Colorectal Cancer
Conditions
Keywords
liver-only metastatic KRAS wild-type colorectal cancer, Panitumumab, Oxaliplatin, Irinotecan, Leucovorin, 5-Fluorouracil
Brief summary
In this Phase II study the investigators plan to determine the overall response rate (ORR) of the combination of FOLFOXIRI plus panitumumab as first-line treatment of patients with liver-only metastatic KRAS wild-type colorectal cancer.
Detailed description
Further data has emerged showing a consistent lack of efficacy using EGFR inhibitor panitumumab in combination with chemotherapy in the treatment of patients with KRAS mutant colorectal cancer. For patients with liver-only metastatic colorectal cancer, improvement in response rates with newer chemotherapy regimens has led to a larger percentage of patients eligible for surgical resection. Treatment with FOLFOXIRI improves response rates when compared to FOLFIRI. Similarly, the addition of an EGFR inhibitor improves the response rate of FOLFIRI in patients with wild-type KRAS. In this trial, we will attempt to maximize the response rate and the surgical resection rate by using FOLFOXIRI and panitumumab.
Interventions
DRUGPanitumumab
6 mg/kg, 60-90 minute IV infusion every 2 weeks
DRUGOxaliplatin
85 mg/m2, 2-hour IV infusion every 2 weeks
DRUGIrinotecan
125 mg/m2, 1-hour IV infusion every 2 weeks
DRUGLeucovorin
200 mg/m2, 2-hour IV infusion every 2 weeks
DRUG5-Fluorouracil
3200 mg/m2 IV, 48-hour continuous infusion every two weeks
Sponsors
Amgen
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient must have a biopsy confirmed adenocarcinoma of the colon or rectum with stage IV (metastatic) liver-only disease, as defined by staging with CT scans. 2. Patients must have a baseline evaluation to determine whether liver metastases are resectable (e.g. a single liver metastasis in a resectable location)or unresectable (surgical consultation is recommended). Both groups are eligible for this study. 3. Tumor tissue must reveal wild-type KRAS expression (i.e. no KRAS mutation) prior to study entry (see Section 7.4.4.). 4. Patients must have at least one unidimensional measurable lesion definable by CT scan. Disease must be measurable per RECIST version 1.1 criteria (see Section 9). 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see Appendix A). 6. Laboratory values as follows: ANC greater than 1500/μL Hgb greater than9 g/dL Platelets greater than 100,000/μL AST/SGOT less than 5.0 x ULN ALT/SGPT less than or equal to 5.0 x ULN Alk Phos less than or equal to 5.0 x ULN Bilirubin less than or equal to 1.5 x ULN Creatinine 1.5 mg/dL or calculated creatinine clearance 50 ml/min Magnesium LLN 7. Patient must have a life expectancy of greater than 12 weeks. 8. Patient must be greater than or equal to 18 years of age. 9. Patient must be accessible for treatment and follow-up. 10. Women of childbearing potential must have a negative serum or urine pregnancy test performed less than or equal to 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment and during the 6 months following completion of study treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately. 11. Patient must be able to understand the nature of the study and give written informed consent prior to study entry.
Exclusion criteria
1. Prior systemic therapy for metastatic colorectal cancer (including chemotherapy, bevacizumab, cetuximab, panitumumab, and other targeted agents). 2. Adjuvant chemotherapy (and/or chemoradiation) for colorectal carcinoma ending less than or equal to 12 months prior to the diagnosis of metastatic cancer. Prior radiation therapy (in the metastatic setting) may be allowed if it was completed greater than or equal to 4 weeks prior to enrollment and measurable lesions are outside the radiation portal site. 3. Any detectable metastases in areas other than the liver. 4. Known liver disease or other significant medical illness that would exclude the patient as a candidate for resection of liver metastases. 5. Patients requiring therapeutic coumadin or heparin (for a history of pulmonary emboli or deep vein thrombosis \[DVT\]) will be excluded. 6. Patients who have had a major surgical procedure (not including mediastinoscopy), open biopsy, or significant traumatic injury less than or equal to 4 weeks prior to beginning treatment. 7. History of Gilbert's disease. 8. History of hypersensitivity to active or inactive excipients of any component of treatment (5 fluorouracil, irinotecan, panitumumab, and/or oxaliplatin), or known dipyrimidine dehydrogenase (DPD) deficiency 9. Serious cardiac arrhythmia requiring medication. 10. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, an infection requiring IV antibiotics, or psychiatric illness/social situations that would limit compliance with study requirements. 11. Patient with known diagnosis of human immunodeficiency virus (HIV), hepatitis C virus or acute or chronic hepatitis B infection. 12. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study. 13. Use of any non-approved or investigational agent less than or equal to 28 days prior to administration of the first dose of study drug. 14. Past or current history of neoplasm other than the entry diagnosis with the exception of treated non melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a DFS greater than or equal to 5 years. 15. Patients with National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE) Grade 2 peripheral neuropathy. 16. Female patients who are pregnant or lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 18 months | The Percentage of Patients Who Experience an Objective Benefit From Treatment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| R0 Resection Rate | 18 months | To determine the rate of complete (R0) resection for patients treated with this regimen. |
| Progression-free Survival (PFS) | 18 months | The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Worsening of Their Disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| To Determine the Acute Toxicity Produced by This Regimen. | 18 months | The analyses of safety will be based on the frequency of adverse events and their severity for patients who received at least one dose of study treatment. |
| Overall Survival (OS) | 18 months | The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FOLFOXIRI+Panitumumab Regimen All patients will receive the FOLFOXIRI/panitumumab regimen, with drugs administered in the following order:
* Panitumumab
* Oxaliplatin
* Irinotecan
* Leucovorin
* 5-Fluorouracil
Panitumumab: 6 mg/kg, 60-90 minute IV infusion every 2 weeks
Oxaliplatin: 85 mg/m2, 2-hour IV infusion every 2 weeks
Irinotecan: 125 mg/m2, 1-hour IV infusion every 2 weeks
Leucovorin: 200 mg/m2, 2-hour IV infusion every 2 weeks
5-Fluorouracil: 3200 mg/m2 IV, 48-hour continuous infusion every two weeks | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | FOLFOXIRI+Panitumumab Regimen |
|---|---|
| Age, Continuous | 55 years |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 2 / 15 |
Outcome results
Primary
Overall Response Rate (ORR)
The Percentage of Patients Who Experience an Objective Benefit From Treatment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 18 months
Population: Includes all patients deemed to be evaluable for response who were evaluated for response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOXIRI+Panitumumab Regimen | Overall Response Rate (ORR) | 75 percentage of evaluable participants |
Secondary
Overall Survival (OS)
The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death
Time frame: 18 months
Population: All patients on study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOXIRI+Panitumumab Regimen | Overall Survival (OS) | NA months |
Secondary
Progression-free Survival (PFS)
The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Worsening of Their Disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 18 months
Population: All patients on study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOXIRI+Panitumumab Regimen | Progression-free Survival (PFS) | 13.3 months |
Secondary
R0 Resection Rate
To determine the rate of complete (R0) resection for patients treated with this regimen.
Time frame: 18 months
Population: Includes patients who were surgical candidates and underwent surgery on study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOXIRI+Panitumumab Regimen | R0 Resection Rate | 100 percentage of patients with surgery |
Secondary
To Determine the Acute Toxicity Produced by This Regimen.
The analyses of safety will be based on the frequency of adverse events and their severity for patients who received at least one dose of study treatment.
Time frame: 18 months
Population: All patients on study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Decreased ejection fraction | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Rash | 12 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Diarrhea | 9 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Fatigue | 8 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Nausea | 8 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Mucositis | 7 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Peripheral neuropathy | 6 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Vomiting | 5 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Anorexia | 4 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Cold sensitivity | 4 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Constipation | 4 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Dehydration | 4 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Leukopenia | 4 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Anemia | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hypokalemia | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hypomagnesemia | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Nail changes | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Neutropenia | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Taste alteration | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Thrombocytopenia | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Weight loss | 3 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Abdominal pain | 2 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Alopecia | 2 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Depression | 2 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Dizziness | 2 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Insomnia | 2 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Alkaline phosphatase increased | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | ALT increased | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Anxiety | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | AST increased | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Asthenia | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Back pain | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Blood bicarbonate increased | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Dry mouth | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Dysesthesia | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Dyspepsia | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Edema | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Epistaxis | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Flashers | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hand-foot syndrome | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hematochezia | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hemorrhoids | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hyperpigmentation | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hypertension | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hypoalbuminemia | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Hyponatremia | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Infection - other | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Infusion related reaction | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Memory loss | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Oral infection | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Paraphasia | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Pruritus | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Speech impairment | 1 participants |
| FOLFOXIRI+Panitumumab Regimen | To Determine the Acute Toxicity Produced by This Regimen. | Swollen tongue | 1 participants |