Study of BO-112 With Pembrolizumab for Colorectal or Gastric/GEJ Cancer With Liver Metastasis

Study Overview
=================
Brief Summary
-----------------
This is an open, single arm, multicenter phase 2 trial in which BO-112 will be administered intratumorally in combination with intravenous pembrolizumab in patients with liver metastasis from colorectal, gastric or gastroesophageal junction cancers. The objective is to reverse the primary resistance that a subgroup of patients from these tumors having microsatellite stability present to the PD-1 inhibitors. Treatment will be administered every 3 weeks, with the exception of the first cycle, in which BO-112 will be also administered on D8, for up to 2 years. The primary objective is overall response rate based on RECIST 1.1 and safety, specifically referred to treatment emergent adverse events (TEAEs) with severity ≥ Grade 3 related to the study treatment (NCI-CTCAE v 5.0). The secondary endpoints include other efficacy endpoints (duration of response, disease control rate, progression-free survival, overall survival at 6 months, all based on RECIST 1.1, and overall response rate based on a specific tumor assessment criteria to evaluate the response to immunotherapies, IRECIST) and safety, in this case considering the number and proportion of subjects with treatment TEAEs (any grade) . In addition, the changes in the tumor microenvironment induced by the injection of BO-112 will be also evaluated as exploratory endpoints.

Detailed Description
-----------------
The purpose of this Phase II study is to evaluate the safety, tolerability, antitumoural activity and systemic exposure of repeated IT administrations of BO-112 percutaneously injected into a hepatic metastatic lesion in combination with pembrolizumab administered intravenously. This is an open-label, non-comparative, 2-cohort study with a Simon's 2-stage design which will include up to 69 evaluable adult subjects with un resectable liver metastasis suitable for IT injection from CRC or GC/GEJ who are naive to anti-PD1/PDL1 therapy. Cohort A will consist of up to 26 subjects with metastatic CRC who have received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Bevacizumab may have been previously administrated. Prior Anti-EGFR drugs are mandatory if applicable depending on the RAS status. Cohort B will consist of up to 43 subjects with gastric or GC/GEJ who have received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease. Prior Her2 blockade will be mandatory in those patients with Her2 positive tumors. The aim of this study is to reverse the primary resistance that the subgroup of patients from these 2 cohorts who present microsatellite stability (MSS), in which data from previous clinical trials have demonstrate that the inhibition of PD-1 has no proven efficacy. For that purpose, the MSI status will be determined in the pre-treatment biopsy, done on C1D1, before the first BO-112 administration. Those patients with a MSI status will continue under study treatment but will be replaced and will not be considered for the efficacy assessment, only for the safety assessment. Those patients having a MSS status will be considered bot both assessments. The recommended dose for further clinical development of BO-112 is 1 mg administered in 1.7 mL volume, based on the data from the 112/2016-IT study, the fist-in-human trial with BO-112. The planned dose of pembrolizumab for this study is 200 mg. Study treatment will consist of BO-112 IT injections in combination with IV pembrolizumab infusions and will be administered in 3-week cycles. For each cycle, BO-112 IT injections will be administered after the pembrolizumab infusion, either the same day or within a period of up to 36 hours after the pembrolizumab infusion (for organisational feasibility at the site). On the first cycle, BO-112 will be administered on D1 and D8. The BO-112 IT injections will be administered by an interventional radiologist under ultrasound guidance, or occasional CT scan guidance, at the discretion of the interventional radiologist. Study treatment should continue as long as there is clinical benefit and it is tolerated, up to a maximum of approx. 2 years (corresponding to 35 treatment cycles).

Official Title
-----------------
Phase IIa Open-label Clinical Study of Intratumoural Administration of BO-112 in Combination With Pembrolizumab in Subjects With Liver Metastasis From Colorectal Cancer or Gastric/Gastro-oesophageal Junction Cancer

Conditions
-----------------
Colorectal Cancer, Gastric Cancer, Oesophageal Cancer

Intervention / Treatment
-----------------
* Procedure: Hepatic Biopsy
* Drug: BO-112 with Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Nonresectable liver metastasis(es) of colorectal or gastric/gastro-oesophageal junction cancer (GC/GEJ). History of resection for liver metastasis is allowed. Histological or cytological proof of colorectal (Cohort A) or GC/GEJ cancer (Cohort B). Progression during or after, or have not tolerated therapy for advanced/metastatic disease as follows: Cohort A (CRC): at least 2 lines of fluoropyrimidine, irinotecan and/or oxaliplatin containing therapy with or without bevacizumab; if epidermal growth factor receptor (EGFR) positive/RAS wild type, prior anti-EGFR treatment is required. Incase of prior resection of hepatic metastasis with hepatic recurrence, only 1 prior line of fluoropyrimidine, irinotecan and/or oxaliplatin containing therapy is required. Cohort B (GC/GEJ): fluoropyrimidine and platinum containing treatment; if Human epidermal growth factor receptor 2 (HER-2) positive, also prior anti-HER-2 treatment is required. At least 1 liver metastasis of minimum 20 mm in diameter that is suitable for percutaneous, IT injection . Presence of at least 1 measurable lesion according to RECIST v1.1. Note: this may be the liver metastasis selected for injection if it is the only measurable lesion present. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate haematologic and end-organ function EXCLUSION CRITERIA Prior treatment with an anti-PD1, anti-PDL1 or anti-PDL2 agent, an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137) or any Toll-like receptor (TLR) agonist. Liver metastasis(es) with macroscopic tumour infiltration into the main portal vein, hepatic vein or vena cava. Contraindications to tumour biopsy and injections of the hepatic metastasis(es). Chemotherapy, definitive (curative) radiation, or biological cancer therapy within 4 weeks prior to the first dose of study treatment. Palliative radiotherapy (≤ 2 weeks of radiotherapy) within 1 week of start of study treatment. Clinically active central nervous system (CNS) metastases and/or carcinomatosis meningitis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, non-comparative study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>The study treatment consists of the combination of BO-112 given intratumorally inside the liver metastasis at the dose of 1gm in 1.2 mL in combination with intravenous pembrolizumab given at the fixed dose of 200 mg. This treatment will be given every 3 weeks, with a maximum duration of 35 cycles (2 years). Of note, during the first cycle, BO-112 will be administered on D1 and D8. | Procedure: Hepatic Biopsy<br>* In this trial a biopsy from the hepatic lesion to be injected will be mandatory on C1D1 and C2D1, prior to the BO-112 administration. On the same timepoints, a biopsy from a non-hepatic, non-injected lesion will be optional.<br>Drug: BO-112 with Pembrolizumab<br>* . The study treatment consists of the combination of BO-112 given intratumorally inside the liver metastasis at the dose of 1gm in 1.2 mL in combination with intravenous pembrolizumab given at the fixed dose of 200 mg. This treatment will be given every 3 weeks, with a maximum duration of 35 cycles (2 years). Of note, during the first cycle, BO-112 will be administered on D1 and D8.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumour efficacy:overall response rate | ORR based on the BOR using RECIST 1.1 of repeated IT administrations of BO-112 in metastatic liver lesions in combination with IV pembrolizumab | Throughout study completion, an average of 3 years. | 
| Safety: Adverse Events | Number and proportion of subjects with study treatment-related TEAEs with severity Grade 3 (NCI-CTCAE v 5.0) | Throughout study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate | Best response for CR, PR as well as stable disease (SD) using RECIST 1.1 | Throughout study completion, an average of 3 years | 
| Objective response rate | Based on best overall response using RECIST modified for immune-based therapies (iRECIST) | Throughout study completion, an average of 3 years | 
| Disease Control Rate | Comprising best response for CR, PR as well as SD using iRECIST | Throughout study completion, an average of 3 years | 
| Duration of response | Duration of response | Up to 36 months | 
| PFS | Progression-free survival | Up to 36 months | 
| Survival Rate | Overall Survival Rate | Up to 36 months |