Injection of IP-001 Into Thermally Ablated Hepatic Tumors in Patients With Colorectal Liver Metastases

This is a Phase 2/3, three-arm, dose finding, randomized, controlled, patient-blinded, international, adaptive design study in patients with liver-only metastatic colorectal cancer. The purpose is to investigate the efficacy and safety of the two different dose concentrations of IP-001 for Injection administered intratumorally following standard of care (SOC) complete thermal ablation of liver tumors with microwave ablation (MWA) compared SOC MWA alone. MWA alone is selected as the control because, in patients with liver-only metastatic colorectal cancer treated with curative intent, MWA is an accepted SOC therapeutic strategy and routine continuation of systemic therapy in this context is not mandated by guidelines and remains heterogeneous across institutions.

The study is designed with a seamless transition from Phase 2 to the Phase 3 based on prespecified dose selection and interim efficacy and safety criteria. Phase 2 will include three-arms: MWA alone, MWA plus 10 mg/ml IP-001, or MWA plus 1 mg/ml IP-001. Crossover from the Control Arm to an Experimental Arm is not allowed. Phase 3 will continue to be randomized between the MWA alone (control) and the MWA plus IP-001 dose selected based on the Phase 2 interim (futility) analysis.

The trial will consist of the following three periods described below.

• Screening Period: Up to 28 days for screening assessments to determine study eligibility.
• Treatment and Follow-up Period: On Treatment Day 1, in a single session, all patients will undergo SOC hepatic tumor MWA with predetermined margins. Immediately following ablation, patients in the Experimental Arms will receive the appropriate dose of IP-001 intratumorally into all ablated tumor(s). Blood samples will be taken before treatment starts, and then again on various days after treatment to help check for important blood markers in and how the drug works in the body. In addition, patients will undergo post-treatment efficacy and safety and tolerability efficacy assessments for 12 weeks before patients move on to standard surveillance monitoring.
• Surveillance Period: Patients will be followed for efficacy, concomitant medication and procedures, and survival, every 3 months for the first year, and then every 6 months thereafter for 5 years after the initial treatment.

Patients who develop a new or recurrent tumor(s) may be eligible receive additional treatment, as appropriate, including study retreatment, other standard liver treatments, or systemic anti-cancer therapy. Patients will be followed for subsequent anticancer therapies/procedures, progression, and survival status, as indicated, for 5 years after the original treatment day to help researchers determine if IP-001 will improve a patient's response to other cancer therapies.

Inclusion criteria

• Patients ≥ 18 y of age at the time of signing the Informed Consent Form in accordance with local regulatory and/or national laws and International Council for Harmonisation (ICH)/Good Clinical Practice (GCP) regulations (consent must be received before any study-specific activity is performed).
• Patients with liver-only metastatic CRC (and no radiologic or clinical evidence of extrahepatic metastases) with:

• No more than 5 CRLM (≤ 3 cm for largest diameter)
• An indication to receive percutaneous or laparoscopic SOC complete CRLM ablation with the intent of leaving no detectable liver disease
• Tumors amenable to ablation treatment in a single session
• No residual primary colorectal tumor at Treatment Day 1 or plans to have the primary tumor excised within 4-12 weeks following Treatment Day 1. (Patients with rectal cancer who underwent chemoradiotherapy for the primary cancer must have a complete clinical response.)
• Prior systemic anticancer treatment for metastatic colorectal cancer is permitted but not required. Patients must have received no more than two prior lines of systemic anticancer treatment for mCRC.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 2.
• Patients with adequate hematological function (defined as an absolute neutrophil count ≥ 1.5 × 109/L, hemoglobin level ≥ 9 g/dL, and platelet count ≥ 50 × 109/L) and coagulation function (defined as a partial thromboplastin time [PTT] or activated PTT [aPTT] and international normalized ratio [INR] ≤ 1.5 × the upper limit of normal [ULN]). (Note: the criteria for adequate hematological function must be met without erythropoietin dependency, use of growth factors, or the requirement for transfusions of blood, coagulation factors, platelets, or albumin within 14 d of Treatment Day 1.)
• Patients with adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) levels of ≤ 5 × the ULN, and a total bilirubin level ≤ 1.5 × the ULN (patients with documented Gilbert disease are allowed to participate in the study if their total bilirubin level is ≤ 3 × the ULN).
• Patients with adequate renal function, defined as an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min or an estimated creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula).
• Women with childbearing potential (WOCBP)

• Must have a negative serum human chorionic gonadotropin pregnancy test in the Screening Period.
• Are using highly effective contraception, are not lactating, and agree not to become pregnant during the trial treatment period and for 187 days after treatment with the investigational drug.
• Men agree not to donate sperm or to father a child during the trial treatment period and for 97 days after treatment with the investigational drug.

Exclusion criteria

• Patients from vulnerable populations (incapacitated or unconscious individuals, persons deprived of liberty).
• Patients with a known allergic reaction or hypersensitivity to shellfish, crabs, crustaceans, or any components used in trial treatment.
• Patients with any prior treatment with IP-001 for Injection in a different clinical trial.
• Patients who underwent any surgical liver resection, hepatic ablation or other hepatic locoregional therapy for CRLM within 3 months before Treatment Day 1; patients who received any other medical procedure, SACT, or treatment with any other investigational anticancer agents within 14 days before Treatment Day 1, or patients who at study enrollment have plans to receive SACT or locoregional therapies/procedures prior to intrahepatic or extrahepatic progression.
• Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 d of randomization. Inhaled or topical steroids and adrenal replacement steroid doses (> 10 mg daily prednisone equivalent) are permitted in the absence of active autoimmune disease.
• Patients who at screening have not recovered back to baseline or ≤ Grade 1 per National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) guidelines v6.0 from ongoing conditions related to any prior medicinal or procedural treatments (including major surgery) except for residual toxicities, unless conditions are deemed clinically non-significant by the Investigator and/or stable on supportive therapy (in consultation with Sponsor Medical Monitor), such as alopecia or Grade 2 neuropathy.
• Patients with any extrahepatic nodal or non-nodal CRC metastases, except:

• History of infiltrated regional lymph nodes associated with the primary tumor if these lymph nodes were removed together with the primary tumor.
• Pulmonary nodules unless they are considered suspect for metastases because they show at least one of the following characteristics:

i. new or increasing in size (at least 20% increase in longest diameter) in the last 12 mo; ii. unequivocal 18F-FDG tracer-uptake on PET; iii. solitary nodule >1 cm; iv. 2 - 5 nodules with at least 1 ≥ 0.8 cm; v. more than 5 nodules (excluding nodules that are stable in size over at least 1 y).

• Patients with a history of another active malignancy within 2 years prior to Treatment Day 1, except for superficial skin cancers or localized, low-grade tumors deemed cured and not treated with systemic therapy. Patients with incidental prostate cancer may enroll if Stage ≤ T2N0M0 and Gleason score ≤ 6.
• Patients with bleeding diathesis or anti-coagulation treatment that cannot be stopped 24 hours prior to Treatment Day 1 (low-dose aspirin will be allowed).
• Patients who have one of the following cardiovascular disorders:

• Severe or uncontrolled cardiovascular disease (congestive heart failure New York Heart Association classification III or IV), or
• Unstable angina pectoris or a history of myocardial infarction within the last 6 mo, or
• Serious arrhythmias requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia), or
• Significant QT-prolongation (QTcF ≥ 480 msec on screening electrocardiogram [ECG] [QTcF interval is not relevant in patients with pacemaker-controlled arrythmia]), or
• Uncontrolled hypertension, defined as a resting systolic blood pressure > 150 mmHg and/or resting diastolic blood pressure > 90 mmHg, which cannot be controlled by anti-hypertensive therapy.
• Patients with any of the following infections/diseases:

• Known history of human immunodeficiency virus infection,
• Known active Hepatitis B or C viral infection,
• Any uncontrolled active systemic infection requiring intravenous antimicrobial treatment during screening,
• Any active, known, or suspected autoimmune disease.
• Patients with a requirement for hemodialysis or peritoneal dialysis.
• Patients with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan or cavitating pulmonary lesion(s) or a known endobronchial disease manifestation.
• Patients who received a live, attenuated vaccine within 28 days of Treatment Day 1.
• Patients with any other serious underlying medical, psychological, familial, or geographical condition that, in the judgment of the Investigator, may limit compliance with the study or place the patient at high risk for treatment-related complications.