Dose Finding, Efficacy and Immunological Response of IP-001 Following MWA or IRE for CRLM

ConditionsColorectal Cancer Liver Metastases Liver Metastasis Colon Cancer

Trial statusRecruiting

Trial phasePhase 1, Phase 2

Trial typeInterventional

Biological sexAll

Age18+

SponsorM.R. Meijerink

About this trial

The primary objectives of this phase I/II, prospective clinical trial, are to assess the optimal dose, efficacy, safety and immunological effect of ablation and intra-tumoral injection of a novel immuno-adjuvant (IP-001) for colorectal liver metastases (CRLM). The study consists of three parts, devided into two phases.

Phase 1 is a dose-escalation study according to a classic '3+3' design, to identify the dose level at which IP-001 exhibits an acceptable level of toxicity following microwave ablation (MWA) of CRLM in refractory metastatic colorectal cancer (CRC) patients.

Phase 2, part 1 and part 2 are performed simultaneously. In phase 2 part 1, a single arm study assesses the efficacy of IP-001 following MWA for CRLM for curative intent. In phase 2 part 2, a randomized, two-armed study assesses the efficacy and immunomodulation of IP-001 following two ablative modalities: arm A (MWA) and arm C (irreversible electroporation (IRE)) for CRLM in refractory metastatic CRC patients.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Measurable metastatic CRC based on RECIST v1.1;

The primary tumor has been resected before study inclusion or the patient is asymptomatic with respect to the in situ primary tumor;

Last imaging ≤ 4 weeks prior to the on-study ablative procedure;

Age ≥ 18 years;

Disqualifiers

Compromised liver function defined as warning signs of portal hypertension, INR &gt; 1,5 without use of anticoagulants, bilirubin &gt; x 1.5 Upper limit of normal range (ULN) ASAT &gt;5.0 x ULN, ALAT &gt;5.0 x ULN.

Compromised kidney function defined as eGFR &lt;45 ml/min (using the Cockcroft Gault formula);

Active autoimmune disease requiring disease-modifying therapy at the time of screening or during the study period: i.e. &gt; 10 mg prednisolone per day or other immunosuppressive therapy (e.g. methotrexate);

Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results;

Trial design

Design model

Sequential

Treatments tested in this trial

IP-001
Drug
Intra-tumoral injection of IP-001 following ablation (MWA or IRE).

Treatment groups

120 Participants

are divided into 4 treatment groups

Group A: Phase 1 Dose esclatation of IP-001Experimental treatment 1 intervention

Group B: Phase 2 Part 1 MWA + IP-001Experimental treatment 1 intervention

Group C: Phase 2 part 2 MWA + IP-001Experimental treatment 1 intervention

Group D: Phase 2 part 2 IRE + IP-001Experimental treatment 1 intervention

Trial outcomes

Primary outcomes

Maximum Tolerated Dose (MTD) (Phase 1)

The highest dose of IP-001 that does not cause unacceptable side effects defined as the dose level below the dose level that caused 2 or more Dose Limiting Toxicites (DLTs).

Time frame

During the 10-day DLT-monitoring period.

1-Year Distant Progression Free Survival (DPFS) (Phase 2 part 1)

Overall DPFS is defined as the time from inclusion to the time of disease progression (according to the RECIST 1.1 guideline) or death (events). Death related to other causes is considered a failure event for DPFS.

Time frame

1 year

Disease Control Rate (DCR) (Phase 2 part 2)

DCR is calculated as the percentage of patients experiencing either iSD (Stable Disease), iPR (Partial Response) or iCR (Complete Response) as best response in target lesions at 16 weeks after treatment according to iRECIST.

Time frame

16 weeks

Secondary outcomes

Elimination half-life of the study drug IP-001 in the blood (t1/2 ) (Phase 1 and phase 2 part 2)

Blood samples will be taken prior to and at different timepoints after the procedure for pharmacokinetic analysis defined as elimination half-life of the study drug IP-001 in the blood.

Time frame

Prior to and +1 hour, +2 hours, +6 hours, +12 hours and + 24 hours after study treatment

Overall Survival (OS; per patient analysis) (All phases)

OS is defined as the time from focal therapy to the time of death due to any cause, assessed up to 5 years;

Time frame

Up to 5 years

(Serious) Adverse Events ((S)AEs) (All phases)

(Serious) adverse events according to CTCAE v5.0, assessed up to 5 years.

Time frame

Up to 5 years

Duration of best overall response (DoR, per patient analysis) (Phase 2 part 2)

DoR is defined from when the time measurement criteria are first met for CR/iCR or PR/iPR until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years;

Time frame

Up to 3 years

Other outcomes

Immunomodulation in tissue biopsies (Phase 1 and phase 2 part 2)

The effect on treated and untreated tumor tissue will be assessed by pre- and post-treatment biopsies of treated and untreated tumor tissue. The pre- and post-treatment biopsies will be compared to determine the evidence for the induction of a sustainable, infiltrative immune response. Tissue biopsies from the untreated metastasis will be used to investigate the possible induction of a systemic immune response;

Time frame

Prior to the procedure and 4 weeks post-procedure.

Immunomodulation in circulating immunecells (Phase 1 and phase 2 part 2)

The effect on circulating immune cells and a possible induction of a systemic anti-tumor immune response will be assessed by taking pre- and post-treatment venous blood samples. Samples will be taken prior to the study procedure and after the study procedure after 1 day, 10 days, 4 weeks and 8 weeks.

Time frame

prior to the study procedure and +1 day, +10 days, +4 weeks and +8 weeks after the study procedure

Effect on circulating tumor DNA (ctDNA) (Phase 2 part 1)

CtDNA is samples to monitor the efficacy of the study treatment (MWA + IP-001), defined as a significant decrease in ctDNA, as well as to predict (radiological) metastatic recurrence or progression, defined as a significant increase in ctDNA.

Time frame

1 year