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Participants received 1mg RO7119929 every week in 3-week cycles.

Participants received 4 mg RO7119929 every week in 3-week cycles

Participants received 6 mg RO7119929 every week in 3-week cycles

Participants received 9 mg RO7119929 every week in 3-week cycles

Participants with both available and evaluable tumor biopsy samples received 5 mg RO7119929 on Cycle 1 Day 1 to month 12

Participants received RO7119929 QW with step-up dosing of 2/5/5 mg during Cycle 1.

Participants received RO7119929 QW with step-up dosing of 2/5/6 mg during Cycle 1.

Participants received tocilizumab pre-treatment on Cycle 1 Day 1, approximately 2 hours prior to RO7119929 administration and 4 mg RO7119929 every week in 3-week cycles

RO7119929 will be administered orally as a capsule

RO7119929

Tocilizumab will be administered in case of severe steroid-refractory cytokine release syndrome.

Tocilizumab will be administered as concentrate for solution for IV infusion at a dose: for participants \> 30 kg: 8 mg/kg, for participants \< 30 kg: 12mg/kg IV

Tocilizumab

Clinical Trials

Phase I study of RO7119929 given orally to participants with unresectable advanced or metastatic primary liver cancers and other solid tumors with predominant liver involvement. The primary objective of the study is to explore the safety and to determine the maximum tolerated dose (MTD) and/or optimal biologic dose (OBD) of RO7119929 as single agent.

Open label, multi-center, single-arm, multiple-ascending dose escalation

A Study Evaluating Safety, Pharmacokinetics, Pharmacodynamics, And Clinical Activity Of RO7119929 (TLR7 Agonist) In Participants With Unresectable Advanced Or Metastatic Hepatocellular Carcinoma, Biliary Tract Cancer, Or Solid Tumors With Hepatic Metastases

A First In Human, Open Label, Dose Escalation Phase I Study Evaluating Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Clinical Activity Profile Of Single Agent RO7119929 (TLR7 Agonist) Administered Orally To Participants With Unresectable Advanced Or Metastatic Hepatocellular Carcinoma, Biliary Tract Cancer, Or Solid Tumors With Hepatic Metastases

Hoffmann-La Roche

Primary Liver Cancer

Hematinics

Liver Extracts

Patients in experimental group will perform a 6 weeks' physical activity program with 3 sessions per week. Physical activity intervention will consist in 2 different interval training programs on cycloergometer: Interval training 1 and Interval training 2, with a difference in exercise intensities.

Interval training

Patients in control group will follow the standard oncologic care. They will perform only 2 sub-maximal exercises.

Standard Oncologic care

The aim of this study is to assess the impact of preoperative physical activity on physical capacities of patients undergoing liver resection for primary or secondary liver cancer.

The purpose of this study is to investigate the effects of a preoperative exercise program in patients with primary or secondary liver cancer undergoing hepatectomy. Preoperative exercise programs have been shown to be effective in other cancer populations, but have been poorly studied in patients with liver cancer. For these patients, it remains unclear what the optimal composition of such programs should be and how they should be delivered. Outcome measures in this study will include preoperative outcomes (oxygen consumption, quality of life, fatigue and physical activity level, anthropometric measures, plasma concentrations of hepatokines) and postoperative outcomes (length of hospital stay and postoperative complications).

After the study is explained and consent obtained, subjects will be tested on a submaximal exercise on cycloergometer with gas exchanges analysis and with pre and post blood test. Then, they will answer various questionnaires assessing physical activity, quality of life and fatigue.

Patients scheduled for liver resection will be randomized to one of two groups. The first group (experimental group) will be subdivided into two groups: interval training 1 and interval training 2, which differentiate themselves by two different intensities.The second group (control group) will receive standard care.

The prehabilitation program will last 6 weeks with 3 sessions per week and will consist in two interval training programs on a cycloergometer with two different intensities.

One month after surgery, peri and postoperative complications will be noted.

Preoperative Physical Activity Intervention in Patients Before Planned Liver Resection for Cancer (APACHE)

Preoperative Physical Activity Intervention in Patients Before Planned Liver Resection for Cancer

Oxygen consumption at anaerobic threshold will be assessed at baseline and at the end of the 6 weeks' program with a submaximal exercise performed on cycloergometer

Postoperative complications will be assessed using the Dindo Clavien classification which consists in a 7 grades classification (I, II, IIIa, IIIb, IVa, IVb and V).

Postoperative intensive care stay will be evaluated (number of days).

Fetuin A (ng/mL) concentrations will be analyzed.

Fibroblast Growth Factor 21 (FGF21) (pg/mL) concentrations will be analyzed.

Physical activity level will be measured using the long-form of the International Physical Activity Questionnaire (IPAQ). It consist in a description of the physical activity level by assessing 5 activity domains during the 7 last days. Physical activity level is expressed in Metabolic Equivalent Tasks (METs). It enables to classify patients in 3 categories : low physical activity level, moderate physical activity level and high physical activity level.

Health related quality of life will be measured with the EORTC Quality of Life Questionnaire QLQ-C30 which is a cancer specific questionnaire. It consists in 30 items to measure 15 dimensions of quality of life. It generates a score between 0 and 100. A higher score means a higher quality of life level.

Fatigue will be measured with the Quality of Life Questionnaire QLQ-FA12 which enables to assess cancer related fatigue. It consists in 12 items to measure 5 dimension go health related fatigue. It generates a score between 0 and 100. A higher score means a higher fatigue level.

Célia Turco

Principal Investigator

The CLINIPORATOR is used to perform percutaneous electrochemotherapy on liver tumours.

CLINIPORATOR

Claire Poulet, PhD

Nathalie Kaufmann, MSc

Kathrin Klasic

Lukas Luerken, Dr

Philipp Wiggermann, Prof. Dr.

Attila Kovacs, PD. Dr. med.

The Registry on Percutaneous ElectroChemoTherapy (RESPECT) is a post-market, prospective, non-randomized, observational study aiming at evaluating the effectiveness of percutaneous electrochemotherapy (ECT) for the treatment of liver cancer.

Electrochemotherapy (ECT) is a local tumour ablation technique that uses reversible electroporation to transiently permeabilize the cell membrane in order to increase the cytotoxicity of chemotherapeutic drugs. A major advantage of ECT is that its antitumour efficacy is driven by the chemotherapeutic agent which predominantly targets rapidly-dividing tumour cells, with very little collateral damage on neighbouring structures.

ECT is typically performed using the CLINIPORATOR®, a medical grade pulse generator for clinical electroporation, whose development was funded by the European Commission in an effort to standardize the operating procedures for ECT. The feasibility, safety and efficacy of ECT with the CLINIPORATOR® have been consistently reported for the management of different types of primary and secondary liver cancers: colorectal liver metastasis, hepatocellular carcinoma, portal vein tumour thrombosis from hepatocellular carcinoma, perihilar cholangiocarcinoma and liver metastasis from renal cancer.

While ECT for liver malignancies has been mostly performed intraoperatively, recent studies have successfully used a percutaneous approach. These studies, which were either single-case reports or involved a very limited number of patients (\< 10), have introduced percutaneous ECT as a very promising minimally invasive treatment option for liver cancer, with the obvious benefits of fewer surgical complications, faster recovery and shorter hospitalization. However, results from a larger and more diverse patient population are needed in order to confirm its therapeutic efficacy.

The aim of the RESPECT study is to expand our understanding of percutaneous ECT for primary and secondary liver cancer by 1) substantiating the evidence base for the effectiveness and safety of percutaneous ECT in a large-scale, multi-centric, cross-border sample; and 2) extending the current evidence base regarding percutaneous ECT with appropriately defined follow-up data, as well as information regarding quality of life.

RESPECT is a post-market, prospective, non-randomized, observational study. Patients with any type of liver cancer will be given the possibility to enrol after they are referred to percutaneous ECT by a multidisciplinary tumour board, hence participation to the registry neither affects treatment plan nor influence treatment quality. Patient enrolment will last 2 years, with a follow-up period of maximum 3 years. Data will be collected less than 1 week before treatment (baseline) and at different intervals following treatment (1 day, 2 weeks, 1 month, 3 months, 6 months, 12 months, and every 6 months until the end of the study). Effectiveness of ECT will be primarily assessed by the status of each treated lesion 12 months after ablation. Overall survival, overall local disease-free survival, hepatic disease-free survival, time to untreatable progression by ECT and vacation from systemic cancer therapy will give further insight into the impact of ECT. Safety will be evaluated based on the occurrence and severity of adverse events associated with the treatment. Quality of life and pain will be documented using questionnaires filled by the patients at the first 3 to 4 follow-ups.

Overall, RESPECT intends to provide healthcare professionals and health authorities with information on percutaneous ECT for liver cancer to help decision-making regarding treatment access and treatment modalities and optimize patient care.

Registry on Percutaneous Electrochemotherapy

Based on the tumour status according to mRECIST assessment

Based on the occurrence of adverse events and their severity according to CTCAE v5.0

Based on the Quality of Life questionnaire EORTC QLQ-C30 filled by the patients before ECT treatment and at different time intervals following ECT treatment.

Quality of life data is measured according to three scales: functional scale, symptom scale and global health. On the functional scale, scores range from 1 to 4, with a score of 1 corresponding to no at all and a score of 4 corresponding to very much. On the symptom scale, scores range from 1 to 4, with a score of 1 corresponding to no at all and a score of 4 corresponding to very much.

For global health, the scores range from 1 to 7, with a score of 1 corresponding to either very poor global health or very poor quality of life, and a score of 7 corresponding to either excellent global health or excellent quality of life.

Based on the pain questionnaire filled by the patients before ECT treatment and at different time intervals following ECT treatment.

Severity of pain is graded on a scale from 0 to 10, with 10 corresponding to the most severe pain. Pain frequency is graded from 0 (no pain) to 4 (chronic pain persistent for more than 3 months). Quality of pain is classified into 4 categories: no, somatic, visceral and neuropathic pain.

Survival will be categorized with respect to overall survival, overall local disease-free survival and hepatic disease-free survival

Based on the timeframe until the progressing tumour is not treatable by ECT anymore

Based on the time frame following ECT treatment during which patients do not need systemic cancer therapy

Based on the duration of hospitalization following ECT treatment

Cardiovascular and Interventional Radiological Society of Europe

Cholangiocarcinoma

Bile Duct Neoplasms

Bile Duct Diseases

Bile Duct Cancer

Selected patients who choose to participate will undergo ablation of the target lesion using irreversible electroporation.

The IRE procedure will be carried out as ultrasound guided technique either percutaneously or during laparotomy. Needle spacing and electrical pulse delivery will be performed in a standardized way.

Irreversible electroporation

Ole Thorlacius-Ussing, Professor, DMSc

The aim of this study is to evaluate the safety and feasibility of curative intended irreversible electroporation (IRE) in the treatment of liver tumors neighboring major vessels or bile ducts.

Patients can be included in the study if they have one or more malignant liver tumors unsuitable for resection and thermal ablation (due to proximity of major vessels or bile duct) or other established liver directed therapies.

Prior to inclusion all potential participant will be evaluated by the local multidisciplinary team, to insure fulfillment of the above-mentioned criteria. In general, the included patient will have tumors with \<1 cm of margin to major hepatic vessels or bile ducts, thereby not allowing for conventional treatments because of risk of i.e. hemorrhage, biliary tract damage, liver failure or ineffective ablation due to heat sink.

IRE will be done under general anesthesia as an in-patient procedure. Patients will be observed for at least 24 hours after IRE.

Patients will attend CT scans 1, 3, 6, 9, 12, 18, 24, 36, 48 and 60 months post-IRE according to national guidelines (for follow-up after radiofrequency ablation (RFA)). Patients will attend the out-patient clinic after 1, 3, 6, 9, 12, 18 and 24 months. During the follow-up period, patients will be asked to fill out electronic forms monitoring pain, quality of life and nutritional status. After 24 months the patients will only be followed with CT scans in accordance with the mentioned schedule. Data collection for scientific purposes will stop when the last included patient has been followed for at least 24 months or when the study period concludes.

In case of multiple liver tumors, where a conventional treatment approach is not possible due to a single lesion being too close to major vessels or bile ducts, IRE may be used in conjunction to conventional therapy.

Irreversible Electroporation of Unresectable Liver Tumors

Irreversible Electroporation of Unresectable Liver Tumors - a Phase I Study of Safety and Feasibility

Adverse events will be registered and scaled according to the Clavien-Dindo classification.

The rate of patients were it is possible to place needles according to the treatment plan and deliver 90 electrical pulses per electrode pair

The rate of patients showing no residual tumor on contrast enhanced computed tomography (ceCT)

The median time from the intervention to progressive disease of the treated lesion, according to RECIST 1.1 or modified RECIST (mRECIST) (only for HCC).

The median time from the intervention to death.

Quality of life questionnaire - Core 30 is used to assess the quality of life in the included patients. Raw scores will be calculated according to the manual. Items will be grouped in: Global health status (range 0 - 100, high is good), Functional scales (range 0 - 100, high is good) and symptom scales (range 0 - 100 low is good). Differences in each scales during the course of the trial will be calculated separately.

Long term pain will be assessed using the modified Danish version of the Brief Pain Inventory - short form. The outcomes assessed will be an average score of pain severity items and interference items in accordance with the manual. The scales range from 0 to 10 (lower is less pain).

Perioperative pain will be scores using the visual analogue pain scale (range 0 - 10, low score is less pain).

Physicians assessment of global functioning using the "Eastern Cooperative Oncology Group" performance status scale (range 0 - 5, low score is better)

Nutritional status assessment using the Scored Patient-Generated Subjective Global Assessment (short form). The short form includes only patient reported measures and will be combined into a single score according to the manual (range 0 - 37, low score is better).

Ole Thorlacius-Ussing, MD, DMSc, Professor of Surgery

Professor of surgery, Consultant surgeon, DMSc

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Irinotecan

Oxaliplatin

Immunoglobulins

Topoisomerase I Inhibitors

Enzyme Inhibitors

Radiofrequency ablation in conjunction with chemotherapy

The RF3000 radiofrequency generator has the capacity to deliver 200 watts of alternating current to the needle electrode for the coagulation necrosis of soft tissue.

Radiofrequency Ablation (RFA)

Chemotherapy

William Jacqmein

The purpose of this study is to determine whether patients treated with Radiofrequency Ablation (RFA) in conjunction with chemotherapy have a better overall survival rate than patients treated with chemotherapy alone.

The American Cancer Society has estimated that colorectal cancer is the second leading cause of cancer related deaths, with 106,370 new cases diagnosed in 2004. Due to the unique nature of the hepatic circulatory system, with preferential portal venous drainage of the gastrointestinal tract, the liver is the most common site for metastatic tumor growth from a colorectal carcinoma. It is estimated that approximately 20% of patients diagnosed with colorectal cancer will present with liver involvement at the time of diagnosis, and 50% of patients will manifest metastatic involvement of the liver following resection of the primary colorectal cancer. Over one half of patients who die of colorectal cancer have liver metastases at autopsy.

The current "gold standard" in the treatment of isolated metastatic liver disease is curative hepatic resection. Only within the last 20 years has surgical resection become a viable option, as in the past it was considered unjustified due to high morbidity and mortality rates. The primary drawback to hepatic resection is the sheer number of patients for whom it is contraindicated. Only 10-20% of patients liver metastases are candidates for surgical resection, owing to factors such as tumor locations, size, extent of disease, and other medical co-morbidities.

Historically, in cases where hepatic resection was contraindicated, systemic chemotherapy was the only alternative treatment. In the last several years an increasing number of hepatic directed therapies have become available such as hepatic artery ligation, radiation, hepatic artery infusion of chemotherapy, chemoembolization, and mechanical ablation of the tumor(s).

One mechanical method of ablation involves the use of radiofrequency thermal technology, also called radiofrequency ablation (RFA). The RFA procedure involves inserting an RF electrode into the center of a hepatic tumor mass under ultrasonic or CT guidance. Radiofrequency energy is then applied through the electrode, causing a thermal injury to the surrounding tumor tissue. Currently there are two basic designs for monitoring inter-procedural progress during RFA; temperature monitoring of set points within the target tissue with thermocouples, or assessing the system-wide impedance of tissue adjacent to the deployed electrode tines. Radiofrequency ablation systems are comprised of three components: a radiofrequency generator, an active electrode, and dispersive electrodes.

To date no prospective multi-center trials have been completed which would conclusively demonstrate whether RFA is an effective adjunct to systemic chemotherapy with respect to advantages in median overall survival compared with chemotherapy alone. The primary objective of this trial is to determine overall survival for subjects with colorectal cancer and incurable metastatic liver disease who fail at least first line chemotherapy and are treated with radiofrequency ablation plus additional chemotherapy, compared to subjects receiving additional chemotherapy only.

Study Comparing Radio Frequency Ablation Plus Chemotherapy and Chemotherapy Alone in Patients With Secondary Liver Metastases

A Prospective, Randomized, Active-Control, Multi-Center Study Assessing Overall Survival Using Chemotherapy With or Without Impedance-Based Radiofrequency Ablation for Subjects With Colorectal Cancer and Incurable Metastatic Liver Disease, Failing at Least First-Line Chemotherapy

Boston Scientific Corporation

All patients will receive liver SABR. Kilovoltage Intrafraction Monitoring (KIM) tracking will be trialed during mock treatment. If KIM is successful, it will be used throughout treatment. If unsuccessful, cone beam CT will be used instead.

KIM is a novel intrafraction real-time tumour localization method. It involves a single gantry-mounted kV x-ray imager acquiring 2D projections of implanted fiducial markers. 3D positions are then reconstructed by maximum likelihood estimation of a 3D probability density function.

Kilovoltage Intrafraction Monitoring

Tim Wang, Dr

Primary and secondary liver cancer patients will receive liver SABR with or without KIM intervention.

This is a single arm, phase II, two stage study designed to evaluate cancer targeting accuracy, treatment outcomes and treatment efficiency in 46 patients eligible for SABR for either primary or secondary liver malignancy with the incorporation of KIM.

Liver Ablative Radiotherapy Utilising Kilovoltage Intrafraction Monitoring (KIM)

LARK: Liver Ablative Radiotherapy Utilising Kilovoltage Intrafraction Monitoring (KIM)

Anonymised data will be made available to researchers upon request, once evidence of ethical approval has been provided.

Isodose distributions and dose volume histograms for each session will be calculated with KIM corrections as treated, and estimated without KIM corrections. The planning CT scan will be used for this assessment

The time taken for the KIM treatments compared with the time taken for similar treatments from previous patients, accounting for the difference in the time and number of patient images acquired and the time taken to adjust the patient's position during treatment

The KIM procedure adds radiation dose with the kilovoltage images. However, there may be fewer volumetric cone beam computed tomography (CBCT) scans acquired. This difference in dose will be estimated and analysed

The clinical target volume (CTV) to planning target volume (PTV) margin with and without KIM will be recorded and analysed.

Isodose distributions and dose volume histograms for each session will be calculated with KIM corrections as treated, and estimated without KIM corrections. The intratreatment CBCT scans will be used for this assessment.

Difference between dose delivered using KIM with or without MLC tracking

Proportion of local failures at two years for patients treated as assessed using modified RECIST criteria

The proportion of grade 3 or higher toxicities, assessed using CTCAE v4.03

To compare change in Quality of Life, as defined by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30 (Version 3)) from baseline at completion of radiation therapy and at 6 weeks, 3, 6, 12, 18 and 24 months post-radiation therapy. The EORTC QLQ-C30 (Version 3) uses for the questions 1 to 28 a 4-point scale. The scale scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit") and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. The EORTC QLQ-C30 (Version 3) uses for the questions 29 and 30 a 7-points scale. The scale scores from 1 to 7: 1 ("very poor") to 7 ("excellent"). The questionnaire will be self-administered and will be given in patient's mother tongue.

To compare change in Quality of Life related to hepatocellular carcinoma (HCC) as defined by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Hepatocellular Carcinoma 18 Module (EORTC QLQ-HCC) from baseline at completion of radiation therapy and at 6 weeks, 3, 6, 12 and 18 months post-radiation therapy. The questionnaire will be self-administered and will be given to patients proficient in English. EORTC-QLQ-HCC18: includes HCC-specific symptoms or problems. Questions used 4-point Likert scale from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit") and 4 ("Very much"). Scores averaged and transformed to 0-100 scale. High score for functional scale=high/healthy level of functioning. High score for single item=high level of symptomatology/problems.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study Evaluating Safety, Pharmacokinetics, Pharmacodynamics, And Clinical Activity Of RO7119929 (TLR7 Agonist) In Participants With Unresectable Advanced Or Metastatic Hepatocellular Carcinoma, Biliary Tract Cancer, Or Solid Tumors With Hepatic Metastases	NCT04338685	Carcinoma, Hepa... Biliary Tract C... Secondary Liver... Liver Metastase...	RO7119929 Tocilizumab	18 Years -	Hoffmann-La Roche
Preoperative Physical Activity Intervention in Patients Before Planned Liver Resection for Cancer (APACHE)	NCT03518632	Primary Liver C... Secondary Liver... Liver Metastase...	Interval traini... Standard Oncolo...	18 Years -	Centre Hospitalier Universitaire de Besancon
Registry on Percutaneous Electrochemotherapy	NCT05267080	Primary Liver C... Secondary Liver...	CLINIPORATOR	18 Years -	Cardiovascular and Interventional Radiological Society of Europe
Registry on Percutaneous Electrochemotherapy	NCT05267080	Primary Liver C... Secondary Liver...	CLINIPORATOR	18 Years -	Cardiovascular and Interventional Radiological Society of Europe
Irreversible Electroporation of Unresectable Liver Tumors	NCT04404647	Liver Metastase... Hepatocellular ... Bile Duct Cance...	Irreversible el...	18 Years -	Aalborg University Hospital
Study Comparing Radio Frequency Ablation Plus Chemotherapy and Chemotherapy Alone in Patients With Secondary Liver Metastases	NCT00510627	Metastatic Live... Secondary Liver... Liver Neoplasm	Radiofrequency ... Chemotherapy	18 Years -	Boston Scientific Corporation
Liver Ablative Radiotherapy Utilising Kilovoltage Intrafraction Monitoring (KIM)	NCT02984566	Liver Cancer	Kilovoltage Int...	18 Years - 85 Years	University of Sydney

Spots Global Cancer Trial Database for secondary liver cancer