Clinical trial NCT05863195: 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
Official title: A Randomized Phase III Study of Systemic Therapy With or Without Hepatic Arterial Infusion for Unresectable Colorectal Liver Metastases: The PUMP Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Metastatic Colorectal Carcinoma
Metastatic Malignant Neoplasm in the Liver
Stage IV Colorectal Cancer AJCC v8
Unresectable Colorectal Carcinoma
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2023-05-17
Enrollment: 408
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: From randomization to death from any cause, assessed up to 5 years
Secondary outcomes:
measure: Progression free survival (PFS)
timeFrame: From randomization to first observed disease progression at any site, or death from any cause, assessed up to 5 years
measure: Hepatic PFS
timeFrame: From randomization to first observed disease progression in the liver, or death from any cause, assessed up to 5 years
measure: Extrahepatic-PFS
timeFrame: From randomization to first observed disease progression outside of the liver, or death from any cause, assessed up to 5 years
measure: Objective response rate
timeFrame: Up to 5 years
measure: Rate of conversion to resectable disease
timeFrame: Up to 5 years
measure: Intra-operative ineligibility rate
timeFrame: Up to 5 years
measure: Incidence of adverse events
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Aventura
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Aventura
state: Florida
city: Coral Gables
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Coral Gables
state: Florida
city: Deerfield Beach
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Hollywood
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Hollywood
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Miami
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Kendall
state: Florida
city: Plantation
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Plantation
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Shiloh
country: United States
facility: Memorial Hospital East
state: Illinois
city: Carmel
country: United States
facility: IU Health North Hospital
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Grand Rapids
country: United States
facility: Corewell Health Grand Rapids Hospitals - Butterworth Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: West Penn Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Parkland Memorial Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: Michael Lidsky
role: PRINCIPAL_INVESTIGATOR
References: