Hepatic Arterial Infusion Pump Chemotherapy Combined With Systemic Chemotherapy (PUMP-IT) (PUMP-IT)

September 10, 2020 updated by: The Netherlands Cancer Institute

Hepatic Arterial Infusion PUMP Chemotherapy Combined With systemIc chemoTherapy for Potentially Resectable Colorectal Liver Metastases: The PUMP-IT Study.

The PUMP-IT study is designed to prove the feasibility of HAIP chemotherapy with concomitant standard systemic chemotherapy (FOLFOX and FOLFIRI) in the Netherlands. This study will include patients with both unresectable CRLM and resectable CRLM with an indication for upfront systemic therapy (further referred to as potentially resectable CRLM), without extrahepatic metastases. The study will be performed in two tertiary referral centers in the Netherlands.

Study Overview

Status

Recruiting

Detailed Description

RATIONALE - Colorectal cancer (CRC) is the third most common cancer with an annual incidence of 14.000 patients in the Netherlands. Of all patients with metastases, 32% have isolated colorectal liver metastases (CRLM). Local treatment of CRLM, i.e. resection, ablation and/or stereotactic radiotherapy, is the only potentially curative option. Unfortunately over 75% of these patients have CRLM which are (initially) not suitable for such local treatment.

Current treatment of unresectable CRLM includes subsequent lines of systemic (chemo)therapy aiming to convert the CRLM from an unresectable to a resectable or local treatable state in order to prolong survival. Conversion rates of modern first line systemic chemotherapeutic regimens, as described in multiple retrospective studies with highly selected patients, are observed in 10-76% of patients, resulting in a 5-year survival of 33-43% after conversion. Patients with progressive disease on first line therapy are offered second line systemic therapy. Conversion during second line systemic therapy is rare and described in only 7-13.5% of patients. These patients have a poor prognosis with a median OS of approximately 10-15 months. However, overall survival (OS) of patients undergoing local treatment after conversion on second line systemic therapy is comparable to what is observed after conversion on first line systemic therapy.

Hepatic arterial infusion pump (HAIP) can deliver high-dose regional chemotherapy to the CRLM using their unique arterial blood supply. Floxuridine is used for HAIP chemotherapy because of the advantages of having a half-life of ten minutes, a 95% first-pass effect and allowing high intrahepatic dosing resulting in increased hepatic exposure by a factor 400, with minimal systemic exposure (e.g. complications). These specific properties of HAIP chemotherapy make it possible to combine high-dose local HAIP therapy with standard of care systemic therapy.

Several single center studies from Memorial Sloan Kettering Cancer Center (MSKCC) (New York, USA) have shown high response rates with HAIP chemotherapy in combination with systemic therapy for unresectable CRLM. Conversion to resection of the initially unresectable CRLM have been observed in up to 57% of chemo-naïve patients and in 20%-38% of patients with prior systemic therapy treated with the combination of HAIP and systemic therapy. Irrespective of conversion, the combined therapy resulted in a median OS of 50.8-76.6 months and a 5-year OS of 51.9% for chemo-naïve patients. The median and 5-year OS was 27.7-35 months and 27.9%, respectively, for patients who have been treated with systemic therapy before.

Although these results are impressive, they come from a single center and have not yet been confirmed elsewhere. Most important reasons were the technically challenging surgical procedure of HAIP implantation and the need for stringent monitoring and specific management of HAIP chemotherapy requiring a highly skilled multidisciplinary treatment team.

A study investigating combined treatment is required to prove feasibility in a multicenter setting outside MSKCC before a multicenter randomized phase III trial can be initiated in the Netherlands.

STUDY DESIGN - All eligible patients who signed informed consent (registration) and meet all inclusion criteria (inclusion) will undergo surgical HAIP implantation. HAIP function is evaluated with a perfusion test during surgery and postoperatively before starting drug treatment. Start of combined HAIP chemotherapy and systemic chemotherapy is aimed within 6 weeks postoperatively. Clinical and laboratory evaluations and chemotherapy administration are scheduled every two weeks. Response evaluations will be conducted with CT thorax/abdomen and CEA measurement every 2 HAIP cycles (every 4 systemic chemotherapy cycles) during combined therapy.

The combined therapy cycles are continued until disease progression, severe toxicity, CRLM conversion to surgical local treatment or patients withdrawal. After HAIP chemotherapy discontinuation, treatment and/or follow-up are according to standard clinical practice.

Study Type

Interventional

Enrollment (Anticipated)

31

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Myrtle F Krul, MD
  • Phone Number: +31205129111
  • Email: pump@nki.nl

Study Contact Backup

  • Name: Roos Steenhuis, MSc
  • Phone Number: +31205129111

Study Locations

      • Amsterdam, Netherlands, 1066 CX
        • Recruiting
        • Antoni van Leeuwenhoek (NKI-AVL)
        • Principal Investigator:
          • Koert FD Kuhlmann, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 115 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18 years.
  • ECOG performance status 0 or 1.
  • Life expectancy of at least 12 weeks.
  • Histologically confirmed CRC.
  • Indication for first or second line systemic therapy, confirmed in a multidisciplinary meeting.
  • Potentially resectable (i.e. unresectable and upfront resectable CRLM with indication for neoadjuvant systemic therapy), confirmed in a multidisciplinary meeting and radio-logically on (PET) CT thorax/abdomen and/or MRI obtained ≤ 4 weeks prior to regis-tration.
  • Positioning of a catheter for HAIP chemotherapy is technically feasible confirmed in the multidisciplinary liver meeting based on imaging. The default site for the catheter insertion is the gastroduodenal artery (GDA). Accessory or aberrant hepatic arteries are no contra-indication for catheter implantation. The GDA should have at least one branch to the liver, accessory or aberrant hepatic arteries should be ligated to allow for cross perfusion to the entire liver through intrahepatic shunts.
  • Indication and eligibility for abdominal surgery confirmed in a multidisciplinary meeting, e.g. primary tumour resection, stoma revision/reversal and diagnostic surgery.
  • In case of primary tumour in situ: tumour should be (potentially) resectable, confirmed in a multidisciplinary meeting.
  • Adequate bone marrow, liver and renal function as assessed by the following labora-tory requirements to be conducted within 15 days prior to inclusion.

    • Hb ≥ 5.5 mmol/L
    • Absolute neutrophil count (ANC) ≥1.5 * 109/L
    • Platelets ≥100 * 109/L
    • Total bilirubin < 1.5 mg/dL
    • ASAT ≤ 5 * times the upper limit of normal (ULN)
    • ALAT ≤ 5 * ULN
    • Alkaline phosphatase ≤ 5 * ULN
    • (estimated) glomerular filtration rate (eGFR) > 45 ml/min.
  • Before patient registration, written informed consent must be given and signed according to ICH-GCP, and national/local regulations.

Exclusion Criteria:

  • Extrahepatic metastases. Confirmed with CT thorax/abdomen obtained ≤ 4 weeks prior to registration. Patients with small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible.
  • Prior hepatic radiation, resection (other than biopsy), or ablation.
  • Concurrent malignancies that interfere with the planned study treatment or the prognosis of CRLM.
  • Participation in other clinical trials interfering with the study treatment as judged by the treating physician.
  • Dihydropyrimidine dehydrogenasedeficiency (DPD deficiency).
  • Pregnant or lactating women.
  • Serious concomitant systemic disorders that would compromise the safety of the patient or his/her ability to complete the study, at the discretion of the investigator.
  • Organ allografts requiring immunosuppressive therapy.
  • Serious, non-healing wound, ulcer, or bone fracture.
  • Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equiv-alent excluding inhaled steroids).
  • Serious infections (uncontrolled or requiring treatment).
  • History of psychiatric disability judged by the investigator to potentially hamper compliance with the study protocol and follow-up schedule.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Colorectal liver metastases
Patients with potentially resectable colorectal liver metastases will undergo hepatic artery infusion pump placement. Subsequent hepatic artery infusion of floxuridine via the HAIP as well as standard of care Dutch systemic chemotherapy (FOLFOX or FOLRIRI) will be administered in a combined chemotherapy schedule.
Administration of intra-arterial floxuridine via the HAIP (HAIP chemotherapy) to the liver with concomitant Dutch standard of care systemic FOLFOX (5-FU, leucovorin and oxaliplatin) or FOLFIRI (5-FU, leucovorin and irinotecan).
Other Names:
  • FUDR
Surgical implantation of hepatic artery infusion pump (HAIP) followed by administration of the combined chemotherapy (HAIP and systemic).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Completion of 2 combined chemotherapy cycles (feasibility)
Time Frame: Approximately 4 months after patient inclusion
The percentage of patients that complete two cycles of combined chemotherapy (HAIP chemotherapy and systemic therapy) after being scheduled for surgical implantation.
Approximately 4 months after patient inclusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety: Postoperative complications
Time Frame: 90 days after surgery
Surgical complications will be defined according to Clavien-Dindo surgical complications score. Complications of Clavien-Dindo grade 3 or higher are recorded for the first 90 days after surgery. Postoperative complications include those related to the HAIP implantation. Postoperative mortality is defined as any death during hospitalization or within 90 days from surgery.
90 days after surgery
Safety: Drug treatment toxicity
Time Frame: 1.5 year
Toxicity grade 3 or higher will be recorded from the time of study inclusion according to the CTCAE criteria.
1.5 year
Safety: Other adverse events
Time Frame: 1.5 year
Treatment related serious adverse events (SAE) and adverse events (AE) of grade 3 or higher will be collected continuously from the time of study inclusion until the end of combined chemotherapy. AE are followed up until the event is either resolved or adequately explained, even after the patient has completed his/her study treatment. Nature and duration of any hospitalization, treatment of any AE, and nature and duration of any outpatient care will be recorded.
1.5 year
Response rate colorectal liver metastases (CRLM)
Time Frame: 8 months after patient registration
Response rates of CRLM will be measured according to RECIST criteria
8 months after patient registration
Progression free survival (PFS)
Time Frame: 1.5 year
PFS will be defined from inclusion date until disease progression.
1.5 year
Overall survival (OS)
Time Frame: 1.5 year
OS will be defined from inclusion date until death.
1.5 year
Conversion rate colorectal liver metastases (CRLM)
Time Frame: 8 months after patient inclusion
Conversion rate is defined as the percentage of patients in whom CRLM convert from an unresectable to a resectable state and undergo surgical treatment with curative intent. Possibility of local treatment is at the discretion of the multidisciplinary liver panel.
8 months after patient inclusion

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of life assessment
Time Frame: 8 months after patient inclusion
The quality of life will be examined with validated questionnaires (EORTC QLQ-C30 & EQ-5D-3L).
8 months after patient inclusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Koert FD Kuhlmann, MD, PhD, Antoni van Leeuwenhoek

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 9, 2020

Primary Completion (Anticipated)

June 30, 2022

Study Completion (Anticipated)

December 31, 2022

Study Registration Dates

First Submitted

September 10, 2020

First Submitted That Met QC Criteria

September 10, 2020

First Posted (Actual)

September 17, 2020

Study Record Updates

Last Update Posted (Actual)

September 17, 2020

Last Update Submitted That Met QC Criteria

September 10, 2020

Last Verified

September 1, 2020

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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