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

Trial Summary

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.

What data supports the effectiveness of the drug Durvalumab in combination with chemotherapy for biliary tract cancer?

Research shows that Durvalumab, when combined with gemcitabine and cisplatin, significantly improves survival rates in patients with advanced biliary tract cancer, as demonstrated in the phase 3 TOPAZ-1 trial. ^{1 2 3 4 5}

Is the combination of durvalumab, gemcitabine, and cisplatin safe for humans?

The combination of durvalumab, gemcitabine, and cisplatin has been shown to be generally safe and manageable in patients with advanced biliary tract cancer, according to several studies. These treatments have been used in clinical trials and are approved in various countries, indicating a level of safety for human use. ^{1 2 6 7 8}

What makes the treatment of Chemoimmunotherapy + Hyperthermia + Radiotherapy for Biliary Tract Cancer unique?

This treatment is unique because it combines chemoimmunotherapy, which includes the use of durvalumab (an immunotherapy drug that helps the immune system fight cancer) and cisplatin (a chemotherapy drug), with hyperthermia (using heat to enhance the effects of cancer treatment) and radiotherapy (using radiation to kill cancer cells), offering a multi-faceted approach that is not standard for biliary tract cancer. ^{1 2 3 4 9}

What is the purpose of this trial?

This study is being done to see if the investigators can improve the outcome of patients with biliary tract cancer that do not qualify for surgery. This study will compare the effects, good and/or bad, of using a combination of standard of care chemoimmunotherapy, with the addition of radiation and deep hyperthermia. In this study, participants will be receiving standard of care chemoimmunotherapy (gemcitabine, cisplatin, and durvalumab), radiation (spatially fractionated radiation therapy), and deep hyperthermia. Chemoimmunotherapy Chemoimmunotherapy is when chemotherapy drugs are combined with immunotherapy drugs. Chemotherapy uses different drugs to kill or slow the growth of cancer cells, whereas immunotherapy drugs are used to help the immune system attack cancer cells. For this study, the drugs Gemcitabine, Cisplatin, and Durvalumab will be used. Chemoimmunotherapy will be delivered over 4 cycles for this study and can continue longer if the treating physician decides this is appropriate. Each cycle will last 3 weeks. Spatially fractionated radiation therapy (SFRT) SFRT is a form of radiation therapy that gives a single large dose of radiation to large tumors or tumors that do not qualify for surgery. This is not a standard type of treatment for people with this diagnosis. For this study, participants will be receiving radiation once on day 1 of the second chemoimmunotherapy cycle. Deep Hyperthermia (HT) Hyperthermia is used in combination with chemoimmunotherapy and radiation treatment in this study. Hyperthermia has the potential to make both chemotherapy and radiation treatments more effective. For this study, participants will receive HT three times: on the first day of cycles 2, 3, and 4 of chemoimmunotherapy.

Research Team

Jason Molitoris, MD

Principal Investigator

University of Maryland Medical Center / Maryland Proton Treatment Center

Eligibility Criteria

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

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

I have never been treated with anti-PD1 or anti-PDL1 antibodies.

Exclusion Criteria

I had cancer before, but it was either treated over 2 years ago, was a non-melanoma skin cancer, or was a carcinoma in situ, all without current signs of disease.

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

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 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]

References

1. France pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Advanced Biliary Tract Cancer. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Moving beyond single-agent checkpoint inhibition in biliary tract cancers: what is the next frontier? [2023]

4. England 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. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Fixed-dose-rate gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas. [2022]

6. England 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. [2021]

7. England 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. [2022]

8. Netherlands 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. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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