Colorectal Cancer, Liver Metastases, Colorectal Adenocarcinoma, Colorectal Cancer With Hepatic Metastases, Colorectal Carcinoma
Conditions
Keywords
Unresectable Liver Tumor, Response Rates, Progression-Free Survival, Patient Survival
Brief summary
Background: Many people with colorectal cancer get liver metastases. Standard treatment for this is a combination of chemotherapy drugs. Directing the chemotherapy to the liver may be effective. A device that does this a pump that delivers drugs over 2 weeks at constant rate into the hepatic artery. The person's body temperature causes the drug to flow from the pump. Researchers want to see if this helps people with colorectal metastases to the liver. Objective: To study the effectiveness of a hepatic artery infusion pump at treating colorectal metastases to the liver. Eligibility: Adults at least 18 years old with colorectal metastases to the liver Design: Participants will be screened with: Medical history Physical exam Heart, blood, and urine tests Scans Participants will stay in the hospital a few days. A small plastic tube (catheter) will be inserted in an artery into the liver. The catheter will be attached to the pump. That will lie under the skin on the abdomen. It will be small and participants will be able to feel it. Participants will get treatment in 28-day cycles. Every Day 1, they will have physical exam, symptom review, and blood tests. Every 2 weeks, they will come to the clinic to get chemotherapy by a catheter or port. Every 12 weeks, they will have a scan. Tissue samples may be taken during the study. When they finish the drug, participants may have the pump removed. They will repeat the Day 1 tests. They will be called every 6 months to see how they are doing.
Detailed description
Background: * Nearly 60% of patients with colorectal cancers will develop liver metastases over the course of their disease. * Of patients with metastatic colorectal cancer, the liver will be the sole site of recurrence or the survival-limiting site of disease for 20%. * Liver directed therapy, which has taken many forms over the last several decades, is a potential means to prolong survival for properly selected patients and delay progression at that site. * Hepatic artery infusion of floxuridine (FUDR) via an implantable hepatic artery infusion pump (HAIP) induces objective clinical response rates of nearly 50% in heavily pre-treated patients with metastatic colorectal cancer to the liver. * The identification of patients likely to respond to HAIP and those likely to suffer pumprelated adverse events is currently unknown, and has limited the wide-spread adoption of this otherwise well tolerated intervention. Objective: * To assess the safety of hepatic artery infusion therapy using the Medtronic pump with the Codman catheter. * To determine the response rate in patients with unresectable metastatic colorectal cancer treated with HAIP chemotherapy as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Eligibility: * Histologically or cytologically confirmed colorectal adenocarcinoma metastatic to the liver. * Patients with liver metastases not amenable to resection to No Evidence of Disease (NED) in one stage. * Patients must have received systemic chemotherapy. * Age greater than or equal to 18 years. Design: \- Single arm, Phase II study of HAIP chemotherapy.
Interventions
DEVICECodman 3000 constant flow pump catheter
Implanted Medtronic SynchroMed II Pump with codman 3000 Constant Flow Pump Catheter
DRUGPanitumumab
6 mg/kg, intravenous (IV)
DRUGFUDR-Dex
Hepatic Artery Infusion Pump (HAIP) will be filled with mixture of Floxuridine and Dexamethasone. Pump will perfuse drugs to liver for 14 days. Floxuridine (0.12 mg/kg X pump volume X pump flow rate), Dexamethasone (1 mg/day X pump volume (30) X pump flow rate)
DRUGOxaliplatin
85 mg/m\^2, intravenous (IV)
DRUG5FU
2000 mg/m\^2, intravenous (IV) 46-hour infusion of 5-Fluorouracil + 400 mg/m\^2, IV of Leucovorin
DRUGIrinotecan
150 mg/m\^2, intravenous (IV)
PROCEDUREHAIP installation
Hepatic Artery Infusion (HAI) pump installation
DRUGcetuximab
500 mg/m\^2, intravenous (IV)
Implanted Medtronic SynchroMed II Pump with Codman 3000 Constant Flow Pump Catheter
DRUGFloxuridine
Floxuridine 0.12 mg/kg X pump volume X pump flow rate
DRUGDexamethasone
1 mg/day X pump volume (30) X pump flow rate
DIAGNOSTIC_TESTEKG
Screening and baseline.
DIAGNOSTIC_TESTCT C/A/P
Screening, baseline and Cycle 1. One cycle is 28 (+/- 2 days).
DIAGNOSTIC_TESTCT Angiogram (abdomen)
Screening
PROCEDURETumor and normal liver biopsy
For research: During surgery to install pump, time of progression per principal investigator discretion if safe, and end of treatment.
DRUGLeucovorin
400 mg/m\^2, intravenous (IV), (Day15, Day1)
Sponsors
National Cancer Institute (NCI)
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
* INCLUSION CRITERIA: * Patients must have histologically or cytologically confirmed diagnosis of colorectal adenocarcinoma. * Patients must have measurable liver metastatic disease. * Patients must have progressed on, been intolerant of or have residual disease after oxaliplatin- or irinotecan-containing, fluorouracil-based, chemotherapeutic regimen. * Age greater than or equal to 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 * Patients must have adequate organ and marrow function as defined below: * leukocytes \> 3,000/mcL * absolute neutrophil count \> 1,500/mcL * platelets \> 90,000/mcL * total bilirubin \< 1.5 X institutional upper limit of normal * Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase (SGOT)/Alanine transaminase (ALT) Serum glutamic-pyruvic transaminase (SGPT) \< 2.5 X institutional upper limit of normal * creatinine within normal institutional limits OR estimated glomerular filtration rate (eGFR) within normal as predicted by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation \> 60 mL/min/1.73 m\^2. * The hepatic artery infusion pump chemotherapy has potential teratogenic and/or abortifacient effects. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and after completion of study treatment : 3 months after the last study drug for men; 6 months after the last study drug for women. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. * Arterial anatomy on computed tomography (CT) angiogram amenable to placement of the Hepatic Artery Infusion Pump (HAIP). * Ability of subject to understand and the willingness to sign a written informed consent document. * Human immunodeficiency virus (HIV)-positive patients may be considered for this study only after consultation with an HIV trained physician. * Patients must agree to co-enroll on the Surgical Oncology Programs tissue collection protocol 13C0176, 'Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors'
Exclusion criteria
* Patients with liver metastases amenable to resection to No Evidence of Disease (NED) in one stage. * Patients who are receiving any other investigational agents. * Patients with incontrovertible radiographic evidence of disease outside of the colon/rectum (primary) and liver given unlikelihood of benefit from liver-directed therapy. Note: The exception to this exclusion is patients with fewer than five lung lesions greater than 1 cm that have not increased in size by more than 10% over a 4-month period of time, and are amenable to resection should subsequent problematic growth occur. Lesions less than 1 cm are indeterminant as far as etiology is concerned and will be ignored. Patients with liver metastases and oligometastatic lung lesions (we define oligometastatic as less than 5 amenable to thoracoscopic removal) are still likely to benefit from liver directed therapy. * Patients who have undergone extra-hepatic metastasectomy and have a documented disease-free interval less than or equal to 4 months. * Microsatellite Instability (MSI)-high patients who need to be treated with check-point inhibitors * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. This also includes any condition, including the presence of laboratory abnormalities, which in the opinion of the Principal Investigator places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study. * Active concurrent malignancies within the last five years other than colorectal primary except basal cell skin carcinoma and thyroid carcinoma. * Prior radiation to liver. * Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects of the HAIP chemotherapy. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with HAIP, breast-feeding should be discontinued if the mother is treated. These potential risks may also apply to other agents used in this study. Lactating women must-not breastfeed during study treatment and until at least 7 days after the final dose of study drug(s). * Patients with active Hepatitis B or C infection because of the potential for increased liver toxicity given the damaging effects of the virus. * History of allergic reactions attributed to compounds of similar chemical composition to floxuridine (FUDR) or heparin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (RR) Reported With an 80% Confidence Interval | 6 months | Response rate is defined as the number of participants who experience a partial response (PR) or complete response (CR) using the study treatment was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) and reported with an 80% confidence interval. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. |
| Response Rate (RR) Reported With a 95% Confidence Interval | 6 months | Response rate is defined as the percentage of participants who experience a partial response (PR) or complete response (CR) using the study treatment determined by dividing the number of responders by the total evaluable participants. RR was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and reported with an 95% confidence interval. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. |
| Number of Grade 1, 2, 3, 4, and/or 5 Serious and/or Non-serious Adverse Events Reported With Type and Frequency | 30 days | Safety was determined by grade 1, 2, 3, 4, and/or 5 serious and/or non-serious adverse events with type and frequency assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Date of Hepatic Artery Infusion Pump (HAIP) insertion through death or study completion, up to 63.1 months | OS is defined as the median amount of time a participant survives after therapy determined using the Kaplan Meier method. The 95% confidence intervals were obtained using the Brookmeyer-Crowley method via a log-log (complementary log-log) transformation. As pre-specified in the protocol Statistical Section 10.4.3 Analysis of the Secondary Efficacy Endpoints, Overall survival (OS) will be calculated "from the date the patient enrolled onto the trial." The Responsible Party's rationale for reporting a different time frame is "The RP's preference is to report from the date of pump insertion given the time variability from enrollment to surgery, which is a function of operating room (OR) availability, and nothing related to the study. |
| Intra-Hepatic Progression-free Survival (PFS) | Date of hepatic artery infusion pump (HAIP) insertion through either the date of first hepatic progression or study completion, up to 63.1 months | Intrahepatic PFS is defined as the duration of time from date of operation to the date of first observation of progressive disease within the liver or death, whichever comes first. Progression was measured by the Response Evaluation Criteria in Solid Tumors and determined using the Kaplan Meier method. Progression is at least a 20% increase in the sum of the diameters of target lesions. The 95% confidence intervals were obtained using the Brookmeyer-Crowley method via a log-log (complementary log-log) transformation. As prespecified in the protocol Statistical Section 10.4.3 Intra-hepatic PFS will be calculated "from the date the patient enrolled onto the trial." The Responsible Party's (RP) rationale for reporting a different time frame is "The RP's preference is to report from the date of pump insertion given the time variability from enrollment to surgery, which is a function of operating room (OR) availability, and nothing related to the study. |
| Extra-hepatic Progression-free Survival (PFS) | Date of hepatic artery infusion pump (HAIP) insertion through either the date of first extra-hepatic progression or study completion, up to 63.1 months | Extra-hepatic PFS is defined as the duration of time from date of operation to the date of first observation of progressive disease outside of the liver or death, whichever comes first. Extra-hepatic PFS was determined using the KaplanMeier method\&reported with a 95% confidence interval. Progression was measured by the Response Evaluation Criteria in Solid Tumors. Progression is at least a 20% increase in the sum of the diameters of target lesions. The 95% confidence intervals were obtained using the Brookmeyer-Crowley method via a log-log(complementary log-log) transformation. As prespecified in the protocol Statistical Section 10.4.3Extra-hepatic PFS will be calculated "from the date the patient enrolled onto the trial." The Responsible Party's((RP) rationale for reporting a differently is "RP's preference is to report from the date of pump insertion given the time variability from enrollment to surgery,which is a function of operating room availability\¬hing related to the study. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJonathan M Hernandez, M.D.
National Cancer Institute (NCI)
Participant flow
Pre-assignment details
History and physical, lab evaluation, computed tomography, etc. are performed after the subject has signed the consent for this study for screening. 28 participants were screened for this study and 4 were initial screen failures. Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently assigned to the study intervention. Thus, 24 participants were enrolled.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 51.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Fong Clinical Risk Score | 3 score on a scale |
| Microsatellite instability | 0 Participants |
| Nagashima Clinical Risk Score | 3 Score on a scale |
| Pathogenic Mutation in B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) | 1 Participants |
| Pathogenic Mutation in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) | 13 Participants |
| Positive Regional Lymph Nodes at Hepatic Artery Infusion Pump Surgery | 5 Participants |
| Prior Bevacizumab | 12 Participants |
| Prior Chemotherapy 5-fluorouracil (5-FU) | 20 Participants |
| Prior Chemotherapy Irinotecan | 9 Participants |
| Prior Chemotherapy Oxaliplatin | 20 Participants |
| Prior Immunotherapy | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 24 |
| other Total, other adverse events | 23 / 24 |
| serious Total, serious adverse events | 7 / 24 |
Outcome results
None listed