Trial Title:
Dose Finding, Efficacy and Immunological Response of IP-001 Following RFA, MWA or IRE for CRLM
NCT ID:
NCT06630624
Condition:
Colorectal Cancer
Liver Metastases
Liver Metastasis Colon Cancer
Conditions: Official terms:
Neoplasm Metastasis
Neoplasms, Second Primary
Liver Neoplasms
Conditions: Keywords:
Colorectal liver metastases
Colorectal hepatic metastases
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Intervention model description:
Firstly, a phase 1, dose-escalation study according to a classic '3+3' design will be
performed to determine the maximum tolerated dose (MTD) of intra-tumoral IP-001 injection
following MWA. In phase 2 part 1, a single arm study will be performed with the optimal
dose found in phase 1 to assess efficacy of intra-tumoral IP-001 injection following MWA
in patients with CRLM who will receive the ablation for curative intent. Phase 2 part 2
will be conducted in parallel to phase 2 part 1 as a randomized, 3-armed study assessing
the efficacy and immunomodulation of intra-tumoral IP-001-injection following three
ablative modalities (arm A (RFA), arm B (MWA) or arm C (IRE)) in patients with refractory
metastatic CRC.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
IP-001
Description:
Intra-tumoral injection of IP-001 following ablation (RFA, MWA or IRE).
Arm group label:
Phase 1 Dose esclatation of IP-001
Arm group label:
Phase 2 Part 1 MWA + IP-001
Arm group label:
Phase 2 part 2 IRE + IP-001
Arm group label:
Phase 2 part 2 MWA + IP-001
Arm group label:
Phase 2 part 2 RFA + IP-001
Summary:
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, 3-armed study assesses the efficacy and immunomodulation of
IP-001 following three ablative modalities: arm A (radiofrequency ablation (RFA)), arm B
(MWA) and arm C (irreversible electroporation (IRE)) for CRLM in refractory metastatic
CRC patients.
Detailed description:
Rationale: As ablative therapies lead to in situ availability of ablated tumor material,
RFA, MWA and IRE have been shown to trigger an anti-tumor immune response. However, the
magnitude of this response seems insufficient to induce a detectable abscopal effect
(shrinkage or disappearance of distant, untreated tumors). In recent years, there has
been a growing interest in exploring the potential synergy between ablative techniques
and immune activating strategies to induce a more robust, long-term, systemic anti-tumor
immune response.
A novel immuno-adjuvant (IP-001) has been developed to address this synergy and trigger a
tumor-specific systemic immune response when exposed to liberated tumor antigens
following tumor ablation. 1.0% IP-001 for Injection (IP-001) is injected in and around
the ablation zone immediately following ablation. IP-001 creates a depot of released
tumor antigens after ablation and drives a potent downstream adaptive immune response
against these antigens.
The combination of IP-001 with an ablative treatment in patients with CRLM could prove
beneficial in terms of improved (distant) progression free survival (PFS) and possibly
OS.
Study design: The INJECTABL-II trial is a phase I-II, prospective clinical trial. The
primary conducting center will be the Amsterdam UMC (Amsterdam, the Netherlands). The
purpose of this trial is to assess the optimal dose, efficacy, safety and immunological
effect intra-tumoral injection of IP-001 following ablation. The trial consists of three
study parts, divided into two phases. In phase 1 a dose-finding study will be conducted
followed by two parallel phase 2 studies, called phase 2 part 1 and phase 2 part 2.
The investigators will first conduct a phase 1, dose-escalation study according to a
classic '3+3' design to determine the maximum tolerated dose (MTD) of intra-tumoral
IP-001 injection following MWA. In phase 2 part 1, a single arm study will be performed
with the optimal dose found in phase 1 to assess efficacy of intra-tumoral IP-001
injection following MWA in patients with CRLM who will receive ablation for curative
intent. The investigators hypothesize that MWA + IP-001 is superior to MWA alone in terms
of 1-year distant progression-free survival (DPFS). 1-year DPFS will be compared to a
matched historical, prospective cohort of the COLLISION trial, in which 126 patients have
been included. For the sample size calculation, the one-sided Z-Test with pooled variance
has been used, yielding 59 patients to be included in this phase of the trial (MWA +
IP-001). Phase 2 part 2 will be conducted in parallel as a randomized, 3-armed study
assessing the efficacy and immunomodulation of intra-tumoral IP-001-injection following
three ablative modalities (arm A (RFA), arm B (MWA) or arm C (IRE)) in patients with
refractory metastatic CRC. Efficacy of each randomized study arm will be assessed
independently, and thus a single-group design has been used for the sample size
calculations. The study treatment is considered effective when a DCR of 25% is reached at
16 weeks. A one-sided, one-sample Z-test has been used to estimate the standard
deviation. Bonferroni correction is used to correct for multiple comparisons. 21 patients
per study arm (arm A (RFA), arm B (MWA) and arm C (IRE)) will be randomized in phase 2
part 2 of the trial.
Study population: In phase 1 of the trial, patients with refractory metastatic CRC and at
least 3 CRLM (1-3 cm) will be included. In phase 2 part 1 of the trial, patients with 1-3
CRLM (≤3 cm), who will receive MWA for curative intent will be included. In phase 2 part
2 of the trial, patients with refractory, liver only or liver dominant, metastatic CRC,
limited extra-hepatic disease and 1-4 CRLM (≤3 cm) eligible for RFA, MWA or IRE will be
included.
Intervention: All patients will receive ablation and intra-tumoral injection of IP-001 of
CRLM. During phase 1, 2 CRLM will be treated with intra-tumoral injection of IP-001
following MWA. During phase 2 part 1, 1-3 CRLM eligble for MWA with curative intent will
be treated with intra-tumoral injection of IP-001 following MWA. During phase 2 part 2,
1-4 CRLM will be treated with intra-tumoral injection of IP-001 following MWA, RFA or
IRE.
Criteria for eligibility:
Criteria:
All phases:
Inclusion Criteria:
- 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;
- 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 conducted
within 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 of
normal range (ULN) ASAT >5.0 x ULN, ALAT >5.0 x ULN.
- Compromised kidney function defined as eGFR <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. > 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;
- 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); requiring
antibiotics;
- Pregnant or breast-feeding subjects; Women of childbearing potential must have a
negative 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 subject
and their compliance in the study;
- Major surgery or radiotherapy ≤ 3 weeks (7 days for single fraction of palliative
radiotherapy) 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 the
time of inclusion.
Phase 1
Inclusion Criteria:
- Progressive metastatic CRC on CT-scan after standard of care systemic treatment.
Standard of care systemic treatment will be defined and determined by the treating
oncologist. Patients can also be included if systemic treatment has to be terminated
due to toxicity or when patients refuse (further) systemic treatment;
- At least 2 CRLM eligible for MWA with a minimum diameter of 1cm and a maximum
diameter of 3cm, and at least one CRLM that will be left untreated and 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 with
curative intent;
- Additional unablatable CRLM should be resectable with a maximum of 10 additional
CRLM;
- Resectability and ablatability should be re-confirmed intra-operatively by US in
case of combined/staged resection and ablation. Intra-operatively also full
exploration for hepatic, peritoneal and regional lymph node metastases should be
performed;
Exclusion Criteria:
- Radical treatment unfeasible or unsafe (e.g. insufficient FLR);
- The presence of extrahepatic nodal or non-nodal metastases. One locally treatable
lung 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 and
estimated volume) exceeding the extrahepatic tumorload, with a maximum of 5
unequivocal extrahepatic metastases in ≤2 different organ systems;
- At least 2 CRLM, of which at least one is eligible for the study treatment (RFA, MWA
and IRE);
- At least 50% (number and estimated volume) of the CRLM should be eligible for
ablation. A maximum of 4 CRLM can be assigned for the study treatment. One CRLM has
to be left untreated;
- At least one untreated CRLM and one 'to-be-treated' CRLM should be eligible for
biopsy;
- 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 a
maximum lesion size of 3cm at time of inclusion. See below for additional
information regarding pulmonary nodules;
- Progressive disease on CT-scan after standard of care systemic treatment. Standard
of care systemic treatment will be defined and determined by the treating
oncologist. Patients can also be included if systemic treatment has to be terminated
due 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 lesion
size 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 start
of the procedure, the patient will not be excluded;
- Metastases in any other organ than the liver, lungs of lymph nodes;
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Amsterdam UMC - location VUmc
Address:
City:
Amsterdam
Zip:
1118 HV
Country:
Netherlands
Status:
Recruiting
Contact:
Last name:
Danielle J. Vos, MD
Phone:
020-44571
Phone ext:
+31
Email:
interventieradiologie@amsterdamumc.nl
Investigator:
Last name:
Martijn R. Meijerink, Prof.
Email:
Principal Investigator
Start date:
July 10, 2024
Completion date:
August 1, 2031
Lead sponsor:
Agency:
M.R. Meijerink
Agency class:
Other
Collaborator:
Agency:
Immunophotonics, Inc.
Agency class:
Industry
Collaborator:
Agency:
Angiodynamics, Inc.
Agency class:
Industry
Source:
Amsterdam UMC, location VUmc
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06630624
