CEeDD

Funding

This study/project is funded by the National Institute for Health and Care Research (NIHR) [i4i PDA (NIHR201655)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care

FULL TITLE

CEeDD: A First-in-Human Clinical Investigation of Cavitation-Enhanced Drug Delivery to Solid Tumours by co-Administration of Sonosensitive Particles and Application of Extracorporeal Ultrasound in Patients with Colorectal Metastases to the Liver

Chief Investigator: Prof. Rachel Kerr

Sponsor: University of Oxford

STATUS

Open to Recruitment

Study Design

Cohort 1: dose escalation (3+3+3) design.

Cohort 2: Group allocation 2-arm (6+6) Proof of Concept study.

Cohort 3: Randomised (12+12) early efficacy and feasibility study.

Study Population

Metastatic colorectal cancer

Study Schema

Study Status

RECRUITING

TARGET RECRUITMENT Total 45-48 patients (Cohort 1: 9-12, Cohort 2: 12, Cohort 3: 24)

PARTICIPATING SITE Churchill Hospital – Oxford University Hospital NHS Trust

Inclusion/Exclusion Criteria

Inclusion/Exclusion criteria Cohort 1 (SAFETY)

Inclusion criteria Cohort 1 (SAFETY):

A patient will be eligible for inclusion in this study if all of the following criteria apply.

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:

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.

Exclusion criteria Cohort 1 (SAFETY):

A patient will not be eligible for the study if any of the following apply:

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

Inclusion/Exclusion criteria Cohort 2 (PERFORMANCE)

Inclusion criteria Cohort 2 (PERFORMANCE):

A patient will be eligible for inclusion in this study if all of the following criteria apply.

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:

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.

Exclusion criteria Cohort 2 (PERFORMANCE):

A patient will not be eligible for the study if any of the following apply:

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.

Inclusion/Exclusion criteria Cohort 3 (EFFICACY)

Inclusion criteria Cohort 3 (EFFICACY):

A patient will be eligible for inclusion in this study if all of the following criteria apply.

1. At least 1 confirmed CRC liver metastasis >1cm in diameter, and metastatic disease that is NOT planned to be IMMEDIATELY resected or ablated.
2. 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. ≥ 18 years of age.
5. Written (signed and dated) informed consent and be capable of cooperating with treatment and follow-up.
6. Haematological and biochemical indices within the ranges shown below within 14 days prior to enrolment:

7. Confirmed RAS wild-type CRC
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.

Exclusion criteria Cohort 3 (EFFICACY):

A patient will not be eligible for the study if any of the following apply:

1. Metastatic disease outside of the liver that is reasonably expected to cause acute deterioration or death within 14 weeks of entry in to 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 inhibitors / immunotherapy) within 4 weeks or liver radiotherapy within 8 weeks, prior to SonoTran intervention.
3. 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.
4. Inadequate recovery from any prior surgical procedure or major surgical procedure performed within 4 weeks prior to enrolment.
5. 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.
6. Serious/symptomatic active infection or infection requiring antibiotics, within 7 days prior to enrolment.
7. Presence of active cholangitis.
8. Known Human Immunodeficiency Virus (HIV) infection or a known HIV-related malignancy.
9. Known bleeding diathesis.
10. Inability to comply with the protocol requirements.
11. Participation in any other clinical trials involving therapeutic agents within the last 4 weeks prior to enrolment.
12. Patients with history of QT prolongation, clinically significant VT, VF, heart block, myocardial infarction within 6 months, CHF NYHA Class III or IV, unstable angina.
13. Pregnant or lactating females.
14. Known DPD deficiency or UGT-1A1 polymorphism.
15. Patients with liver metastases that are IMMEDIATELY amenable to surgical resection without neoadjuvant treatment.
16. Patients for whom IMMEDIATE ablation is felt to be appropriate.

Primary Objective

Cohort 1 (SAFETY): To assess whether the SonoTran Platform is capable of inducing detectable and reproducible inertial cavitation activity in the target tumour during the intervention

Cohort 2 (PERFORMANCE): To assess the safety of a single small dose of drugs when combined with the use of SonoTran Platform pre-liver resection compared to giving the drugs alone.

Cohort 3 (EFFICACY): To assess the safety of the repeated use of the SonoTran Platform performed synchronously with multiple administrations of cetuximab antibody and FOLFIRI chemotherapy.

To assess whether the addition of the SonoTran Platform increases conversion to resectability of those patients whose liver metastases are not resectable initially.

Key Dates

1^st patient recruited by 31Dec2021

Cohort 1 recruitment complete by 30Apr2022

Cohort 2 & 3 recruitment complete by 31Aug2023