PS101-mediated ACT With Chemotherapy in Liver Metastases From Cancer of Gastrointestinal Origin

Study Overview
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Brief Summary
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Part 1: This clinical study will first test the safety and initial effect on the tumour of PS101-mediated ACT when given in combination with standard of care chemotherapy in patients with liver metastases (initially those with any solid tumors and then further in patients just with colorectal cancer [CRC]) in order to identify the recommended dose and schedule of PS101-mediated ACT that can be taken forward for further testing. Part 2: Based on the Part 1 results, another part in patients with liver metastases from CRC and pancreatic cancer (if indicated) may take place following a substantial protocol amendment. This record will focus on Part 1 of the study only and will be updated if Part 2 occurs.

Detailed Description
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The suboptimal delivery of an anticancer agent to the target cancer cells represent a significant problem in many solid tumours, as it compromises the effectiveness of established therapeutics. If the amount of drug that reached any tumour could be increased without changing the amount administered systemically, it should be possible to increase the effectiveness of the treatment without adding to systemic toxicity. PS101-mediated ACT involves the use of an experimental drug and an experimental device in patients with colon/rectal cancer that has spread to the liver and is given in combination with standard of care chemotherapy. The experimental drug, called PS101, is a liquid containing a mixture of positively and negatively charged microbubbles and microdroplets. It is injected into a vein (blood vessel) and from there follows the blood flow around the body to where the cancerous tumours are found. PS101 is given at the same time as a special type of ultrasound (performed using an ultrasound device) at the place in the liver where the cancerous tumour is found. The combination of PS101 and ultrasound is called Acoustic Cluster Therapy (ACT). PS101-mediated ACT can potentially increase the uptake of an anticancer agent over the ultrasound targeted area. The preclinical development of PS101-mediated ACT suggests that this therapy may be of meaningful benefit while significant additional toxicity is not anticipated.

Official Title
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Phase I Trial of the Combination of PS101-Mediated Acoustic Cluster Therapy (ACT) With Chemotherapy for Treatment of Liver Metastasis In Patients With Solid Tumours With an Expansion Cohort in Metastatic Colorectal And Pancreatic Cancer

Conditions
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Solid Tumor, Colorectal Cancer

Intervention / Treatment
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* Drug: 20 uL/kg PS101
* Drug: 40 uL/kg PS101
* Device: Ultrasound


Participation Criteria
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Eligibility Criteria
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MAIN INCLUSION CRITERIA Providing informed consent and able to co-operate with the study requirements. Diagnosis of any advanced solid tumour with liver metastases suitable for FOLFOX or FOLFIRI chemotherapy (Part 1a) / Diagnosis of any metastatic CRC with liver metastases suitable for FOLFIRI chemotherapy (Part 1b) . At least two distinct target liver metastases (visible on computed tomography (CT)/magnetic resonance imaging (MRI) and of a suitable size), one being suitable for ultrasound and suitably spaced apart. Eastern Co-operative Oncology performance status of 0 or 1 and with a predicted meaningful survival of at least 6 months. . Suitable laboratory test results to receive chemotherapy. Females who are not pregnant or lactating; males and females willing to follow contraceptive requirements. Able to receive CT/MRI contrast agents. MAIN EXCLUSION CRITERIA Liver metastases suitable for immediate resection (and therefore neoadjuvant therapy unnecessary) or planned to be treated with radio-frequency ablation or other local therapies. Liver radiotherapy in the last 2 months. Use of tyrosine kinase inhibitors or monoclonal antibodies that are known to target angiogenesis receptors and/or their ligands. Persistent, unresolved National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) Version 5.0 Grade 2 or higher drug-related toxicity (except alopecia, erectile dysfunction, hot flashes, decreased libido) following previous treatment. Grade 2 or greater sensory/motor neuropathy. Inadequate recovery from any prior surgical procedure or major surgical procedure in the last 4 weeks Serious/symptomatic active infection, or infection requiring antibiotics in the last 7 days, active cholangitis, disease requiring metal biliary stent(s), HIV infection, bleeding diathesis or other medical or psychiatric condition that might interfere with the patient's participation in the trial or results. Hypersensitivity to any of the components of PS101 (e.g. eggs or egg products). Hypersensitivity to FOLFOX or FOLFIRI, or previously having to discontinue either due to adverse events. Participation in any other clinical trials involving therapeutic agents in the last 4 weeks. History of QT prolongation, clinically significant ventricular tachycardia, ventricular fibrillation, heart block, myocardial infarction within 6 months, congestive heart failure New York Heart Association Class III or IV, unstable angina or any relevant clinical history, signs or symptoms suggestive of clinically significant, uncontrolled cardiovascular or pulmonary disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 is divided into two stages: Part 1a: 3+3 open label non-randomized design to evaluate two doses Part 1b: Single blind, randomized design to evaluate two doses
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a: ACT with chemotherapy in metastatic solid tumours<br>20 uL/kg or 40 uL/kg PS101 administered together with standard of care chemotherapy (FOLFOX or FOLFIRI) and ultrasound insonation over the targeted liver metastasis in patients with solid tumours | Drug: 20 uL/kg PS101<br>* 20 uL/kg PS101 and chemotherapy given for 4 cycles over 6 weeks<br>Drug: 40 uL/kg PS101<br>* 40 uL/kg PS101 and chemotherapy given for 4 cycles over 6 weeks<br>Device: Ultrasound<br>* Ultrasound activation and enhancement<br>|
| Experimental: Part 1b ACT with chemotherapy in metastatic CRC<br>20 uL/kg or 40 uL/kg PS101 administered together with standard of care chemotherapy (FOLFIRI) and ultrasound insonation over the targeted liver metastasis in patients with metastatic colorectal cancer | Drug: 20 uL/kg PS101<br>* 20 uL/kg PS101 and chemotherapy given for 4 cycles over 6 weeks<br>Drug: 40 uL/kg PS101<br>* 40 uL/kg PS101 and chemotherapy given for 4 cycles over 6 weeks<br>Device: Ultrasound<br>* Ultrasound activation and enhancement<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability: DLTs (Part 1a only) | Proportion of patients with DLTs related to administration of PS101 IV bolus injection alone (without chemotherapy) or due to the addition of PS101 to FOLFOX or FOLFIRI | 4 weeks from the first ACT treatment in each patient | 
| Number of patients with adverse events | Adverse events are summarised in the adverse event section. An overall summary will be presented here | From informed consent to 12 weeks from study start | 
| Number of patients with adverse device effects | Number of patients with any AE related to the use of an Investigational Medical Device. | From the first PS101-mediated ACT procedure to 12 weeks from study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary anti-tumor activity at Week 8 | Change from baseline in maximum tumor diameter and volume in liver metastases | Baseline to Week 8 | 
| Best overall response (Part 1b only) | Best overall response based on CR, PR, SD, PR according to RECIST Version 1.1 | Baseline to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PS101-mediated ACT: the combination of PS101 with ultrasound, PS101-mediated ACT procedure: PS101 and ultrasound, ACT treatment: 3 × PS101-mediated ACT procedures