## Protocol Section
### Identification Module
**NCT ID:** NCT06434493

**Acronym:** EMPHATIC

**Brief Title:** Evaluation of Combined Modality Protons and Hepatic Transplantation for Hilar Cholangiocarcinoma

**Official Title:** Evaluation of Combined Modality Protons and Hepatic Transplantation for Hilar Cholangiocarcinoma (an Evaluative Commissioning in Protons Study)

#### Organization Study ID Info
**ID:** CFTSp218 (02)
#### Organization
**Class:** OTHER
**Full Name:** The Christie NHS Foundation Trust
### Status Module
#### Completion Date
**Date:** 2029-01-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-30

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-23

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2028-01-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-30
**Type:** ACTUAL
**Study First Submit Date:** 2024-04-25
**Study First Submit QC Date:** 2024-05-23
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** University College London Hospitals

**Class:** OTHER

**Name:** University College, London

**Class:** OTHER

**Name:** Royal Free Hospital NHS Foundation Trust

#### Lead Sponsor

**Class:** OTHER

**Name:** The Christie NHS Foundation Trust

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Proton Beam Therapy (PBT) is an advanced radiotherapy technique. There are two National Health Service (NHS) PBT treatment centres in the United Kingdom (UK), in Manchester and London. The NHS is committed to ensuring the best use of this limited resource by investigating which patients will benefit from PBT.

Evaluative Commissioning in Protons (ECIP) is a programme of studies exploring the role of PBT in different types of cancer. The studies are funded by NHS England. ECIP studies are not randomised studies, which means that all eligible patients will be offered PBT. Any eligible patient in the UK can be referred, and accommodation is available for patients who don't live close to a PBT centre.

The main benefit of PBT, compared with standard photon radiotherapy, is the predicted reduction in radiation dose to surrounding healthy tissues. With photon radiotherapy, some radiation passes beyond the target area, affecting healthy tissues and causing side-effects. With PBT, the radiation dose stops within the target area, causing less damage to surrounding tissues, and limiting side effects.

EMPHATIC is a study within the ECIP programme. In EMPHATIC, the investigators are looking to see whether a combination of treatments, including PBT, chemotherapy and a liver transplant, can be used to treat patients with cholangiocarcinoma (bile duct cancer).

EMPHATIC offers patients whose cancer can't be removed with surgery (unresectable) a potentially curative treatment option. There is evidence that liver transplant is a curative treatment option in patients with cholangiocarcinoma. There is a risk that the cancer may grow or spread whilst waiting for a transplant, potentially making patients ineligible. PBT and chemotherapy is thought to be the best way to control the cancer, until a liver transplant can be performed. EMPHATIC will look at how a combination of PBT and chemotherapy, followed by a liver transplant, can be used to curatively treat patients with unresectable cholangiocarcinomas.

**Detailed Description:** Liver and bile duct resection with lymphadenectomy is the standard of care for patients with hilar cholangiocarcinoma. Unfortunately, resection is only possible in a minority of patients for many reasons including, the extent of cancer or the presence of background primary sclerosing cholangitis (PSC). For patients with a background of PSC, liver transplantation is a potential treatment, and it was recently approved as an indication for a commissioned pilot service evaluation of liver transplantation in the UK.

Until recently, the use of liver transplantation for hilar cholangiocarcinoma was confined to a few centres in the United States. The initial publications from the Mayo Clinic and Nebraska, as well as more recent experience from other centres, support strict selection protocols to identify patients likely to benefit from liver transplantation. In 2000, the initial experience at the Mayo Clinic in which 19 patients enrolled in a pre-transplant neoadjuvant therapy protocol was published. 11 patients underwent subsequent liver transplantation. Of the 8 with long term follow up (median 44 months), only one patient developed cancer recurrence. Similarly, the long-term experience of patients in Nebraska, where 11 patients underwent liver transplantation after neoadjuvant chemoradiotherapy was published in 2002. 5 of the 11 patients were alive and disease free at a median follow up of 7.5 years .

Most recent experience is based on adopting the Mayo protocol. In general, the inclusion criteria define patients with early cancers, with a dominant stricture or tumour less than 3cm. Intra and extrahepatic disease including any site of nodal metastases precluded selection. Controversially, histology or cytology was not considered essential for diagnosis of cholangiocarcinoma by most centres. Elevated Ca 19.9 of \>100, Fluorescence In Situ Hybridization (FISH) polysomy 9p21 or tumour mass in the presence of a dominant stricture were considered sufficient for enrolment. Prior (attempts at) trans-peritoneal biopsy was another exclusion criterion based on concerns of increased risk of tumour dissemination. Neoadjuvant therapy involved external beam radiation therapy (EBRT) with concurrent chemotherapy (chemo sensitisation), followed by brachytherapy whenever possible. Patients were then re-staged and remain on systemic chemotherapy until the time of transplant.

A recent review looked at all studies from 2000 until 2019. 20 studies with 428 patients were eligible for analysis. The pooled 1, 3-, and 5-year overall survival rates following liver transplantation without neoadjuvant therapy (n=156) were 71.2%. In patients who had neoadjuvant therapy prior to transplantation (n=272), the survival improved to 82.8% at 1,3 and 5 years respectively.

The cancer recurrence rate was 51.7% in patients who did not receive neoadjuvant therapy compared to 24.1% for patients who had. Only 4 of the 20 studies reported pre-transplant histological confirmation of adenocarcinoma or malignant/suspicious cells on cytology. 98% of liver explants from studies not using neoadjuvant therapy confirmed malignancy, compared to 50.5% in those who had received neoadjuvant therapy. Patients in whom malignancy was not found are presumed to have had complete pathological response to neoadjuvant therapy (approximately 50% following neoadjuvant therapy). Patients with background PSC had better outcomes compared to patients with de novo cancers.

Study Design \& development of an evaluative commissioning study within ECIP:

It is not possible to design EMPHATIC, a study for patients with unresectable cholangiocarcinoma, as a randomised controlled trial (RCT), because there is no ethically acceptable control arm. In an RCT, patients in a theoretical control arm would be offered either no transplant, or no neoadjuvant therapy prior to the transplant. Based on the published literature summarised above, the adverse anticipated outcomes of patients in such a control arm would not be considered justified.

Neoadjuvant therapy is required to control the tumour prior to transplant. In the Mayo protocol described above, patients received external beam (chemo)radiotherapy followed by brachytherapy, and thereafter received chemotherapy until the time of transplant. Unfortunately, in the UK, brachytherapy services were not seen as a viable option, and hence the Mayo protocol is not feasible.

There is good scientific rationale that proton beam radiotherapy (PBT) offers the optimal technique for delivering neoadjuvant therapy as it is non-invasive, and spares as much functional liver as possible, compared with alternatives such as photon-EBRT techniques or invasive techniques (e.g. brachytherapy). Compared with photon-EBRT techniques, PBT delivers highly conformal radiotherapy, with a significantly reduced integral body dose, and no exit beam. It is expected to be associated with an improved toxicity profile.

### Conditions Module

**Conditions:**

- Cholangiocarcinoma

**Keywords:**

- proton beam therapy

- protons

- evaluative commissioning

- liver transplant

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 30

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** All patients to be offered neoadjuvant proton beam therapy to a dose of 45 Gray (Gy) in 15 fractions over 3 weeks, with a tumour boost to 67.5 Gray (Gy), and alongside concurrent oral capecitabine 625mg/m2 twice daily on radiation days.

**Intervention Names:**

- Radiation: Proton Beam Therapy

- Drug: Concurrent oral capecitabine chemotherapy

- Drug: Cisplatin & Gemcitabine intravenous chemotherapy

- Procedure: Orthotropic Liver Transplant

**Label:** Proton Beam Therapy

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Proton Beam Therapy

**Description:** All patients to be offered neoadjuvant proton beam therapy to a dose of 45 Gray (Gy) in 15 fractions over 3 weeks, with a tumour boost to 67.5 Gray (Gy)

**Name:** Proton Beam Therapy

**Type:** RADIATION

#### Intervention 2

**Arm Group Labels:**

- Proton Beam Therapy

**Description:** All patients to be offered concurrent oral capecitabine 625mg/m2 twice daily on radiation days

**Name:** Concurrent oral capecitabine chemotherapy

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Proton Beam Therapy

**Description:** Following chemoradiotherapy (PBT + capecitabine), and whilst on the liver transplant waiting list, patients will be offered up to 6 cycles of standard chemotherapy with cisplatin and gemcitabine.

**Name:** Cisplatin & Gemcitabine intravenous chemotherapy

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Proton Beam Therapy

**Description:** If still eligible after neoadjuvant treatment (PBT + capecitabine), patients will be added to the liver transplant waiting list.

**Name:** Orthotropic Liver Transplant

**Type:** PROCEDURE

### Outcomes Module

#### Primary Outcomes

**Description:** Incidence of Grade ≥ 3 toxicity using CTCAE (grades 0-5) up to 90 days following completion of neoadjuvant (chemo)-PBT and liver transplant. Higher score indicates worse outcome.

**Measure:** Incidence of Common Toxicity Criteria for recording Adverse Events (CTCAE) Grade 3 and above toxicity

**Time Frame:** Up to 90 days post neoadjuvant chemo-radiation.

**Description:** The proportion of patients who, following neoadjuvant (chemo)-PBT, undergo a successful liver transplant (measured at 90 days post-transplant).

**Measure:** Proportion of patients who undergo a successful liver transplant

**Time Frame:** 90 days post transplant.

#### Secondary Outcomes

**Description:** Number of patients completing planned radiotherapy

**Measure:** Number of patients completing planned radiotherapy

**Time Frame:** Up to 1 year

**Description:** Rate of Common Toxicity Criteria for recording Adverse Events (CTCAE) Grade 3 and above toxicity (Grades 0-5). Higher score may mean a worse outcome.

**Measure:** Incidence of severe treatment related side effects

**Time Frame:** Up to 2 years

**Description:** Calculated from date of last PBT treatment and defined as time to death or censoring at 1 year.

**Measure:** 1 year post completion of neoadjuvant therapy cancer-related mortality

**Time Frame:** At 1 year

**Description:** Calculated from date of liver transplant and defined as time to death or censoring at 1 year.

**Measure:** 1 year post transplant overall survival

**Time Frame:** At 1 year

**Description:** Calculated from date of transplant and defined as time to death or censoring at 1 year.

**Measure:** 1 year post transplant graft survival

**Time Frame:** At 1 year

**Description:** Calculated from the date the patient was added to the transplant waiting list and defined as time to death or censoring at 1 year.

**Measure:** 1 year post listing patient survival

**Time Frame:** At 1 year

**Description:** Calculated as time to cancer recurrence or death whichever is earliest, from date of transplant, with censoring at 1 year.

**Measure:** Disease free survival from transplant

**Time Frame:** At 1 year

**Description:** Described as local, regional or metastatic disease

**Measure:** Recurrent cancer within 6 months of transplant

**Time Frame:** Up to 6 months following transplant

**Description:** Reported as time to loss of cancer control with censoring at time of transplant

**Measure:** Cancer control at time of transplant

**Time Frame:** Up to 2 years

**Description:** Reported as time to loss of cancer control with censoring at date of removal from transplant waiting list

**Measure:** Cancer control at time of removal from transplant list

**Time Frame:** Up to 2 years

**Description:** Surgical complication rates according to Clavien Dindo scale, measured from grades 1-5, higher grade may mean worse outcome.

**Measure:** Transplant complication rates

**Time Frame:** Within 3 months of surgery

**Description:** Review of patient pathway deliverability defined as time interval from patient referral to the start of chemo-PBT treatment

**Measure:** Patient pathway

**Time Frame:** Up to 2 years

**Description:** Measured in days from last day of PBT to date of transplant

**Measure:** Time to completion of neoadjuvant chemo-PBT treatment to liver transplant

**Time Frame:** Up to 2 years

**Description:** Measured in weeks from transplant listing date to liver transplant date

**Measure:** Time spent on transplant waiting list

**Time Frame:** Up to 2 years

**Description:** Review annual referral rates to the study

**Measure:** Referral rates

**Time Frame:** At 6 months, 12 months, 18 months and 24 months following the opening of the study

**Description:** Number of patients participating in the study

**Measure:** Recruitment rates

**Time Frame:** At 6 months, 12 months, 18 months and 24 months following the opening of the study

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

General criteria

* Age 17 years and over
* Performance status 0 or 1 (Eastern Cooperative Oncology Group)
* Suitable for liver transplantation as determined by Multi Disciplinary Team (MDT)
* Able to tolerate neoadjuvant therapy.
* A history of primary sclerosing cholangitis (PSC) will be a necessary eligibility criterion at the start of the study. Part-way through recruitment to the study, the eligibility criteria may be broadened, allowing patients with sporadic / non-PSC unresectable cholangiocarcinoma to also be considered. The decision to do this will be taken by the Study Management Group, who will be monitor results closely, following an interim analysis after the first 10 patients. Suitability for Orthotropic Liver Transplant will continue to be confirmed in the regional Hepato Biliary cancer MDT.

Specific criteria

* Presence of a dominant hilar stricture or mass \<3cm on cross-sectional imaging
* Histologically proven cholangiocarcinoma by brush cytology or biopsy via Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiography (PTC)
* No metastatic disease, including to regional lymph nodes.

Exclusion Criteria:

General criteria

* Inability to consent
* Poor performance status
* Failed fitness assessment
* Extrahepatic disease at any stage of presentation, assessment and treatment
* Prior biliary resection or hilar dissection for attempted resection within the past 12 months
* Prior malignancy in the last 5 years (excluding early breast, prostate, cervix and non melanoma skin cancers)

Specific criteria

* Estimated Glomerular Filtration Rate (eGFR) \<30
* Prior radiation to the upper abdomen
* Uncontrolled infection
* Duodenal invasion

**Minimum Age:** 17 Years

**Sex:** ALL

**Standard Ages:**

- CHILD

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** romelie.rieu@nhs.net

**Name:** Romelie Rieu

**Phone:** 0044 1619187172

**Role:** CONTACT

**Contact 2:**

**Email:** sally.falk@nhs.net

**Name:** Sally Falk

**Phone:** 0044 1619187172

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** University College, London

**Name:** Maria Hawkins

**Role:** PRINCIPAL_INVESTIGATOR

**Official 2:**

**Affiliation:** The Royal Free NHS Foundation Trust

**Name:** Douglas Thorburn

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** De Vreede I, Steers JL, Burch PA, Rosen CB, Gunderson LL, Haddock MG, Burgart L, Gores GJ. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2000 May;6(3):309-16. doi: 10.1053/lv.2000.6143.

**PMID:** 10827231

**Citation:** Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B Jr, McCashland T, Sorrell M, Tempero M, Langnas A. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant. 2002 Sep;2(8):774-9. doi: 10.1034/j.1600-6143.2002.20812.x.

**PMID:** 12243499

**Citation:** Cambridge WA, Fairfield C, Powell JJ, Harrison EM, Soreide K, Wigmore SJ, Guest RV. Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma. Ann Surg. 2021 Feb 1;273(2):240-250. doi: 10.1097/SLA.0000000000003801.

**PMID:** 32097164

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000000230

- Term: Adenocarcinoma

- ID: D000002277

- Term: Carcinoma

- ID: D000009375

- Term: Neoplasms, Glandular and Epithelial

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M20426

- Name: Cholangiocarcinoma

- Relevance: HIGH

- As Found: Cholangiocarcinoma

- ID: M20430

- Name: Klatskin Tumor

- Relevance: HIGH

- As Found: Hilar Cholangiocarcinoma

- ID: M3585

- Name: Adenocarcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M5534

- Name: Carcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M12320

- Name: Neoplasms, Glandular and Epithelial

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: T755

- Name: Bile Duct Cancer

- Relevance: HIGH

- As Found: Cholangiocarcinoma

- ID: T3241

- Name: Klatskin Tumor

- Relevance: HIGH

- As Found: Hilar Cholangiocarcinoma

### Condition Browse Module - Meshes

- ID: D000018281

- Term: Cholangiocarcinoma

- ID: D000018285

- Term: Klatskin Tumor

### Intervention Browse Module - Ancestors

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000000964

- Term: Antimetabolites, Antineoplastic

- ID: D000000963

- Term: Antimetabolites

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Hemat

- Name: Hematinics

### Intervention Browse Module - Browse Leaves

- ID: M2985

- Name: Gemcitabine

- Relevance: HIGH

- As Found: Activity

- ID: M377

- Name: Capecitabine

- Relevance: HIGH

- As Found: Function

- ID: M6182

- Name: Cisplatin

- Relevance: LOW

- As Found: Unknown

- ID: M11110

- Name: Liver Extracts

- Relevance: LOW

- As Found: Unknown

- ID: M4281

- Name: Antimetabolites

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000093542

- Term: Gemcitabine

- ID: D000069287

- Term: Capecitabine

### Misc Info Module

- Version Holder: 2024-05-31
