Chemoimmunotherapy + Hyperthermia + Radiotherapy for Biliary Tract Cancer

Recruiting at 1 trial location

Overseen By Caitlin Eggleston

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Maryland, Baltimore

Must not be taking: Immunosuppressive medications

Disqualifiers: Ampullary carcinoma, Organ transplant, Autoimmune disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 11

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding deep heat treatment and special radiation to standard chemoimmunotherapy can combat biliary tract cancer, which affects the liver and surrounding areas and is not treatable with surgery. The treatment combines chemotherapy drugs, including Cisplatin, and immunotherapy, such as Durvalumab, with radiation and deep heat to enhance effectiveness. Individuals with advanced biliary tract cancer, who have not received prior treatment for this condition and have a specific type of tumor, might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment, except for hormonal therapy for non-cancer related conditions. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the chemoimmunotherapy drugs used in this trial—Gemcitabine, Cisplatin, and Durvalumab—are commonly used to treat biliary tract cancer. One study found that combining Cisplatin with Gemcitabine extended patients' lives by an average of 3.6 months compared to using Gemcitabine alone. Adding Durvalumab to this combination resulted in a 72% response rate in other trials, with no new safety issues reported.

Deep hyperthermia involves heating tumor tissues to enhance the effectiveness of treatments like chemotherapy and radiation. Some studies suggest it can improve treatment outcomes, but its use is still being researched, and there is limited safety data in this specific context.

Spatially fractionated radiation therapy (SFRT) targets large tumors with a single, high dose of radiation. This method has been shown to safely increase the radiation dose and is a new technique being explored.

Overall, while these treatments have been used safely in other situations, their combined use in this trial is still under investigation. As this is a Phase 1 trial, the primary goal is to assess safety and tolerance, with careful monitoring for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for biliary tract cancer because it combines chemoimmunotherapy with hyperthermia and radiotherapy, offering a multi-pronged attack on cancer cells. Unlike traditional treatments that typically involve chemotherapy alone, this approach uses cisplatin and durvalumab to not only directly attack tumors but also harness the immune system to fight the cancer. The addition of deep hyperthermia is particularly intriguing as it enhances the effects of chemotherapy and radiotherapy by increasing the sensitivity of cancer cells. This comprehensive strategy aims to improve patient outcomes more effectively than existing options.

What evidence suggests that this trial's treatments could be effective for biliary tract cancer?

In this trial, participants will receive a combination of treatments, including cisplatin and gemcitabine. Research has shown that this combination can help biliary tract cancer patients live longer. One study found that 59.3% of patients receiving this combination were alive without cancer progression after six months, compared to 42.5% of those receiving only gemcitabine. The trial also includes durvalumab, a type of immunotherapy, which evidence suggests can further improve outcomes by extending overall survival. Additionally, deep hyperthermia, which involves heating body tissues to enhance treatment effectiveness, has shown high success rates when combined with chemotherapy. Spatially fractionated radiotherapy (SFRT), which targets different parts of the tumor separately, has been effective in shrinking tumors and controlling cancer growth. Together, these treatments offer a promising approach for those with advanced biliary tract cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Jason Molitoris, MD

Principal Investigator

University of Maryland Medical Center / Maryland Proton Treatment Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced biliary tract cancer who are not candidates for surgery. Participants will receive a combination of standard chemoimmunotherapy (gemcitabine, cisplatin, durvalumab), radiation therapy, and deep hyperthermia to test if this improves outcomes.

Inclusion Criteria

Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

Adequate organ and marrow function as defined below: Hemoglobin ≥ 9.0 g/dL, ANC ≥ 1.5 x 109/L, Platelet count ≥ 100 x 109/L, Serum bilirubin ≤ 2.5 x upper limit of normal (ULN), Alanine aminotransferase and aspartate aminotransferase ≤ 3 x ULN, Measured creatinine clearance > 50 mL/min or calculated creatinine clearance > 50 mL/min as determined by Cockcroft-Gault (using actual body weight)

I have never been treated with gemcitabine or platinum-based chemotherapy.

Exclusion Criteria

Participation in another clinical study with an investigational product administered in the last 3 months

Concurrent enrollment in another clinical study, unless it is an observational clinical study or during the follow-up period of an interventional study

Judgement by the investigator that the participant should not participate in the study if they are unlikely to comply with study procedures, restrictions, and requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoimmunotherapy

Participants receive standard of care chemoimmunotherapy (gemcitabine, cisplatin, and durvalumab) over 4 cycles, each lasting 3 weeks

12 weeks

8 visits (in-person)

Radiation and Hyperthermia

Participants receive spatially-fractionated radiotherapy on day 1 of the second chemoimmunotherapy cycle and deep hyperthermia on the first day of cycles 2, 3, and 4

9 weeks

3 visits (in-person) for hyperthermia

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and radiographic response

16 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Deep Hyperthermia
• Durvalumab
• Spatially Fractionated RT

Trial Overview The study tests the effectiveness of adding spatially fractionated radiation therapy and deep hyperthermia to standard chemoimmunotherapy in treating biliary tract cancer. The treatment includes four cycles of chemotherapy combined with immunotherapy drugs and targeted radiation.

How Is the Trial Designed?

Group I: Chemoimmunotherapy + SFRT + Deep Hyperthermia Experimental Treatment 5 Interventions

1. Gemcitabine 1000mg/m2 via intravenous infusion on days 1 and 8 of every 21-day cycle for up to 8 cycles 2. Cisplatin 25mg/m2 via intravenous infusion on days 1 and 8 of every 21-day cycle for up to 8 cycles 3. Durvalumab 1500mg via intravenous infusion on day 1 of every 21-day cycle for up to 8 cycles 4. Deep hyperthermia and spatially-fractionated radiotherapy will be administered to 1 measurable lesion on cycle 2-day 1 and deep hyperthermia alone will be delivered to the same lesion on cycle 3-day 1 and cycle 4-day 1

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Published Research Related to This Trial

In a phase II study involving 42 patients with unresectable biliary tract carcinoma, LFP therapy (5-FU continuous infusion and low-dose cisplatin) showed an overall response rate of 42.9%, indicating its potential efficacy in treating advanced biliary tract malignancies.

The treatment was generally well-tolerated, with anemia being the most common side effect, but no treatment-related deaths or severe toxicities occurred, suggesting a favorable safety profile for outpatient administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma. Kobayashi, K., Tsuji, A., Morita, S., et al.[2021]

In a phase II trial involving 50 patients with inoperable biliary tract cancers, the combination of fixed-dose-rate gemcitabine and cisplatin resulted in a 26% partial response rate and a median response duration of 8.3 months.

The treatment was generally well tolerated, with low rates of severe side effects, although 38% of patients discontinued due to toxicity or personal preference, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-dose-rate gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas. Goldstein, D., Gainford, MC., Brown, C., et al.[2022]

In a real-world study of 145 patients with advanced biliary tract cancer, the combination of durvalumab with gemcitabine and cisplatin achieved a median progression-free survival (PFS) of 8.9 months and a median overall survival (OS) of 12.9 months, confirming the efficacy seen in the TOPAZ-1 trial.

The treatment was associated with a high rate of adverse events (94.5%), with 35.2% experiencing severe (grades 3-4) adverse events, but only 2.1% had severe immune-mediated adverse events, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data. Rimini, M., Fornaro, L., Lonardi, S., et al.[2023]

In a phase 2 study involving 128 patients with advanced biliary tract cancer, the combination of gemcitabine and cisplatin with the immunotherapy durvalumab (and tremelimumab for some) resulted in a promising objective response rate of 66%, indicating potential efficacy as a first-line treatment.

The treatment was generally safe, with the most common severe side effects being decreased neutrophil count and anemia, but no unexpected safety events or treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Oh, DY., Lee, KH., Lee, DW., et al.[2023]

A comprehensive analysis of 161 trials involving 6,337 patients found that the standard gemcitabine platinum (GP) chemotherapy has a median overall survival of 9.5 months and a tumor control rate of 63.5%.

Newer treatment regimens, including triplet combinations of gemcitabine, fluoropyrimidine, and platinum (GFP) or gemcitabine with targeted therapies, showed significantly better tumor control and overall survival compared to the standard GP regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy and targeted therapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Eckel, F., Schmid, RM.[2022]

The study established that the maximum tolerated dose and recommended dose for the combination of S-1, gemcitabine, and cisplatin in treating advanced biliary tract adenocarcinoma is level 0: gemcitabine at 800 mg/m²/week, cisplatin at 25 mg/m²/week, and S-1 at 40 mg/m²/day, based on treatment of 17 patients.

The treatment regimen was well tolerated, with some dose-limiting toxicities observed, and it demonstrated promising antitumor activity, with five partial responses noted among the participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of oral administration of S-1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer. Shoji, H., Morizane, C., Sakamoto, Y., et al.[2022]

In the phase 3 TOPAZ-1 trial, the combination of durvalumab with gemcitabine and cisplatin significantly improved overall survival and progression-free survival in adults with advanced biliary tract cancer, compared to the placebo group.

Durvalumab's benefits were consistent across various patient factors, including tumor location and PD-L1 expression levels, and the treatment was found to be manageable in terms of tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Advanced Biliary Tract Cancer. Fung, S., Syed, YY.[2023]

In the safety run-in of the IMMUNOBIL PRODIGE 57 trial involving 20 patients, the combination of durvalumab and tremelimumab with paclitaxel resulted in a high rate of dose-limiting toxicities (50%), including serious anaphylactic reactions and other severe adverse events.

Due to the safety concerns raised by the combination therapy, the trial will proceed with only the durvalumab and tremelimumab combination, indicating that the addition of paclitaxel may not be safe for patients with advanced biliary tract carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Boilève, A., Hilmi, M., Gougis, P., et al.[2021]

Durvalumab, an anti-PD-L1 antibody, has been shown to improve overall survival in patients with advanced biliary tract cancers when combined with chemotherapy, based on results from a randomized phase III trial.

Future research is focusing on new combinations of immunotherapy agents, such as those targeting CTLA-4 or OX40, which may enhance T-cell activation and lead to better treatment outcomes compared to current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving beyond single-agent checkpoint inhibition in biliary tract cancers: what is the next frontier? Serrano Uson Junior, PL., Bekaii-Saab, T.[2023]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa0908721

Cisplatin plus Gemcitabine versus Gemcitabine for Biliary ... The 6-month progression-free survival rate was 59.3% in the cisplatin–gemcitabine group and 42.5% in the gemcitabine-only group. Figure 2.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4509359/

Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable.

3. sciencedirect.com sciencedirect.com/science/article/pii/S2589555924002945

A systematic review and meta-analysis using reconstructed ... Median survival with GemCis remained at 12 months over time, indicating no significant second-line treatment improvement. Background & Aims. Gemcitabine/ ...

4. academic.oup.com academic.oup.com/oncolo/article/30/8/oyae306/7905746

Real-world effectiveness and prognostic factors of durvalumab ... The TOPAZ-1 trial of durvalumab plus first-line chemotherapy (gemcitabine plus cisplatin) showed improved survival vs chemotherapy alone.

5. esmogastro.org esmogastro.org/article/S2949-8198(24)00016-5/fulltext

Second-line FOLFOX chemotherapy for patients with ... Second-line FOLFOX appears to be an effective treatment for advanced-stage biliary tract cancers. FOLFOX has a manageable toxicity profile.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10453877/

Safety and Effectiveness of Chemotherapy in Elderly Biliary ... The safety and effectiveness of chemotherapy in elderly patients with biliary tract cancer (BTC) remain unclear. Therefore, we retrospectively reviewed ...

7. thelancet.com thelancet.com/journals/lanwpc/article/PIIS2666-6065(24)00347-X/fulltext

Updated efficacy and safety data from a phase II, single ... This study aims to provide an updated analysis of the safety and efficacy of neoadjuvant DurGAP for resectable BTC in our latest cohort of 30 patients.

8. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2839520

Gemcitabine and Cisplatin Plus Polymeric Micellar ... The prognosis for advanced biliary tract cancer is poor, with a median overall survival (OS) of approximately 1 year. Treatment with gemcitabine ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4093

Three-year follow-up data from KEYNOTE-966 We present updated efficacy and safety data after 11 mo of additional follow-up. ... cisplatin (gem/cis) for advanced biliary tract cancer (BTC).