Esophageal Cancer, Lung Cancer, Pancreatic Cancer
Conditions
Keywords
Advanced Cancer, AMG 706, Panitumumab, Gemcitabine-Cisplatin
Brief summary
The purpose of this study is to characterize the safety and tolerability of AMG 706 plus panitumumab when administered with gemcitabine and cisplatin chemotherapy. This is a Phase 1b clinical study.
Interventions
DRUGAMG 706
AMG 706 will be provided as 25-mg and 100-mg tablets and will be continuously self-administered orally once or twice daily based on cohort assignment starting on day 1 of Cycle 1.
BIOLOGICALPanitumumab
Panitumumab will be administered by intravenous (IV) infusion at a dose of 9 mg/kg on Day 1 of each 3-week cycle.
DRUGGemcitabine
Gemcitabine will be administered intravenously on Day 1 and Day 8 of each 21-day cycle at a dose of 1250 mg/m\^2.
DRUGCisplatin
Cisplatin will be administered intravenously on Day 1 of each 3-week cycle at a dose of 75 mg/m\^2.
Sponsors
Amgen
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
For complete inclusion and exclusion, please refer to the investigator. Inclusion Criteria: * Competent to comprehend, sign, and date an Institutional Review Board (IRB) approved informed consent form * Subjects with advanced cancer in whom the gemcitabine and cisplatin chemotherapy regimen is clinically indicated * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate hematological function * Adequate renal function * Adequate hepatic function * Life expectancy of greater than or equal to 3 months as documented by the investigator
Exclusion criteria
* More than 1 prior chemotherapy regimen * History of venous thrombosis * Myocardial infarction, cerebrovascular accident, transient ischemic attack, percutaneous transluminal coronary angioplasty/stent, or unstable angina within 1 year before study enrollment * History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on screening chest computed tomograph (CT) scan * Average systolic blood pressure of greater than 145 mm Hg or average diastolic blood pressure of greater than 85 mm Hg * Radiotherapy within 28 days of study enrollment or within 14 days of study enrollment for peripheral lesions * Prior AMG 706, panitumumab, or another anti-EGFr monoclonal antibody (mAb) (e.g., cetuximab \[Erbitux®\] or EMD 72000) * Systemic chemotherapy within 28 days before study enrollment * Major surgery within 28 days or minor surgery within 14 days of study enrollment * Central nervous system metastases (Exception: subjects with treated asymptomatic central nervous system metastases, those who have been clinically stable in the judgment of the investigator and off steroids for at least 30 days before the study enrollment are eligible)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participant Incidence of Adverse Events | From the first dose of any study treatment until 30 days after the last dose of study treatment, up to a maximum of 509 days. | The number of participants who experienced at least one treatment-emergent adverse event. Additional details regarding specfic adverse events are provided in the Adverse Event section of this posting. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Objective Tumor Response | From enrollment until date of last follow-up visit. The median follow-up time was 24 weeks, with a range of 3 to 73 weeks. | The number of participants with a confirmed objective tumor response, defined as a complete response (CR) or partial response (PR) throughout based on modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Any CR or PR was to be confirmed 4 to 6 weeks after the initial CR or PR. |
| Tmax | Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose. | Time after dosing when maximum plasma concentration was observed for AMG 706 |
| Cmax | Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose. | The maximum observed plasma concentration after AMG 706 dosing |
| AUC0-24 | Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose. | Area under the plasma concentration-time curve from time 0 to 24 hours postdose (AUC0-24) with AMG 706. AUC0-24 was estimated using the linear/log trapezoidal method. For the BID cohort, AUC0 24 was estimated as 2 times the AUC from time 0 to 12 hours post the first daily dose (AUC0-12) using the linear/log trapezoidal method. |
| AUC0-inf | Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose. | Area under the concentration-time curve from time 0 to infinite time (AUC0-inf) postdose with AMG 706. AUC0-inf was estimated using the linear/log trapezoidal method. AUC0-inf was not calculated for the BID cohort. |
Participant flow
Recruitment details
Participants were enrolled from 2 December 2004 through 7 March 2007. This study was designed with two parts. However, Part 2 was not conducted due to safety issues found in Part 1. Thus Part 1 is referenced as the overall study here.
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab + Gem/Cis Panitumumab 9 mg/kg on Day 1 + gemcitabine (gem) 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin (cis) 75 mg/m\^2 on Day 1 of each 3-week cycle. | 8 |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis AMG 706 50 mg administered orally once daily (QD) + panitumumab 9 mg/kg on Day 1 + gemcitabine 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin 75 mg/m\^2 on Day 1 of each 3-week cycle. | 8 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis AMG 706 75 mg administered orally once daily (QD) + panitumumab 9 mg/kg on Day 1 + gemcitabine 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin 75 mg/m\^2 on Day 1 of each 3-week cycle. | 6 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis AMG 706 100 mg administered orally once daily + panitumumab 9 mg/kg on Day 1 + gemcitabine 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin 75 mg/m\^2 on Day 1 of each 3-week cycle. | 6 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis AMG 706 125 mg administered orally once daily + panitumumab 9 mg/kg on Day 1 + gemcitabine 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin 75 mg/m\^2 on Day 1 of each 3-week cycle. | 11 |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis AMG 706 75 mg administered orally twice daily (BID) + panitumumab 9 mg/kg on Day 1 + gemcitabine 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin 75 mg/m\^2 on Day 1 of each 3-week cycle. | 2 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 3 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Panitumumab + Gem/Cis | 50 mg QD AMG 706 + Panitumumab + Gem/Cis | 75 mg QD AMG 706 + Panitumumab + Gem/Cis | 100 mg QD AMG 706 + Panitumumab + Gem/Cis | 125 mg QD AMG 706 + Panitumumab + Gem/Cis | 75 mg BID AMG 706 + Panitumumab + Gem/Cis |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 12 | 55.5 years STANDARD_DEVIATION 12.4 | 60.4 years STANDARD_DEVIATION 13.8 | 56.0 years STANDARD_DEVIATION 13.3 | 51.5 years STANDARD_DEVIATION 13.5 | 61.1 years STANDARD_DEVIATION 8.3 | 65.0 years STANDARD_DEVIATION 17 |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White or Caucasian | 36 Participants | 6 Participants | 7 Participants | 4 Participants | 6 Participants | 11 Participants | 2 Participants |
| Sex: Female, Male Female | 18 Participants | 4 Participants | 3 Participants | 2 Participants | 4 Participants | 5 Participants | 0 Participants |
| Sex: Female, Male Male | 23 Participants | 4 Participants | 5 Participants | 4 Participants | 2 Participants | 6 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 8 / 8 | 6 / 6 | 6 / 6 | 11 / 11 | 2 / 2 |
| serious Total, serious adverse events | 2 / 8 | 4 / 8 | 3 / 6 | 4 / 6 | 9 / 11 | 1 / 2 |
Outcome results
Primary
Participant Incidence of Adverse Events
The number of participants who experienced at least one treatment-emergent adverse event. Additional details regarding specfic adverse events are provided in the Adverse Event section of this posting.
Time frame: From the first dose of any study treatment until 30 days after the last dose of study treatment, up to a maximum of 509 days.
Population: Safety Analysis Set, composed of all participants in the AMG 706 treatment groups who received at least one dose of AMG 706 and all participants in the panitumumab-only treatment group who received at least one dose of panitumumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab + Gem/Cis | Participant Incidence of Adverse Events | 8 Participants |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | Participant Incidence of Adverse Events | 8 Participants |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | Participant Incidence of Adverse Events | 6 Participants |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | Participant Incidence of Adverse Events | 6 Participants |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | Participant Incidence of Adverse Events | 11 Participants |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis | Participant Incidence of Adverse Events | 2 Participants |
Secondary
AUC0-24
Area under the plasma concentration-time curve from time 0 to 24 hours postdose (AUC0-24) with AMG 706. AUC0-24 was estimated using the linear/log trapezoidal method. For the BID cohort, AUC0 24 was estimated as 2 times the AUC from time 0 to 12 hours post the first daily dose (AUC0-12) using the linear/log trapezoidal method.
Time frame: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
Population: PK Analysis set; Patients with elevated AMG 706 concentrations at 24 hours were excluded from the AUC summary statistics calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panitumumab + Gem/Cis | AUC0-24 | 1.03 μg*hr/mL | Standard Deviation 0.5 |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | AUC0-24 | 1.31 μg*hr/mL | Standard Deviation 0.51 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | AUC0-24 | 2.38 μg*hr/mL | — |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | AUC0-24 | 2.82 μg*hr/mL | Standard Deviation 1.02 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | AUC0-24 | 2.54 μg*hr/mL | — |
Secondary
AUC0-inf
Area under the concentration-time curve from time 0 to infinite time (AUC0-inf) postdose with AMG 706. AUC0-inf was estimated using the linear/log trapezoidal method. AUC0-inf was not calculated for the BID cohort.
Time frame: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
Population: PK analysis set. Patients with elevated AMG 706 concentrations at 24 hours were excluded from the AUC summary statistics calculations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panitumumab + Gem/Cis | AUC0-inf | 1.12 μg*hr/mL | Standard Deviation 0.52 |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | AUC0-inf | 1.64 μg*hr/mL | Standard Deviation 0.48 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | AUC0-inf | 2.59 μg*hr/mL | — |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | AUC0-inf | 3.05 μg*hr/mL | Standard Deviation 1.34 |
Secondary
Cmax
The maximum observed plasma concentration after AMG 706 dosing
Time frame: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
Population: PK analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panitumumab + Gem/Cis | Cmax | 152 ng/mL | Standard Deviation 78 |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | Cmax | 186 ng/mL | Standard Deviation 92 |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | Cmax | 278 ng/mL | Standard Deviation 90 |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | Cmax | 458 ng/mL | Standard Deviation 208 |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | Cmax | 268 ng/mL | — |
Secondary
Number of Participants With an Objective Tumor Response
The number of participants with a confirmed objective tumor response, defined as a complete response (CR) or partial response (PR) throughout based on modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Any CR or PR was to be confirmed 4 to 6 weeks after the initial CR or PR.
Time frame: From enrollment until date of last follow-up visit. The median follow-up time was 24 weeks, with a range of 3 to 73 weeks.
Population: Efficacy Analysis Set, defined as defined as patients who received at least 1 dose of AMG 706 for AMG 706 treatment groups and patients who received at least 1 dose of panitumumab for the panitumumab-only treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab + Gem/Cis | Number of Participants With an Objective Tumor Response | 2 participants |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | Number of Participants With an Objective Tumor Response | 0 participants |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | Number of Participants With an Objective Tumor Response | 1 participants |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | Number of Participants With an Objective Tumor Response | 4 participants |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | Number of Participants With an Objective Tumor Response | 2 participants |
| 75 mg BID AMG 706 + Panitumumab + Gem/Cis | Number of Participants With an Objective Tumor Response | 1 participants |
Secondary
Tmax
Time after dosing when maximum plasma concentration was observed for AMG 706
Time frame: Day 1, pre-dose and at 1, 3, 6,12 (BID cohort only) and 24 hours post-dose.
Population: The Pharmacokinetic (PK) Analysis Set consists of patients who had dosing and PK sampling times recorded on the day of PK sample collection and no significant protocol deviations that impacted the quality of the PK data (for example, sample processing errors and/or inaccurate dosing on the day of the PK sampling).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab + Gem/Cis | Tmax | 1.00 hours |
| 50 mg QD AMG 706 + Panitumumab + Gem/Cis | Tmax | 1.00 hours |
| 75 mg QD AMG 706 + Panitumumab + Gem/Cis | Tmax | 1.38 hours |
| 100 mg QD AMG 706 + Panitumumab + Gem/Cis | Tmax | 1.00 hours |
| 125 mg QD AMG 706 + Panitumumab + Gem/Cis | Tmax | 1.00 hours |