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

Rationale: As ablative therapies lead to in situ availability of ablated tumor material, 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, two-armed study assessing the efficacy and immunomodulation of intra-tumoral IP-001-injection following three ablative modalities (arm A (MWA) or arm C (IRE)) in patients with 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 (MWA) and arm B (IRE)) will be randomized in phase 2 part 2 of the trial. Study population: : In phase 1 of the trial, patients with metastatic CRC and at least 2 CRLM (1-3 cm) that have received at least 1 line of systemic therapy 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 MWA and 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 or IRE.