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

All phases:

Inclusion Criteria:

• Measurable metastatic CRC based on RECIST v1.1;

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

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

• Age ≥ 18 years;

• Eastern Cooperative Oncology Group (ECOG) performance status of no more than 1;

• A life expectancy of at least 3 months at the time of inclusion;

• Adequate bone marrow, liver, and renal function as assessed by laboratory tests.These results should be judged by the local investigator and should be conductedwithin 7 days prior to definite inclusion;

• Written informed consent.

Exclusion Criteria:

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

• Compromised kidney function defined as eGFR <45 ml/min (using the CockcroftGault formula);

• Active autoimmune disease requiring disease-modifying therapy at the time ofscreening or during the study period: i.e. > 10 mg prednisolone per day orother immunosuppressive therapy (e.g. methotrexate);

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

• Known allergic reaction to shellfish, crabs, crustaceans, or any trial components;

• Known history of HIV or active Hepatitis C or Hepatitis B infection;

• Uncontrolled infections (> grade 2 NCI-CTC version 3.0); requiringantibiotics;

• Pregnant or breast-feeding subjects; Women of childbearing potential must have anegative pregnancy test performed within 7 days of the start of treatment;

• Known allergy to contrast agent that cannot be adequately prevented;

• Any condition that is unstable or that could jeopardize the safety of the subjectand their compliance in the study;

• Major surgery or radiotherapy ≤ 3 weeks (7 days for single fraction of palliativeradiotherapy) prior to the on-study ablative procedure;

• Systemic therapy ≤ 4 weeks prior to the on-study ablative procedure;

• CTCAE Grade ≥1 from all side effects of prior therapies or prior procedures at thetime of inclusion.

Phase 1

Inclusion Criteria:

• Progressive or stable metastatic CRC on CT-scan after at least 1 lines of standardof care systemic treatment. Standard of care systemic treatment will be defined anddetermined by the treating oncologist. A summary of standard of care systemictreatment for CRLM as used by the medical oncologists at Amsterdam UMC has beenlisted in Table 1. Patients can also be included if systemic treatment has to beterminated due to toxicity or when patients refuse (further) systemic treatment, orwhen patients are in a therapy break from systemic therapy as patients can continuewith further systemic treatment one month after the study treatment;

• At least 2 CRLM eligible for MWA with a minimum diameter of 1cm and a maximumdiameter of 3cm and one (optional but not required) CRLM that will be left untreatedand is eligible for biopsy;

• No limitations on intrahepatic or extrahepatic disease;

Exclusion Criteria:

• No additional exclusion criteria.

Phase 2 part 1:

Inclusion Criteria:

• At least one CRLM and a maximum of three CRLM size ≤ 3 cm eligible for MWA withcurative intent;

• Additional unablatable CRLM should be resectable with a maximum of 10 additionalCRLM;

• Resectability and ablatability should be re-confirmed intra-operatively by US incase of combined/staged resection and ablation. Intra-operatively also fullexploration for hepatic, peritoneal and regional lymph node metastases should beperformed;

Exclusion Criteria:

• Radical treatment unfeasible or unsafe (e.g. insufficient FLR);

• The presence of extrahepatic nodal or non-nodal metastases. One locally treatablelung metastasis is allowed;

• Any surgical resection or focal ablative liver therapy for CRLM prior to inclusion;

Phase 2 part 2:

Inclusion Criteria:

• Liver only or liver dominant measurable metastatic CRC based on RECIST v1.1;

• Liver dominant metastatic disease is defined as the hepatic tumorload (number andestimated volume) exceeding the extrahepatic tumorload, with a maximum of 5unequivocal extrahepatic metastases in ≤2 different organ systems;

• At least 2 CRLM, of which at least one is eligible for the study treatment (RFA, MWAand IRE);

• At least 50% (number and estimated volume) of the CRLM should be eligible forablation. A maximum of 4 CRLM can be assigned for the study treatment. One CRLM hasto be left untreated;

• At least one untreated CRLM and one 'to-be-treated' CRLM should be eligible forbiopsy;

• Maximum size of CRLM for study treatment is 3cm;

• Any CRLM with a maximum lesion size of 5cm at time of inclusion;

• Limited extrahepatic disease, restricted to the lungs and lymph nodes, with amaximum lesion size of 3cm at time of inclusion. See below for additionalinformation regarding pulmonary nodules;

• Progressive disease on CT-scan after standard of care systemic treatment. Standardof care systemic treatment will be defined and determined by the treatingoncologist. Patients can also be included if systemic treatment has to be terminateddue to toxicity or when patients refuse (further) systemic treatment.;

Exclusion Criteria:

• Tumor diameter of ≥ 5 cm of any hepatic lesion at the time of inclusion. If lesionsize exceeds 5 cm at start of the procedure, the patient will not be excluded;

• Metastases in the lungs or lymph nodes ≥ 3 cm. If lesion size exceeds 3 cm at startof the procedure, the patient will not be excluded;

• Metastases in any other organ than the liver, lungs of lymph nodes;