Testing Pump Chemotherapy in Addition to Standard of Care Chemotherapy Versus Standard of Care Chemotherapy Alone for Patients With Unresectable Colorectal Liver Metastases: The PUMP Trial

Study Overview
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Brief Summary
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This phase III trial compares hepatic arterial infusion (HAI) (pump chemotherapy) in addition to standard of care chemotherapy versus standard of care chemotherapy alone in treating patients with colorectal cancer that has spread to the liver (liver metastases) and cannot be removed by surgery (unresectable). HAI uses a catheter to carry a tumor-killing chemotherapy drug called floxuridine directly into the liver. HAI is already approved by the Food and Drug Administration (FDA) for use in metastatic colorectal cancer to the liver, but it is only available at a small number of hospitals, and most of the time it is not used until standard chemotherapy stops working. Standard chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding HAI to standard chemotherapy may be effective in shrinking or stabilizing unresectable colorectal liver metastases.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine if patients with persistently unresectable colorectal liver metastases (CRLM) after treatment with first-line chemotherapy have improved overall survival (OS) with hepatic arterial infusion (HAI) and systemic chemotherapy versus systemic chemotherapy alone. SECONDARY OBJECTIVES: I. To determine whether there is a direct association between hepatic progression free survival (hPFS) and overall survival (OS) when patients are treated with HAI combined with systemic chemotherapy for unresectable CRLM. II To determine the impact on progression free survival (overall, hepatic and extrahepatic) for patients with unresectable CRLM treated with HAI in combination with systemic chemotherapy. III. To determine objective response rate (ORR) in the liver, defined as the proportion of patients achieving complete or partial response by Response Evaluation Criteria is Solid Tumors (RECIST) 1.1. IV. To determine the rate of conversion to resectable disease, defined as the proportion of patients who successfully convert from unresectable to resectable status and undergo R0/R1 resection/ablation. V. To determine the rate in which patients are intended to be treated with HAI but are deemed ineligible at the time of planned pump insertion due to detection of occult extrahepatic disease or unsuitable arterial anatomy (Intra-Operative Ineligibility, IOI). VI. To determine the extent to which patient and disease-specific factors correlate with short- and long-term risk of HAI-specific complications. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients undergo surgery to place the HAI pump, followed by single photon emission computed tomography/computed tomography (SPECT/CT) on study. Patients then receive floxuridine via the HAI pump on study. Patients also receive one of the following standard chemotherapy regimens per the treating physician: FOLFOX (fluorouracil intravenously [IV], oxaliplatin IV, and leucovorin IV), FOLFIRI (fluorouracil IV, irinotecan IV, and leucovorin IV), or OX/IRI (oxaliplatin IV and irinotecan IV) with or without cetuximab IV and/or panitumumab IV on study. Patients also undergo CT scans throughout the trial. ARM B: Patients receive one of the following standard chemotherapy regimens per the treating physician: FOLFOXIRI (fluorouracil IV, oxaliplatin IV, irinotecan IV, and leucovorin IV), FOLFOX, FOLFIRI, or OX/IRI with or without cetuximab IV, panitumumab IV, and/or bevacizumab IV on study. Patients also undergo CT scans throughout the trial.

Official Title
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A Randomized Phase III Study of Systemic Therapy With or Without Hepatic Arterial Infusion for Unresectable Colorectal Liver Metastases: The PUMP Trial

Conditions
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Metastatic Colorectal Carcinoma, Metastatic Malignant Neoplasm in the Liver, Stage IV Colorectal Cancer AJCC v8, Unresectable Colorectal Carcinoma

Intervention / Treatment
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* Biological: Bevacizumab
* Biological: Cetuximab
* Procedure: Computed Tomography
* Drug: Floxuridine
* Drug: Fluorouracil
* Procedure: Implantation
* Procedure: Intrahepatic Infusion Procedure
* Drug: Irinotecan
* Drug: Leucovorin
* Drug: Oxaliplatin
* Biological: Panitumumab
* Procedure: Single Photon Emission Computed Tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be >= 18 years of age Patient must have confirmed unresectable liver confined metastatic colorectal cancer (CRC). Patient must not have radiographically or clinically evident extrahepatic disease (including but not limited to radiographically positive periportal lymph nodes). NOTE: Patients found to have positive periportal nodes at the time of HAI placement can remain on study. Patient may have calcified pulmonary nodules, and/or =< 5 indeterminate and stable (for a minimum of 3 months on chemotherapy) pulmonary nodules each measuring =< 6 mm in maximal axial dimension. Patient's primary tumor may be in place. Patient must have received 3-6 months of previous first-line chemotherapy that meet one of the following three criteria: a) have received at least 6 but no more than 12 cycles of first-line cytotoxic chemotherapy (where 1 cycle = 14 days) OR b) have received at least 4 but no more than 8 cycles of first-line cytotoxic chemotherapy (where 1 cycle = 21 days) OR c) have developed new colorectal liver metastases (CRLM) within 12 months of completing adjuvant systemic therapy for stage II-III colorectal cancer. NOTE: First-line chemotherapy may have included any of the following regimens as listed in the National Comprehensive Cancer Network (NCCN) Guidelines: leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) (or equivalent), leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan (FOLFIRI) (or equivalent), leucovorin calcium (calcium folinate), 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI), each with or without any of the following: bevacizumab, cetuximab, or panitumumab. Patient must have stable or responding disease on first-line chemotherapy by RECIST 1.1 criteria Patient must meet the following criteria for technical unresectability: A margin-negative resection requires resection of three hepatic veins, both portal veins, or the retrohepatic vena cava OR a resection that leaves less than two adequately perfused and drained segments. NOTE: Institutional multidisciplinary review is required to confirm unresectability and rule out radiographically positive extrahepatic disease. Patient must undergo CT angiography (chest/abdomen/pelvis) to confirm acceptable hepatic arterial anatomy for HAI and to rule out extrahepatic disease within 4 weeks prior to randomization. Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 and be clinically fit to undergo surgery as determined by the pre-operative evaluation. Leukocytes >= 3,000/mcL (obtained =< 14 days prior to protocol randomization) Absolute neutrophil count (ANC) >= 1,500/mcL (obtained =< 14 days prior to protocol randomization) Platelets >= 100,000/mcL (obtained =< 14 days prior to protocol randomization) Total Bilirubin =< 1.5 mg/dL (obtained =< 14 days prior to protocol randomization) Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (ULN) (obtained =< 14 days prior to protocol randomization) Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 50 mL/min calculated by the Cockcroft-Gault method (obtained =< 14 days prior to protocol randomization) Calcium >= institutional lower limit of normal (LLN) Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial. Testing for HIV is not required for entry onto the study Exclusion Criteria: Patient must not have a liver tumor burden exceeding 70% of total liver volume. Patient must not have had prior radiation to the liver (prior radiation therapy to the pelvis is acceptable if completed at least 2 weeks prior to randomization). Patient must not have had prior trans-arterial bland embolization, chemoembolization (TACE) or radioembolization (TARE). Patient must not have had prior treatment with HAI/floxuridine (FUDR) Patient must not have microsatellite instability-high (MSI-H) colorectal cancer. Patient must not have CRLM that could be resected with 2-stage hepatectomy, including associating liver partition and portal vein ligation (ALPPS). Patient must not have an active infection, serious or non-healing active wound, ulcer, or bone fracture. Patient must not have any serious medical problems which would preclude receiving the protocol treatment or would interfere with the cooperation with the requirements of this trial. Patient must not have cirrhosis and/or clinical or radiographic evidence of portal hypertension Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (HAI, floxuridine, standard chemotherapy)<br>Patients undergo surgery to place the HAI pump, followed by SPECT/CT on study. Patients then receive floxuridine via the HAI pump on study. Patients also receive one of the following standard chemotherapy regimens per the treating physician: FOLFOX, FOLFIRI, or OX/IRI with or without cetuximab IV and/or panitumumab IV on study. Patients also undergo CT scans throughout the trial. | Biological: Cetuximab<br>* Given IV<br>* Other names: IMC-C225;Procedure: Computed Tomography<br>* Undergo SPECT/CT and/or CT<br>* Other names: tomography;Drug: Floxuridine<br>* Given via HAI pump<br>* Other names: WR-138720;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Procedure: Implantation<br>* Undergo surgery to place the HAI pump<br>Procedure: Intrahepatic Infusion Procedure<br>* Undergo HAI<br>* Other names: Intrahepatic Infusion;Drug: Irinotecan<br>* Given IV<br>Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;Biological: Panitumumab<br>* Given IV<br>* Other names: Vectibix;Procedure: Single Photon Emission Computed Tomography<br>* Undergo SPECT/CT<br>* Other names: Tomography, Emission-Computed, Single-Photon;|
| Active Comparator: Arm B (standard chemotherapy)<br>Patients receive one of the following standard chemotherapy regimens per the treating physician: FOLFOXIRI, FOLFOX, FOLFIRI, or OX/IRI with or without cetuximab IV, panitumumab IV, and/or bevacizumab IV on study. Patients also undergo CT scans throughout the trial. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Biological: Cetuximab<br>* Given IV<br>* Other names: IMC-C225;Procedure: Computed Tomography<br>* Undergo SPECT/CT and/or CT<br>* Other names: tomography;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Irinotecan<br>* Given IV<br>Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;Biological: Panitumumab<br>* Given IV<br>* Other names: Vectibix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Patients still living will be censored at the date last known alive. OS will be evaluated using the Kaplan-Meier method, and arms will be compared via a stratified log rank test. | From randomization to death from any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Patients still living without disease progression will be censored at the date of last disease assessment. Disease progression will be based on findings from surveillance cross-sectional imaging of the chest/abdomen/pelvis every 3 months after randomization, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be analyzed similarly to OS, but with and without stratification for sensitivity. | From randomization to first observed disease progression at any site, or death from any cause, assessed up to 5 years | 
| Hepatic PFS | Patients still living without hepatic disease progression will be censored at the date of last disease assessment. Hepatic disease progression will be based on findings from surveillance cross-sectional imaging of the chest/abdomen/pelvis every 3 months after randomization, defined by RECIST 1.1. | From randomization to first observed disease progression in the liver, or death from any cause, assessed up to 5 years | 
| Extrahepatic-PFS | Patients still living without extrahepatic disease progression will be censored at the date of last disease assessment. Extrahepatic disease progression will be based on findings from surveillance cross-sectional imaging of the chest/abdomen/pelvis every 3 months after randomization, defined by RECIST 1.1. | From randomization to first observed disease progression outside of the liver, or death from any cause, assessed up to 5 years | 
| Objective response rate | Will assess hepatic disease burden specifically. Defined as the proportion of patients achieving complete or partial response by RECIST 1.1. Response will be based on surveillance cross-sectional imaging of the chest/abdomen/pelvis every 3 months (+/- 2 weeks) after initiation of treatment (Arm A = surgery, Arm B = cycle 1, day 1 of chemotherapy). Arms will be compared via a Pearson chi-square test. All rates will be reported with exact binomial 95% confidence intervals. | Up to 5 years | 
| Rate of conversion to resectable disease | Defined as the proportion of patients who successfully convert from unresectable to resectable status and undergo R0/R1 resection/ablation. All rates will be reported with exact binomial 95% confidence intervals. | Up to 5 years | 
| Intra-operative ineligibility rate | Defined as the proportion of patients intended to receive hepatic arterial infusion that do not undergo pump implantation due to intraoperative detection of occult extrahepatic disease or unsuitable hepatic arterial anatomy. All rates will be reported with exact binomial 95% confidence intervals. | Up to 5 years | 
| Incidence of adverse events | Defined according to the Common Terminology Criteria for Adverse Events. | Up to 5 years |