Consolidative Radiotherapy (CSRT) in Patients With Oligometastatic/Locally Advanced Unresectable Bilary Tract Cancer (BTC) (RADITOP)

Standard-of-care Systemic Therapy With or Without Consolidative Radiotherapy in Patients With Oligometastatic/Locally Advanced Unresectable Biliary Tract Cancer: an Open-label, Randomised, Controlled Study

The purpose of this clinical trial is to investigate whether the inclusion of radiotherapy, in addition to standard-of-care systemic therapy, could improve the treatment effectiveness of patients with oligometastatic/locally advanced unresectable biliary tract cancer. The primary question that the trial aims to address is: does the addition of consolidative radiotherapy to standard-of-care systemic therapy for treating oligometastatic/locally advanced unresectable biliary tract cancer, result in a prolonged progression-free survival (PFS)?

Researchers will assess whether radiotherapy can enhance PFS by comparing the survival time of patients with oligometastatic/locally advanced unresectable biliary tract cancer who receive standard-of-care systemic therapy alone versus those who receive standard-of-care systemic therapy along with consolidative radiotherapy.

Participants in this trial will:

Either receive or not receive consolidative radiotherapy following six cycles of standard-of-care systemic therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Biliary Tract Cancer
• Intervention / Treatment: Radiation: Consolidative radiotherapy; Drug: Standard-of-care systemic therapy: Gemcitabine + cisplatin/oxaliplatin + Durvalumab/Pembrolizumab/Sintilimab/Toripalimab

Detailed Description

Standard-of-care systemic therapy with or without consolidative radiotherapy in patients with oligometastatic/locally advanced unresectable biliary tract cancer: an open-label, randomised, controlled study.

Eligible patients will be randomized in a 1:1 ratio to receive either current standard systemic therapy alone (control arm) or standard systemic therapy plus consolidative radiotherapy to all sites of known disease (experimental arm). Patients in both arms have the option of receiving upfront or subsequent standard palliative radiotherapy to any symptomatic sites requiring prompt intervention.

Because of the different treatment modalities in the study, it is not possible to blind the patient or physician to the treatment arm. Follow-ups for tumor assessment will conclude 2 years after randomization.

• Study Type: Interventional
• Enrollment (Estimated): 128
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Qianqian Zhao; Phone Number: +8618217008910; Email: zhao.qianqian1@zs-hospital.sh.cn
• Study Contact Backup: Name: Zhaochong Zeng; Phone Number: +8613817076800; Email: zeng.zhaochong@zs-hospital.sh.cn

Study Locations

• China
  • Shanghai, China, 200032
    • Zhongshan Hospital
    • Contact: Zhaochong Zeng; Phone Number: +8613817076800; Email: zeng.zhaochong@zs-hospital.sh.cn
    • Principal Investigator: Zhaochong Zeng

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The disease has not progressed following the restaging imaging evaluation in patients with oligometastatic/locally advanced unresectable BTC after four cycles of first-line systemic treatment.
2. Definition of oligometastatic/locally advanced unresectable BTC disease: not a candidate for surgical resection at all sites: surgery to all sites not recommended by multidisciplinary team, or unfit or declining surgery.
3. Definition of oligometastatic disease: patients with distant organ metastasis or nonregional lymph node metastasis, or distant organ/nonregional lymph node metastasis and regional lymph node metastasis, as defined by the American Joint Committee on Cancer, 8th edition. The total number of metastases is ≤5 and the number of metastases in any single organ system (e.g., lung, liver) is ≤3.
4. All sites of disease must be amenable to radiotherapy and can be safely treated. Each lesion is counted separately at the time of registration and contributes to the total number of metastases. For regional lymph nodes metastases, all positive regional lymph nodes are counted together as one lesion. For nonregional lymph node metastases, adjacent metastatic lymph nodes can be treated as one lesion. Lesions that have subsided during previous treatment (i.e., are no longer visible on CT scan or have eliminated affinity on positron emission tomography [PET]-CT) are not included in the total number. At least one metastatic lesion meets the RECIST v1.1 criteria for assessable lesions. Bone metastases without soft tissue involvement can be included but are not considered assessable lesions. However, if bone metastases have soft tissue involvement and meet the criteria for assessable lesions, they are considered measurable lesions.
5. Patients who experience recurrence after curative surgery with a time interval of >6 months can be eligible for inclusion. If adjuvant therapy (excluding radiotherapy) is administered, the patient must have completed adjuvant therapy for a period of at least 6 months before meeting the inclusion criteria.
6. Primary tumor lesions and all metastases of current diagnosis have not received local treatment, such as radiotherapy, surgery or radiofrequency ablation, prior to enrollment.
7. The patient is over 18 years old and has an Eastern Cooperative Oncology Group score of 0-1;
8. Life expectancy is greater than 12 weeks.
9. Vital organ function meets the following requirements: absolute neutrophil count ≥1.5 × 109/l; platelet count ≥100 × 109/l; hemoglobin ≥9 g/dl; serum albumin ≥2.8 g/dl; total bilirubin ≤1.5 × upper limit of normal (ULN) and alanine transaminase, aspartate aminotransferase and/or alkaline phosphatase ≤2.5 × ULN (if there is liver metastasis, alanine transaminase and/or aspartate aminotransferase ≤5 × ULN; if there is liver metastasis or bone metastasis, alkaline phosphatase ≤5 × ULN); serum creatinine ≤1.5 × ULN or creatinine clearance >60 ml/min. For patients with pulmonary lesions or previous lung irradiation who are known or suspected to have impaired lung function, the forced expiratory volume for 1 second of lung function must be above 1 l.
10. Female subjects of childbearing age must have a negative urine or serum pregnancy test within 72 h prior to randomization. Subjects must agree to adequate contraception during the trial.
11. Each patient is voluntarily enrolled, and the informed consent form is signed by the patient or their legal representative.

Exclusion Criteria:

1. Histology includes components of mixed hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, or biliary adenocarcinoma.
2. Complete response to four cycles of first-line systemic treatment (i.e. no measurable target for radiotherapy).
3. There is new metastasis during the four cycles of first-line systemic treatment and the number of metastases is more than five.
4. Patient has uncontrolled brain metastases or vertebral body metastasis with spinal cord compression symptoms.
5. The toxicity of previous antitumor treatment has not recovered to ≤1 based on National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 (except for hair loss) or the level specified by the inclusion/exclusion criteria.
6. Patient has uncontrolled pleural, pericardial or pelvic effusion that requires repeated drainage.
7. Patient is a pregnant or breastfeeding woman.
8. Patient has a history of immunodeficiency or severe medical disease that is not well controlled and may have an effect on study treatment.
9. Any other malignant tumor has been diagnosed within 5 years prior to or after the diagnosis of BTC, except for malignant tumors with a low risk of metastasis and death (5-year survival rate >90%), such as well-treated basal cell or squamous cell skin cancer or cervical cancer in situ.
10. Any other condition which in the judgment of the investigator would make the patient inappropriate for entry into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group: consolidative radiotherapy group; patients treated with standard-of-care systemic therapy combined with consolidative radiotherapy	Radiation: Consolidative radiotherapy; Consolidative radiotherapy: total dose and number of fractions will depend on the site of disease. Treatment will be given daily, or every other day, over 1 -3 weeks. Physicians should try to give the highest BED whenever possible while respecting normal tissue tolerance. All lesions are recommended to receive a biologically effective dose (BED) of 60 Gy or higher (BED10≥70), assuming α/β ratio of 10 and using the linear-quadratic model: BED = nd x [1 + d/(α/β)] where n is number of fractions and d is dose per fraction. Sometimes BED ≥80 Gy is preferred, with lower doses ≥50 Gy allowed at the discretion of the treating physician for concerns about normal tissue toxicity.; Drug: Standard-of-care systemic therapy: Gemcitabine + cisplatin/oxaliplatin + Durvalumab/Pembrolizumab/Sintilimab/Toripalimab; Standard-of-care systemic therapy as decided by the treating medical oncologist: Gemcitabine + cisplatin/oxaliplatin + Durvalumab/Pembrolizumab/Sintilimab/Toripalimab
Other: control group: standard-of-care systemic therapy alone; patients treated with standard-of-care systemic therapy	Drug: Standard-of-care systemic therapy: Gemcitabine + cisplatin/oxaliplatin + Durvalumab/Pembrolizumab/Sintilimab/Toripalimab; Standard-of-care systemic therapy as decided by the treating medical oncologist: Gemcitabine + cisplatin/oxaliplatin + Durvalumab/Pembrolizumab/Sintilimab/Toripalimab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression free survival is defined as the duration between the date of randomization to the date of first documented progression or death due to any cause or date of last follow-up, whichever is earlier.	Upto 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Overall survival is defined as the duration between the date of randomization to the date of death due to any cause or the date of last follow-up, whichever is earlier.	Upto 2 years
Local control rates of treated sites	Local control rate will be defined as the absence of progressive disease at the treated sites.	Upto 2 years
New distant metastases	Time to onset of new distant metastases.	Upto 2 years
Response rates	To compare response rates between the two arms.	From randomization every 3 months upto 2 years
Radiotherapy related toxicity using CTC v5.0 (radiotherapy related acute and late toxicity)	At baseline and at subsequent follow up till 2 years.	Upto 2 years
Health Related QOL using the EORTC-QLQ-C30 questionnaire	To evaluate patient reported outcomes between the two arms. EORTC QLQ-C30 scales: global health/QoL, functional domains (physical, role, cognitive, emotional, social), and symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea). Recall period: past week; response range: not at all to very much, global/QOL range: very poor to excellent. Scale score range: 0 to 100. Higher functional/global QoL score = better functioning and higher symptom score = greater degree of symptoms.	From randomization every 3 months till 2 years
Health Related QOL using the EORTC QLQ-BIL21 questionnaire	To evaluate patient reported outcomes between the two arms. EORTC QLQ-BIL21 (European Organisation for Research and Treatment of Cancer questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the gallbladder), scores range from 0 to 100, where a lower score means a better quality of life.	From randomization every 3 months till 2 years

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital
• Investigators: Principal Investigator: Zhaochong Zeng, Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: July 7, 2024
• First Submitted That Met QC Criteria: July 14, 2024
• First Posted (Actual): July 15, 2024

Study Record Updates

• Last Update Posted (Actual): July 17, 2024
• Last Update Submitted That Met QC Criteria: July 15, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: biliary tract cancer; consolidative radiotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Biliary Tract Diseases; Biliary Tract Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Oxaliplatin; Durvalumab; Pembrolizumab; Gemcitabine
• Other Study ID Numbers: KY2024139; ZSLCYJ202308 (Other Grant/Funding Number: Zhongshan Hospital, Fudan University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The IPD will not be shared with other researchers in order to protect patients' privacy.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No