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| ID | Type | Description | Link |
|---|---|---|---|
| 2019-004624-38 | EudraCT Number | ||
| KEYNOTE-A06 | Other Identifier | Merck Sharp & Dohme LLC |
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Low recruitment rate
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort A | Experimental | Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study. BO-112 was administered in the liver metastasis at the dose of 1mg (1.2 mL) in combination with intravenous pembrolizumab given at the fixed dose of 200 mg, every 3 weeks for up to 35 cycles (2 years). During the first cycle, BO-112 was administered on D1 and D8. |
|
| Cohort B | Experimental | Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease. BO-112 was administered in the liver metastasis at the dose of 1 mg (1.2 mL) in combination with intravenous pembrolizumab given at the fixed dose of 200 mg, every 3 weeks for up to 35 cycles (2 years). During the first cycle, BO-112 was administered on D1 and D8. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hepatic Biopsy | Procedure | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Anti-tumour Efficacy:Overall Response Rate (ORR) Based on RECIST 1.1 | ORR based on the best objective response (BOR) using RECIST 1.1 of repeated IT administrations of BO-112 in metastatic liver lesions in combination with IV pembrolizumab | from baseline to approximately 8 months |
| Safety: Adverse Events | Number and proportion of subjects with study treatment-related TEAEs with severity Grade 3 and higher (NCI-CTCAE v 5.0) | from baseline to approximately 8 months |
| Measure | Description | Time Frame |
|---|---|---|
| Disease Control Rate Based on RECIST 1.1 | Best response for CR, PR as well as stable disease (SD) using RECIST 1.1 | from baseline to approximately 8 months |
| Objective Response Rate Based iRECIST |
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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:
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
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| Name | Affiliation | Role |
|---|---|---|
| Vanesa Pons, MD, PhD | Highlight Therapeutics | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Institut Jules Bordet | Brussels | Belgium | ||||
| UCL St-Luc |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35623069 | Derived | Chang X, Ge X, Zhang Y, Xue X. The current management and biomarkers of immunotherapy in advanced gastric cancer. Medicine (Baltimore). 2022 May 27;101(21):e29304. doi: 10.1097/MD.0000000000029304. |
| Label | URL |
|---|---|
| Company web site | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort A | Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 15, 2021 |
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Open-label, non-comparative study.
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| BO-112 with pembrolizumab | Drug | BO-112 was administered in the liver metastasis at the dose of 1mg (1.2 mL) in combination with intravenous pembrolizumab given at the fixed dose of 200 mg, every 3 weeks for up to 35 cycles (2 years). During the first cycle, BO-112 was administered on D1 and D8. |
|
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Based on best overall response using RECIST modified for immune-based therapies (iRECIST)
| from baseline to approximately 8 months |
| Disease Control Rate Based on iRECIST | Comprising best response for CR, PR as well as SD using iRECIST | from baseline to approximately 8 months |
| Progression-free Survival | Progression-free survival (PFS) | from baseline to approximately 8 months |
| Overall Survival Rate | Number of subjects alive at 6 months | at 6 months from enrolment |
| Brussels |
| Belgium |
| University Hospital Antwerp (UZA) | Edegem | Belgium |
| Universitair Ziekenhus Gent | Ghent | Belgium |
| IRCCS Ospedale Policlinico San Martino | Genova | Italy |
| Azienda Ospedaliera Ospedale Niguarda Ca'Granda | Milan | Italy |
| Hospital Reina SofÃa | Córdoba | Cordoba | Spain |
| Hospital Valle Hebrón | Barcelona | Spain |
| Hospital Gregorio Marañón | Madrid | Spain |
| Hospital Ramón y Cajal | Madrid | Spain |
| ClÃnica Universitaria de Navarra | Pamplona | Spain |
| Hospital ClÃnico de Valencia | Valencia | Spain |
| FG001 | Cohort B | Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort A | Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study. |
| BG001 | Cohort B | Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Anti-tumour Efficacy:Overall Response Rate (ORR) Based on RECIST 1.1 | ORR based on the best objective response (BOR) using RECIST 1.1 of repeated IT administrations of BO-112 in metastatic liver lesions in combination with IV pembrolizumab | Cohort B: only 5 patients were evaluable for efficacy with one baseline and at least one on treatment efficacy assessment. | Posted | Count of Participants | Participants | from baseline to approximately 8 months |
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| |||||||||||||||||||||||||||||
| Primary | Safety: Adverse Events | Number and proportion of subjects with study treatment-related TEAEs with severity Grade 3 and higher (NCI-CTCAE v 5.0) | Posted | Count of Participants | Participants | from baseline to approximately 8 months |
|
| |||||||||||||||||||||||||||||||
| Secondary | Disease Control Rate Based on RECIST 1.1 | Best response for CR, PR as well as stable disease (SD) using RECIST 1.1 | Cohort B: only 5 patients were valid for efficacy with one baseline and at least one on-treatment efficacy assessment | Posted | Count of Participants | Participants | from baseline to approximately 8 months |
|
| ||||||||||||||||||||||||||||||
| Secondary | Objective Response Rate Based iRECIST | Based on best overall response using RECIST modified for immune-based therapies (iRECIST) | Posted | Count of Participants | Participants | from baseline to approximately 8 months |
|
| |||||||||||||||||||||||||||||||
| Secondary | Disease Control Rate Based on iRECIST | Comprising best response for CR, PR as well as SD using iRECIST | Cohort B: only 5 patients were evaluable for efficacy with one baseline and at least one on-treatment efficacy assessment | Posted | Count of Participants | Participants | from baseline to approximately 8 months |
|
| ||||||||||||||||||||||||||||||
| Secondary | Progression-free Survival | Progression-free survival (PFS) | Cohort B: only 5 patients were evaluable for efficacy with one baseline and at least one on-treatment assessment | Posted | Median | Inter-Quartile Range | months | from baseline to approximately 8 months |
|
| |||||||||||||||||||||||||||||
| Secondary | Overall Survival Rate | Number of subjects alive at 6 months | only 5 patients were evaluable for efficacy with both baseline and at least one post-baseline imaging | Posted | Count of Participants | Participants | at 6 months from enrolment |
|
from baseline to approximately 8 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort A | Cohort A consisted of 11 patients with CRC (microsatellite stable [MSS]) with nonresectable liver metastases suitable for IT injection and who had received at least 2 prior standard of care systemic anticancer therapies for advanced/metastatic disease. Patients who had resection of hepatic metastases and had hepatic recurrence, needed to have 1 or more prior standard of care systemic anticancer therapies in order to be eligible for this study. | 2 | 11 | 5 | 11 | 11 | 11 |
| EG001 | Cohort B | Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease. | 2 | 7 | 2 | 7 | 7 | 7 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| back pain | Musculoskeletal and connective tissue disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| pyrexia | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| alpha hemolytic streptococcal infection | Infections and infestations | NCI CTCAE 4.03 | Systematic Assessment |
| |
| COVID 19 pneumonia | Infections and infestations | NCI CTCAE 4.03 | Systematic Assessment |
| |
| bacteriemia | Infections and infestations | NCI CTCAE 4.03 | Systematic Assessment |
| |
| syncope | Nervous system disorders | NCI CTCAE 4.03 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| pyrexia | General disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Hypertension | Vascular disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Hypotension | Vascular disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Asthenia | General disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Chills | General disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Fatigue | General disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Injection site pain | General disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Cytokine release syndrome | Immune system disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | NCI CTCAE 4.03 | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Blood alkaline phosphatase increased | Investigations | NCI CTCAE 4.03 | Systematic Assessment |
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| Blood lactate dehydrogenase increased | Investigations | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Gamma-glutamyltransferase increased | Investigations | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Headache | Nervous system disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Presyncope | Nervous system disorders | NCI CTCAE 4.03 | Systematic Assessment |
| |
| Tremor | Nervous system disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Syncope | Nervous system disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Anemia | Blood and lymphatic system disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Eczema eyelids | Eye disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Abdominal discomfort | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Dysphagia | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Hepatic pain | Hepatobiliary disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Hepatomegaly | Hepatobiliary disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Disuria | Renal and urinary disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Hematuria | Renal and urinary disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Hyperthyroidism | Endocrine disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Groin pain | Musculoskeletal and connective tissue disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | NCI CTCAE 4.03 | Systematic Assessment |
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| Asymptomatic COVID-19 | Infections and infestations | NCI CTCAE 4.03 | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marisol Quintero | Highlight Therapeutics S.L. | +34 961 10 99 55 | mquintero@highlighttherapeutics.com |
| Feb 2, 2024 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D013274 | Stomach Neoplasms |
| D004938 | Esophageal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D013272 | Stomach Diseases |
| D006258 | Head and Neck Neoplasms |
| D004935 | Esophageal Diseases |
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| ID | Term |
|---|---|
| C000727548 | BO-112 |
| C582435 | pembrolizumab |
Not provided
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| >=65 years |
|
| Male |
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| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
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| White |
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| More than one race |
|
| Unknown or Not Reported |
|
| Italy |
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| Spain |
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Cohort B consisted of 7 patients with gastric or GC/GEJ with nonresectable liver metastases suitable for IT injection and who had received at least 1 prior standard of care systemic anticancer therapy for advanced/metastatic disease. BO-112 was administered in the liver metastasis at the dose of 1 mg (1.2 mL) in combination with intravenous pembrolizumab given at the fixed dose of 200 mg, every 3 weeks for up to 35 cycles (2 years). During the first cycle, BO-112 was administered on D1 and D8. Hepatic Biopsy: 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. BO-112 with pembrolizumab: BO-112 was administered in the liver metastasis at the dose of 1mg (1.2 mL) in combination with intravenous pembrolizumab given at the fixed dose of 200 mg, every 3 weeks for up to 35 cycles (2 years). During the first cycle, BO-112 was administered on D1 and D8. |
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