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

Registration Number
NCT05863195
Lead Sponsor
ECOG-ACRIN Cancer Research Group
Brief Summary

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 chem...

Detailed Description

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:
...

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
408
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

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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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Arm A (HAI, floxuridine, standard chemotherapy)ImplantationPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)CetuximabPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)Computed TomographyPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)Intrahepatic Infusion ProcedurePatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)PanitumumabPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)Single Photon Emission Computed TomographyPatients 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.
Arm B (standard chemotherapy)CetuximabPatients 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.
Arm B (standard chemotherapy)Computed TomographyPatients 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.
Arm B (standard chemotherapy)FluorouracilPatients 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.
Arm B (standard chemotherapy)IrinotecanPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)FluorouracilPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)FloxuridinePatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)IrinotecanPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)LeucovorinPatients 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.
Arm A (HAI, floxuridine, standard chemotherapy)OxaliplatinPatients 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.
Arm B (standard chemotherapy)LeucovorinPatients 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.
Arm B (standard chemotherapy)OxaliplatinPatients 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.
Arm B (standard chemotherapy)BevacizumabPatients 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.
Arm B (standard chemotherapy)PanitumumabPatients 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.
Primary Outcome Measures
NameTimeMethod
Overall survival (OS)From randomization to death from any cause, assessed up to 5 years

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.

Secondary Outcome Measures
NameTimeMethod
Incidence of adverse eventsUp to 5 years

Defined according to the Common Terminology Criteria for Adverse Events.

Progression free survival (PFS)From randomization to first observed disease progression at any site, or death from any cause, assessed up to 5 years

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 O...

Hepatic PFSFrom randomization to first observed disease progression in the liver, or death from any cause, assessed up to 5 years

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.

Extrahepatic-PFSFrom randomization to first observed disease progression outside of the liver, or death from any cause, assessed up to 5 years

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.

Rate of conversion to resectable diseaseUp to 5 years

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.

Intra-operative ineligibility rateUp to 5 years

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.

Objective response rateUp to 5 years

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 ...

Trial Locations

Locations (39)

UM Sylvester Comprehensive Cancer Center at Aventura

🇺🇸

Aventura, Florida, United States

UM Sylvester Comprehensive Cancer Center at Coral Gables

🇺🇸

Coral Gables, Florida, United States

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

🇺🇸

Deerfield Beach, Florida, United States

UM Sylvester Comprehensive Cancer Center at Hollywood

🇺🇸

Hollywood, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

🇺🇸

Miami, Florida, United States

UM Sylvester Comprehensive Cancer Center at Kendall

🇺🇸

Miami, Florida, United States

UM Sylvester Comprehensive Cancer Center at Plantation

🇺🇸

Plantation, Florida, United States

IU Health North Hospital

🇺🇸

Carmel, Indiana, United States

Indiana University/Melvin and Bren Simon Cancer Center

🇺🇸

Indianapolis, Indiana, United States

Vanderbilt University/Ingram Cancer Center

🇺🇸

Nashville, Tennessee, United States

University of Alabama at Birmingham Cancer Center

🇺🇸

Birmingham, Alabama, United States

UCHealth University of Colorado Hospital

🇺🇸

Aurora, Colorado, United States

Emory University Hospital/Winship Cancer Institute

🇺🇸

Atlanta, Georgia, United States

University of Chicago Comprehensive Cancer Center

🇺🇸

Chicago, Illinois, United States

University of Michigan Comprehensive Cancer Center

🇺🇸

Ann Arbor, Michigan, United States

Memorial Hospital East

🇺🇸

Shiloh, Illinois, United States

University of Kentucky/Markey Cancer Center

🇺🇸

Lexington, Kentucky, United States

Corewell Health Grand Rapids Hospitals - Butterworth Hospital

🇺🇸

Grand Rapids, Michigan, United States

Mayo Clinic in Rochester

🇺🇸

Rochester, Minnesota, United States

Siteman Cancer Center at West County Hospital

🇺🇸

Creve Coeur, Missouri, United States

Washington University School of Medicine

🇺🇸

Saint Louis, Missouri, United States

Siteman Cancer Center-South County

🇺🇸

Saint Louis, Missouri, United States

Siteman Cancer Center at Christian Hospital

🇺🇸

Saint Louis, Missouri, United States

Siteman Cancer Center at Saint Peters Hospital

🇺🇸

Saint Peters, Missouri, United States

Memorial Sloan Kettering Basking Ridge

🇺🇸

Basking Ridge, New Jersey, United States

Memorial Sloan Kettering Commack

🇺🇸

Commack, New York, United States

Memorial Sloan Kettering Monmouth

🇺🇸

Middletown, New Jersey, United States

Memorial Sloan Kettering Bergen

🇺🇸

Montvale, New Jersey, United States

Memorial Sloan Kettering Westchester

🇺🇸

Harrison, New York, United States

Mount Sinai Hospital

🇺🇸

New York, New York, United States

Memorial Sloan Kettering Cancer Center

🇺🇸

New York, New York, United States

Memorial Sloan Kettering Nassau

🇺🇸

Uniondale, New York, United States

Duke University Medical Center

🇺🇸

Durham, North Carolina, United States

Case Western Reserve University

🇺🇸

Cleveland, Ohio, United States

Fox Chase Cancer Center

🇺🇸

Philadelphia, Pennsylvania, United States

Allegheny General Hospital

🇺🇸

Pittsburgh, Pennsylvania, United States

West Penn Hospital

🇺🇸

Pittsburgh, Pennsylvania, United States

Parkland Memorial Hospital

🇺🇸

Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas

🇺🇸

Dallas, Texas, United States

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