PUMP-IT RCT: Hepatic arterial infusion PUMP chemotherapy combined with systemic therapy versus systemic therapy alone as Induction Therapy for initially unresectable colorectal liver metastases: a randomised controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Analytical,Diagnostic,Therapeutic Techniques and Equipment [E]-Surgical Procedures, Operative [E04], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Diseases [C] - Neoplasms [C04]

Trial duration

21 Nov 2024 → ongoing

Decision date (initial)

2024-07-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To investigate whether HAIP-SYST prolongs survival in chemo-naive patients with initially unresectable colorectal liver metastases as compared with systemic therapy alone.

Secondary objectives 8

1. To investigate whether HAIP-SYST prolongs progression-free survival in chemo-naive patients with initially unresectable colorectal liver metastases as compared with systemic therapy alone.
2. To investigate the local effect of adding HAIP therapy to the liver in terms of hepatic disease progression
3. To investigate the effect of HAIP-SYST on the chance to undergo subsequent local treatment versus systemic therapy alone.
4. To investigate the anti-tumour effect of the combination of HAIP-SYST compared to systemic therapy alone.
5. To assess additional surgical morbidity of patients who underwent HAIP placement and/or any tumour related surgery.
6. To assess the toxicity of the combination of HAIP-SYST versus systemic therapy alone
7. To compare Quality of Life (QoL) of patients treated with HAIP-SYST versus systemic therapy alone
8. To compare the Cost Effectiveness of induction treatment with HAIP-SYST versus systemic therapy alone

Conditions and MedDRA coding

Colorectal liver metastases

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Age ≥ 18 years ≤ 75 years
2. Histologically confirmed colorectal adenocarcinoma.
3. Unresectable synchronous colorectal liver metastases according to a Liver Expert Panel (CT-scan obtained ≤ 4 weeks prior to registration for screening), defined as: o CRLM that are potentially resectable or locally treatable with two-stage approach, with resection and/or ablation or after portal vein embolization AND for which starting with systemic therapy is preferred because of the number, size, location or distribution of the metastases. o CRLM that are technically untreatable with local therapies without first downsizing
4. No extrahepatic metastases. Patients with small (≤ 10 mm) extrahepatic lesions that are not clearly suspicious of metastases are eligible.
5. No previous systemic therapy for colorectal cancer.
6. Positioning of a catheter for HAIP chemotherapy is technically feasible based on imaging. The default site for the catheter insertion is the gastroduodenal artery (GDA). Accessory or aberrant hepatic arteries are no contraindication 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. Not eligible: o Patients with significant (>50%) celiac trunk or superior mesenteric artery (SMA) stenosis o Patients with any celiac trunk stenosis and a replaced or accessory hepatic artery o Patients with both a replaced right and replaced left hepatic artery. A CT arterial phase is mandatory before randomisation in case of any celiac trunk or SMA stenosis. The sponsor study team is consulted in case of doubt about technical feasibility.
7. ECOG performance status 0 or 1.
8. Life expectancy of at least 12 weeks.
9. Known mutation status of RAS and BRAFV600E.
10. Primary tumour in situ and resectable without neoadjuvant therapy.
11. Patient is eligible for surgery, as assessed by the treating surgeon
12. Patient is eligible for at least doublet chemotherapy, as assessed by the treating oncologist.
13. Laboratory requirements: i.e. adequate bone marrow, liver and renal function (obtained within 15 days prior to registration for screening). o Hb ≥ 5.5 mmol/L o absolute neutrophil count (ANC) ≥1.5 x 109/L o platelets ≥100 x 109/L o total bilirubin ≤ 1.5 times the upper limit of normal (ULN) o ASAT/AST ≤ 5 x ULN o ALAT/ALT ≤ 5 x ULN o alkaline phosphatase ≤ 5 x ULN o Serum creatinine ≤ 1.5 x upper limit of normal or a MDRD (eGFR) ≥ 45 ml/min; o Prothrombin time or INR < 1.5 x ULN (> 1.5 x ULN accepted for patients treated with coumarin derivates. These patients will be treated with LMWH or DOAC instead)
14. Before registration, written informed consent must be given and signed according to ICH/GCP, and national/local regulations.

Exclusion criteria 16

1. Prior hepatic radiation, resection, or ablation.
2. Serious non-healing wound, ulcer, or bone fracture.
3. Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent excluding inhaled steroids).
4. Known serious infections (uncontrolled or requiring treatment).
5. History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for HAIP-SYST or standard systemic therapy.
6. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
7. Underlying liver disease including liver fibrosis and cirrhosis
8. Any comorbidity or condition that interferes with the planned study treatment or the prognosis of CRLM, determined by the treating physician.
9. Prior or concurrent second malignancy other than the disease under study or one whose natural history or treatment is likely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) as discussed in the local MDT. The following malignancies are allowed: (a) malignancy treated with curative intent and with no evidence of active disease present within 3 years prior to inclusion (b) adequately controlled nonmelanomatous skin cancer (c) adequately treated carcinoma in situ without current evidence of disease Prior or concurrent second malignancies other than (a), (b) and (c) must be reviewed and agreed to with the sponsor study team.
10. Obstructive primary tumour requiring emergency surgery, primary tumour necessitating a multivisceral resection/abdominoperineal resection or an intermediate (N+) or locally advanced rectal tumour (defined as a tumour with at least one of the following characteristics: tumour >5 cm; mesorectal fascia (MRF) ingrowth or ingrowth in adjacent organ on MRI (T4); Nodal positive primary tumour, i.e. at least one lymph node >8 mm or 4 lymph nodes >5 mm on CT scan or MRI.)
11. MMR deficiency.
12. DPD-deficiency.
13. Pregnant or lactating women.
14. 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.
15. Organ allografts requiring immunosuppressive therapy.
16. History of clinically significant cardiovascular disease including, but not limited to, the following: New York Heart Association Heart Failure Class 2 or greater (Appendix G), major cardiovascular events or interventions within 6 months prior to registration for screening (e.g. myocardial infarction, endarterectomy) randomisation, unstable arrhythmias or unstable angina.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Survival (OS)

Secondary endpoints 8

1. Progression-free Survival (PFS)
2. Hepatic Progression-free Survival (hPFS)
3. Conversion to resection rate
4. Objective response rate (ORR), Disease Control Rate (DCR), Pathological response rate
5. Surgical complication rate (Clavien Dindo classification)
6. Adverse events and toxicity ≥ 3 (according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0)
7. Quality of Life (QoL)
8. Costs per quality adjusted life years (QALYs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Department

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Department

Locations

1 EU/EEA country · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications