Colorectal cancer liver metastases (CRLM) Cancer
Conditions
Interventions
The randomisation for patients into Cohort 3 will be on a 1:1 basis, using a validated computer randomisation program called Registration / Randomisation and Management of Product (RRAMP) managed thro
plus scans (CT/MRI PET) at baseline and after 4 weeks (to assess any radiological changes). The follow-up visits are likely to take approximately 2 hours maximum. On Day 1 (intervention day) baseline
Sponsors
University of Oxford
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 12/06/2023: Current participant inclusion criteria as of 12/06/2023: Cohort 1 (safety): 1. At least 1 confirmed CRC liver metastasis >1cm in diameter that is geographically accessible to SonoTran intervention 2. = 18 years of age. 3. Written (signed and dated) informed consent and be capable of cooperating with treatment and follow-up. 4. Haematological and biochemical indices within the ranges shown below within 14 days prior to enrolment: 4.1. Haemoglobin (Hb) =9.0 g/dl (can be transfused to this value) 4.2. Absolute neutrophil count =1.5 x 10e9/l 4.3. Platelet count =100 x 10e9/l 4.4. Serum bilirubin =1.5 x upper limit of normal (ULN) 4.5. Alanine aminotransferase (ALT) =5 x ULN 4.6. Aspartate aminotransferase (AST) =5 x ULN 4.7. Serum creatinine =1.5 x ULN 4.8. PT and APTT =1.25 x ULN 4.9 Albumin =28 g/l 5. Female subjects of childbearing potential must have negative pregnancy test within 14 days prior to SonoTran intervention. 6. Patients with a diagnosis of mCRC, who are either not eligible to receive the standard of care chemotherapy or who have exhausted all lines of standard of care; or who are presently on a planned break from SOC chemotherapy. 7. ECOG performance status of 0, 1 or 2. Cohort 2 (performance): 1. At least 1 confirmed CRC liver metastasis >1cm in diameter, and metastatic disease that is planned to be IMMEDIATELY resected is without formal neo-adjuvant chemotherapy. 2. The metastasis(es) can be geographically inaccessible to SonoTran intervention as long as there are still spaces in Cohort 2A of the study (i.e. drugs alone prior to surgical resection). If there are no spaces on Arm 2A and spaces still remain on Arm 2B, the patients will require to have at least one geographically-accessible lesion amenable to SonoTran intervention. 3. Chemotherapy-naïve in terms of chemotherapy for metastatic CRC (patients can have received adjuvant chemotherapy as long as this has been completed at least 3 months prior to planned intervention within the study) 4. If there is disease outside of the liver, there must be a plan to eradicate this e.g. by surgery, ablation or SABR treatment as part of the curative strategy. 5. = 18 years of age. 6. Written (signed and dated) informed consent and be capable of cooperating with treatment and follow-up. 7. Haematological and biochemical indices within the ranges shown below within 14 days prior to enrolment: 7.1. Haemoglobin (Hb) =9.0 g/dL (can be transfused to this value) 7.2. Absolute neutrophil count =1.5 x 10e9/l 7.3. Platelet count =100 x 10e9/L 7.4. Serum bilirubin =1.5 x upper limit of normal (ULN) 7.5. Alanine aminotransferase (ALT) =5 x ULN 7.6. Aspartate aminotransferase (AST) =5 x ULN 7.7. Serum creatinine =1.5 x ULN 7.8. PT and APTT =1.25 x ULN 7.9. Albumin =28g/l 8. Female subjects of childbearing potential must have negative pregnancy test within 14 days prior to SonoTran intervention. 9. ECOG performance status of 0 or 1. 10. Female subjects of childbearing potential and male subjects whose sexual partners are of childbearing potential must agree to abstain from sexual intercourse or to use an effective method of contraception during the study and up to 6 months after the end of study. Examples of effective methods of contraception include oral or injected contraceptives or double barrier methods such as condom plus spermicide or condom plus diaphragm. Cohort 3 (efficacy): 1. At least 1 confirmed CRC liver metastasis >1cm in diameter, and
Exclusion criteria
Exclusion criteria: Current participant exclusion criteria as of 12/06/2023: Cohort 1 (safety): 1. Any active anti-cancer therapy (chemotherapy / small molecule inhibitors / immunotherapy) within 4 weeks or liver radiotherapy within 8 weeks, prior to planned intervention in the study. 2. Persistent, unresolved CTCAE v5.0 Grade 2 or higher drug-related toxicity (except alopecia, erectile dysfunction, hot flashes, decreased libido, chronic neuropathy) following previous treatment. 3. Inadequate recovery from any prior surgical procedure or major surgical procedure performed within 4 weeks prior to enrolment. 4. Any other medical or psychiatric condition that, in the opinion of the investigator, might interfere with the subject's participation in the clinical investigation or interfere with the interpretation of clinical investigation results. 5. Serious/symptomatic active infection or infection requiring antibiotics, within 7 days prior to enrolment. 6. Presence of active cholangitis. 7. Known Human Immunodeficiency Virus (HIV) infection or a known HIV-related malignancy. 8. Known bleeding diathesis. 9. Inability to comply with the protocol requirements. 10. Participation in any other clinical trials involving therapeutic agents within the last 4 weeks prior to enrolment. 11. Pregnant or lactating females. 12. Patients with liver metastases eligible for immediate surgical resection or other radical therapy such as ablation, unless these interventions are not expected to occur within the next 8 weeks, allowing participation in the study and completion of follow-up, prior to that specified intervention Cohort 2 (performance): 1. Any active anti-cancer therapy (chemotherapy / small molecule inhibitors / immunotherapy) within 4 weeks or liver radiotherapy within 8 weeks, prior to SonoTran intervention. 2. Persistent, unresolved CTCAE v5.0 Grade 2 or higher drug-related toxicity (except alopecia, erectile dysfunction, hot flashes, decreased libido, chronic neuropathy) following previous treatment. 3. Inadequate recovery from any prior surgical procedure or major surgical procedure performed within 4 weeks prior to enrolment. 4. Any other medical or psychiatric condition that, in the opinion of the investigator, might interfere with the subject's participation in the clinical investigation or interfere with the interpretation of clinical investigation results. 5. Serious/symptomatic active infection or infection requiring antibiotics, within 7 days prior to enrolment. 6. Presence of active cholangitis. 7. Known Human Immunodeficiency Virus (HIV) infection or a known HIV-related malignancy. 8. Known bleeding diathesis. 9. Inability to comply with the protocol requirements. 10. Participation in any other clinical trials involving therapeutic agents within the last 4 weeks prior to enrolment. 11. Pregnant or lactating females. 12. Known UGT-1A1 polymorphism. 13. Patients with liver metastases that require formal neoadjuvant chemotherapy to downstage prior to resection. 14. Patients whose main radical intervention to the liver at outset is planned to be ablation rather than surgery. Cohort 3 (efficacy): 1. Metastatic disease outside of the liver that is reasonably expected to cause acute deterioration or death within 14 weeks of entry into the study i.e. the patient’s life expectancy should be at least 14 weeks in order to allow completion of protocolled intervention and primary endpoint read-out. 2. Any active anti-cancer therapy (chemotherapy / small molecule inhi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cohort 1: Safety assessed using: 1. Immediate ill effects e.g. pain, fever 2. Full blood count (FBC), urea and electrolytes (U&E), creatinine and liver function tests (LFTs) (ALT/AST/alkaline phosphatase/albumin) 3. Acute radiological changes In terms of all of the above the researchers will be looking at the presence of grade 3 /4 Common Terminology Criteria for Adverse Events (CTCAE) events that are not expected within the context of the disease state for that patient Timepoint(s): Cohort 1 - Cumulative up to 28 days post-intervention, measured weekly for 4 weeks post-intervention. All grades will be recorded. The worst grade reached will define the maximum toxicity for that event. Cohort 2: Drug delivery assessed using the intratumoural concentration of cetuximab, irinotecan, SN38 and SN38G in resected tumour tissues in the SonoTran Platform group compared to the group receiving drug treatment alone (2B versus 2A) The timepoint is the time of resection of the surgical specimen as this is the point at which no further drugs will reach the tumour tissue. Tumour will be carried immediately to the pathology lab where the pathologist will dissect appropriate tissue for fresh frozen allocation for future assays. The remainder of the tissue will be embedded and some used for standard path data; slices will subsequently be taken for formalin-fixed, paraffin-embedded (FFPE) analysis of cetuximab distribution. Cohort 3: Efficacy, comparing Arm 3B (drugs plus SonoTran intervention) versus Arm 3A (drugs alone) by: 1. Response on CT (response evaluation criteria in solid tumors (RECIST)/immune-related RECIST (irRECIST)/Choi) 2. Response on PET-CT (SUV Max and glycolytic volume) 3. Response on MRI The timepoints are pre-treatment and post cycle 3 and post cycle 6, for each modality. | — |
Secondary
| Measure | Time frame |
|---|---|
| Cohort 1 Safety: The detection of acoustic emissions in the target tumour by Passive Acoustic Mapping (PAM) at the time of the single intervention on day 1 Cohort 2 Performance: Adverse events (symptoms and haematological/liver function tests (LFTs) (ALT/AST/alkaline phosphatase/albumin)) weekly up to 28 days post-intervention in Arm 2B versus 2A control Cohort 3 Efficacy: 1. Adverse events (symptoms and haematological/liver function tests - ALT/AST/alkaline phosphatase/albumin) pre-each cycle of drugs (+/- SonoTran) and at the exit from the study 2. Radiological read-outs of damage to normal liver as measured by CT and MRI after 3 and 6 cycles of intervention and compared with baseline 3. Downstream liver metastatic resectability as measured by local MTD at the patient’s exit point from the clinical investigation after completing drug (+/- SonoTran) intervention | — |
Countries
England, United Kingdom
Outcome results
None listed