Metastatic Colorectal Cancer
Conditions
Keywords
colorectal cancer, chemotherapy, cancer, metastatic, irinotecan, EGFr, epidermal growth factor
Brief summary
The primary objective of this study is to determine if panitumumab affects the pharmacokinetic (PK) profile of irinotecan.
Interventions
DRUGPanitumumab
The first infusion of panitumumab will occur on Cycle 1 Day 4. On Cycle 2 Day 1, panitumumab will be administered on the same day as irinotecan and every 2 weeks thereafter.
DRUGIrinotecan
The first infusion of irinotecan will occur on Cycle 1 Day 1. Irinotecan will be administered on the same day as panitumumab on Cycle 2 Day 1 and every 2 weeks thereafter.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed unresectable metastatic colorectal cancer (mCRC) which has progressed on at least one prior 5-fluorouracil (5FU)-containing chemotherapy regimen * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Life expectancy of ≥ 3 months as documented by the investigator * Baseline actual body weight ≤ 160 kg * Competent to comprehend, sign, and date a written Institutional Review Board (IRB) approved informed consent form before any study-specific procedures are performed
Exclusion criteria
* Treatment with radiotherapy ≤ 14 days before enrollment. Patients must have recovered from all radiotherapy-related toxicities * Known presence of central nervous systems (CNS) metastases * Any prior malignancy (except for non-melanomatous skin cancer or in situ cervical cancer) other than the study disease, unless treated with curative intent with no evidence of disease ≤ 2 years before enrollment * History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan * Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as \> Common Terminology Criteria for Adverse Events (CTCAE version 3) grade 2 * Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrollment * UGT1A1\*28 TA7/7, TA7/8, TA8/8 genetic polymorphisms; Gilbert's Disease * Treatment with CYP3A4 enzyme inhibiting or inducing medications ≤ 2 weeks before enrollment * Prior anti-epidermal growth factor receptor (EGFr) antibody therapy (eg, cetuximab) or treatment with small molecule EGFr inhibitors (eg, gefitinib, erlotinib, lapatinib) * Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (eg, bevacizumab) ≤ 30 days before enrollment * Subjects requiring immunosuppressive agents (eg, methotrexate and cyclosporine), however corticosteroids are allowed * Major surgery \< 28 days prior to enrollment or minor surgery (excluding catheter placement) \< 14 days before enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Irinotecan | Predose and at 10 minutes, and 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after the end of the irinotecan infusion at cycle 1 (irinotecan alone, week 1 day 1) and cycle 2 (irinotecan with panitumumab, week 3, day 1). | To analyze the effect, if any, that panitumumab had on the pharmacokinetics of irinotecan, the Cmax of irinotecan administered alone (Cycle 1) and with concomitant panitumumab (Cycle 2) was measured. Plasma samples were assayed by a validated high performance liquid chromatography (HPLC)-fluorescence method for the measurement of irinotecan. The lower limit of quantitation (LLOQ) was 2 ng/mL. |
| Area Under the Plasma Concentration-time Curve From the Time of Dosing to Infinity (AUCinf) for Irinotecan | Predose and at 10 minutes, and 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after the end of the irinotecan infusion at cycle 1 (irinotecan alone, week 1 day 1) and cycle 2 (irinotecan with panitumumab, week 3, day 1). | To analyze the effect, if any, that panitumumab had on the pharmacokinetics of irinotecan, the AUCinf of irinotecan administered alone (Cycle 1) and with concomitant panitumumab (Cycle 2) was measured. |
| Area Under the Plasma Concentration-time Curve From the Time of the Last Quantifiable Concentration (AUClast) for Irinotecan | Predose and at 10 minutes, and 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after the end of the irinotecan infusion at cycle 1 (irinotecan alone, week 1 day 1) and cycle 2 (irinotecan with panitumumab, week 3, day 1). | To analyze the effect, if any, that panitumumab had on the pharmacokinetics of irinotecan, the AUClast of irinotecan administered alone (Cycle 1) and with concomitant panitumumab (Cycle 2) was measured. |
| Number of Participants With Clinically Significant Adverse Events (AEs) | The reporting time frame for Adverse Events is from first dose date to 30 days since the last dose date, until the data cut-off date of 16 July 2009. The median time frame is 5.7 months. | Adverse events of special interest include infusion reactions, integument toxicities, diarrhea, stomatitis, hypomagnesemia, and pulmonary, vascular, and cardiac toxicities. Infusion reactions were defined as 1. Prespecified signs and symptoms indicating a possible infusion reaction (derived from Common Terminology Criteria for Adverse Events (CTCAE) definitions of allergic reaction/hypersensitivity and cytokine release syndrome/acute infusion reaction) with onset day coincident with any study drug infusion and which resolved the day of, or the day after, onset; 2. incidence of AE with terms consistent with the panitumumab US package insert (USPI) (any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea). Data are summarized overall and by treatment phase. |
Countries
Canada, United States
Participant flow
Recruitment details
This study was conducted at 6 sites in the United States and Canada. The first patient enrolled on 28 March 2008 and the last patient enrolled on 30 January 2009. Results are reported up until the data cut-off date of 16 July 2009.
Participants by arm
| Arm | Count |
|---|---|
| Panitumumab + Irinotecan Participants received panitumumab 6 mg/kg and irinotecan 180 mg/m² administered by intravenous (IV) infusion every 2 weeks until disease progression or intolerance of panitumumab, irinotecan or both. | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | On-going in study as of 16 July 2009. | 5 |
| Overall Study | Other | 1 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Panitumumab + Irinotecan |
|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 10.7 |
| Primary Tumor Type Colon Cancer | 17 participants |
| Primary Tumor Type Rectal Cancer | 10 participants |
| Race/Ethnicity, Customized Aborigine | 0 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 8 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants |
| Race/Ethnicity, Customized Japanese | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Other | 1 participants |
| Race/Ethnicity, Customized White or Caucasian | 17 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 4 / 27 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From the Time of Dosing to Infinity (AUCinf) for Irinotecan
To analyze the effect, if any, that panitumumab had on the pharmacokinetics of irinotecan, the AUCinf of irinotecan administered alone (Cycle 1) and with concomitant panitumumab (Cycle 2) was measured.
Time frame: Predose and at 10 minutes, and 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after the end of the irinotecan infusion at cycle 1 (irinotecan alone, week 1 day 1) and cycle 2 (irinotecan with panitumumab, week 3, day 1).
Population: The pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panitumumab + Irinotecan | Area Under the Plasma Concentration-time Curve From the Time of Dosing to Infinity (AUCinf) for Irinotecan | Cycle 1 | 12000 hr*ng/mL | Standard Deviation 4350 |
| Panitumumab + Irinotecan | Area Under the Plasma Concentration-time Curve From the Time of Dosing to Infinity (AUCinf) for Irinotecan | Cycle 2 | 10700 hr*ng/mL | Standard Deviation 3930 |
90% CI: [0.819, 0.985]
Primary
Area Under the Plasma Concentration-time Curve From the Time of the Last Quantifiable Concentration (AUClast) for Irinotecan
To analyze the effect, if any, that panitumumab had on the pharmacokinetics of irinotecan, the AUClast of irinotecan administered alone (Cycle 1) and with concomitant panitumumab (Cycle 2) was measured.
Time frame: Predose and at 10 minutes, and 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after the end of the irinotecan infusion at cycle 1 (irinotecan alone, week 1 day 1) and cycle 2 (irinotecan with panitumumab, week 3, day 1).
Population: The pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panitumumab + Irinotecan | Area Under the Plasma Concentration-time Curve From the Time of the Last Quantifiable Concentration (AUClast) for Irinotecan | Cycle 1 | 11900 hr*ng/mL | Standard Deviation 4290 |
| Panitumumab + Irinotecan | Area Under the Plasma Concentration-time Curve From the Time of the Last Quantifiable Concentration (AUClast) for Irinotecan | Cycle 2 | 10600 hr*ng/mL | Standard Deviation 3870 |
90% CI: [0.818, 0.983]
Primary
Maximum Observed Plasma Concentration (Cmax) of Irinotecan
To analyze the effect, if any, that panitumumab had on the pharmacokinetics of irinotecan, the Cmax of irinotecan administered alone (Cycle 1) and with concomitant panitumumab (Cycle 2) was measured. Plasma samples were assayed by a validated high performance liquid chromatography (HPLC)-fluorescence method for the measurement of irinotecan. The lower limit of quantitation (LLOQ) was 2 ng/mL.
Time frame: Predose and at 10 minutes, and 0.5, 1, 2, 4, 8, 24, 48, and 72 hours after the end of the irinotecan infusion at cycle 1 (irinotecan alone, week 1 day 1) and cycle 2 (irinotecan with panitumumab, week 3, day 1).
Population: The pharmacokinetic analysis set included all participants who received panitumumab 6 mg/kg and irinotecan 180 mg/m² without dose reductions or delays and who completed the blood sample collection for pharmacokinetic analysis during cycles 1 and 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panitumumab + Irinotecan | Maximum Observed Plasma Concentration (Cmax) of Irinotecan | Cycle 2 | 1570 ng/mL | Standard Deviation 520 |
| Panitumumab + Irinotecan | Maximum Observed Plasma Concentration (Cmax) of Irinotecan | Cycle 1 | 1570 ng/mL | Standard Deviation 321 |
90% CI: [0.894, 1.074]
Primary
Number of Participants With Clinically Significant Adverse Events (AEs)
Adverse events of special interest include infusion reactions, integument toxicities, diarrhea, stomatitis, hypomagnesemia, and pulmonary, vascular, and cardiac toxicities. Infusion reactions were defined as 1. Prespecified signs and symptoms indicating a possible infusion reaction (derived from Common Terminology Criteria for Adverse Events (CTCAE) definitions of allergic reaction/hypersensitivity and cytokine release syndrome/acute infusion reaction) with onset day coincident with any study drug infusion and which resolved the day of, or the day after, onset; 2. incidence of AE with terms consistent with the panitumumab US package insert (USPI) (any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea). Data are summarized overall and by treatment phase.
Time frame: The reporting time frame for Adverse Events is from first dose date to 30 days since the last dose date, until the data cut-off date of 16 July 2009. The median time frame is 5.7 months.
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction CTCAE | 8 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Any adverse events of Interest | 27 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Hypomagnesemia | 13 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Pulmonary Toxicity | 9 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Neuro Toxicities | 3 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Hematological Toxicities | 2 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction USPI | 2 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Cardiac Toxicity | 2 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Stomatitis/Oral Mucositis | 13 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Integument Toxicities | 25 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Diarrhea | 23 participants |
| Panitumumab + Irinotecan | Number of Participants With Clinically Significant Adverse Events (AEs) | Vascular Toxicity | 5 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hematological Toxicities | 0 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Diarrhea | 2 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction USPI | 1 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hypomagnesemia | 0 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Vascular Toxicity | 0 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction CTCAE | 2 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Neuro Toxicities | 0 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Pulmonary Toxicity | 0 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Cardiac Toxicity | 1 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Any adverse events of Interest | 5 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Stomatitis/Oral Mucositis | 0 participants |
| Treatment Phase 1 | Number of Participants With Clinically Significant Adverse Events (AEs) | Integument Toxicities | 0 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Stomatitis/Oral Mucositis | 6 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Vascular Toxicity | 2 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction USPI | 0 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Pulmonary Toxicity | 4 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hypomagnesemia | 1 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Diarrhea | 12 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Any adverse events of Interest | 26 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction CTCAE | 0 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Neuro Toxicities | 1 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hematological Toxicities | 0 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Integument Toxicities | 24 participants |
| Treatment Phase 2 | Number of Participants With Clinically Significant Adverse Events (AEs) | Cardiac Toxicity | 0 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Neuro Toxicities | 1 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Pulmonary Toxicity | 1 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction USPI | 0 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hematological Toxicities | 0 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Cardiac Toxicity | 0 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Vascular Toxicity | 0 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Any adverse events of Interest | 9 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Integument Toxicities | 2 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Diarrhea | 4 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hypomagnesemia | 0 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Stomatitis/Oral Mucositis | 0 participants |
| Treatment Phase 3 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction CTCAE | 5 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Integument Toxicities | 24 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Any adverse events of Interest | 26 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Cardiac Toxicity | 2 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction CTCAE | 4 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Stomatitis/Oral Mucositis | 8 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Neuro Toxicities | 1 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Vascular Toxicity | 3 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Infusion Reaction USPI | 1 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Pulmonary Toxicity | 7 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Diarrhea | 20 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hematological Toxicities | 2 participants |
| Treatment Phase 4 | Number of Participants With Clinically Significant Adverse Events (AEs) | Hypomagnesemia | 13 participants |