered, typically measured in nanograms/milliliter (ng/mL), reported as mg/L.
Time frame: on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion
Population: Pharmacokinetic analysis subset, defined as all participants from either cohort with adequate data for performing PK analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Peak Plasma Concentration (Cmax) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | 231 mg/L | Standard Deviation 55.3 |
Secondary
Percentage of Participants Classified as Responders
Responders are participants who achieved either a complete response or a partial response according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. RECIST is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment.
Time frame: within 18 weeks
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Percentage of Participants Classified as Responders | 20 percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants Classified as Responders | 33.3 percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants Classified as Responders | 11.1 percentage of participants |
Secondary
Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6
Complete and partial responses were determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A complete response was defined as the disappearance of all target and non-target lesions. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter.
Time frame: From baseline to the end of the study (up to 42 weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 2 | 33.3 Percentage of participants |
| Erlotinib 100 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 4 | 33.3 Percentage of participants |
| Erlotinib 100 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 3 | 0 Percentage of participants |
| Erlotinib 100 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 6 | 16.7 Percentage of participants |
| Erlotinib 100 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 1 | 0 Percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 6 | 11.1 Percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 1 | 0 Percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 2 | 11.1 Percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 3 | 0 Percentage of participants |
| Erlotinib 150 mg + Pertuzumab 420 mg | Percentage of Participants With a Complete Response or Partial Response at the End of Cycles 1, 2, 3, 4, and 6 | Cycle 4 | 11.1 Percentage of participants |
Secondary
Terminal Phase Plasma Half-life (t ½) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC
Terminal phase plasma half-life (t ½) is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, rather than the time required to eliminate half the administered dose.
Time frame: on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion
Population: PK analysis subset with adequate data for this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Terminal Phase Plasma Half-life (t ½) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | 17.9 days | Standard Deviation 2.18 |
Secondary
Time of Cmax (Tmax) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC
The time at which maximum concentration (Cmax), which is the maximum (peak) concentration (amount of drug) measurable in blood plasma after a dose is administered, is reached (Tmax).
Time frame: on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion
Population: PK analysis subset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Time of Cmax (Tmax) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | 0.23 days | Standard Deviation 0.11 |
Secondary
Volume of Distribution at Steady-state (Vss) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC
Steady-state volume of distribution of a drug is an estimate of drug distribution independent of elimination processes. It is most useful for predicting the plasma concentrations following multiple dosing to a steady-state or pseudo-equilibrium. Vss is proportional to the amount of drug in the body versus the plasma concentration of the drug at steady state (pseudo-equilibrium). It is a calculated measure.
Time frame: on day 1 of cycle 2, 1 hour pre-dose and 0.5, 1.5, 4, 8, 24, 168, 336 and 504 hours after the start of the infusion
Population: PK analysis subset
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erlotinib 100 mg + Pertuzumab 420 mg | Volume of Distribution at Steady-state (Vss) for Pertuzumab (Cycle 2) in the Presence of Erlotinib (at Steady-state) in Patients With NSCLC | 4.9 Liters | Standard Deviation 1.3 |