Durvalumab + Chemotherapy for Bile Duct Cancer

Recruiting at 56 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disorders, Active infection, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 13

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well giving durvalumab with standard chemotherapy, gemcitabine and cisplatin, before surgery works in treating patients with high risk liver cancer (cholangiocarcinoma) that can be removed by surgery (resectable). Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving durvalumab with gemcitabine and cisplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed in patients with high risk resectable cholangiocarcinoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use immunosuppressive medications within 14 days before starting the trial, except for certain types of steroids. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Durvalumab, Gemcitabine, and Cisplatin for bile duct cancer?

Research shows that adding Durvalumab to Gemcitabine and Cisplatin significantly improves survival in patients with advanced bile duct cancer, as seen in the TOPAZ-1 trial. This combination is now a valuable treatment option for this condition. ^{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 studied in patients with advanced biliary tract cancer, and the safety profile was found to be manageable. This means that while there may be side effects, they are generally considered acceptable and can be managed with medical care. ^{1 2 4 6 7}

What makes the drug combination of Durvalumab, Cisplatin, and Gemcitabine unique for bile duct cancer?

This drug combination is unique because it includes Durvalumab, an immunotherapy that blocks a protein called PD-L1, helping the immune system fight cancer more effectively. In studies, this combination has shown to significantly improve survival in patients with advanced bile duct cancer compared to the standard chemotherapy alone. ^{1 2 6 8 9}

Research Team

Hop Tran Cao, MD

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

This trial is for patients with a specific liver cancer called intrahepatic cholangiocarcinoma that can be surgically removed. They must have measurable disease, no prior treatments for this cancer, and be fit for surgery. The tumor should be larger than 5 cm or there may be regional lymph node metastases or vascular invasion.

Inclusion Criteria

I have a tumor that can be measured and is at least 1 cm in size.

A surgeon has approved me for surgery.

My bile duct cancer is confirmed and can be surgically removed.

Exclusion Criteria

Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment, Major surgical procedure (as defined by the Investigator) within 14 days prior to the first dose of durvalumab. Note: Local surgery of isolated lesions for palliative intent or biliary stents is acceptable, Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection), Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent, Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication), Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 30 days after the last dose of durvalumab, Patients who are receiving any other investigational agents, History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab, gemcitabine, cisplatin, or other platinum-containing compounds, Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make this protocol unreasonably hazardous, Pregnant women are excluded from this study because durvalumab (MEDI4736) is an anti-PD-L1 monoclonal antibody agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with durvalumab, breastfeeding should be discontinued if the mother is treated with durvalumab. These potential risks may also apply to other agents used in this study. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months after durvalumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately, Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of durvalumab, Patients with active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: Patients with vitiligo or alopecia, Patients with hypothyroidism (e.g. following Hashimoro syndrome) stable on hormone replacement, Any chronic skin condition that does not require systemic therapy, Patients without active disease in the last 5 years may be included but only after consultation with the study physician, Patients with celiac disease controlled by diet alone, Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA, History of allogenic organ transplantation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Neoadjuvant Therapy

Participants receive durvalumab with gemcitabine and cisplatin for 4 cycles before surgery

12 weeks

4 visits (in-person)

Surgical Resection

Participants undergo surgical resection to remove the tumor

1 week

1 visit (in-person)

Adjuvant Therapy

Participants may continue durvalumab, gemcitabine, and cisplatin regimen for up to 4 additional cycles

12 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months for 2 years, then every 6 months for 5 years, then yearly

Treatment Details

Interventions

• Cisplatin
• Durvalumab
• Gemcitabine

Trial Overview The study tests the combination of durvalumab (a monoclonal antibody) with standard chemotherapy drugs gemcitabine and cisplatin before surgery in high risk liver cancer patients to see if it reduces the tumor size more effectively than current methods.

Participant Groups

Group I: Treatment (durvalumab, gemcitabine, cisplatin) Experimental Treatment 8 Interventions

Patients receive durvalumab IV over 60 minutes on day 1 with gemcitabine IV over 30 minutes and cisplatin IV over 60 minutes on days 1 and 8 for 4 cycles and then undergo surgical resection on study. Following surgery, patients may continue the durvalumab, gemcitabine and cisplatin regimen for up to 4 additional cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT scans and/or MRI scans and blood sample collection throughout study, as well as tissue biopsies during screening and on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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]

In a study of 29 patients with unresectable biliary tract cancer, the combination therapy of gemcitabine (GEM) and cisplatin (CDDP) demonstrated a disease control rate of 66.7%, indicating its effectiveness as a treatment option.

The therapy was found to be safe, with manageable adverse effects; the most common severe hematological toxicity was neutropenia (65.5%), but there were no cases of interstitial pneumonia reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience]. Muneta, M., Ohmura, Y., Takeda, Y., et al.[2023]

In a phase II study involving 38 patients with unresectable or metastatic biliary tree carcinoma, the combination of gemcitabine and cisplatin showed an overall response rate of 32%, with one complete response and 11 partial responses, indicating its efficacy in treating this type of cancer.

The treatment was generally well-tolerated, with mild side effects and only a few cases of severe toxicity, suggesting that the GEM/CDDP regimen is a safe and reasonable option for palliative care in advanced biliary tree carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM). Giuliani, F., Gebbia, V., Maiello, E., et al.[2022]

In a study of 43 patients with unresectable biliary tract cancer, the combination of gemcitabine and cisplatin showed an overall response rate of 27.5%, indicating it has potential efficacy in treating this difficult-to-treat cancer.

The treatment was generally well-tolerated, with manageable side effects, including low rates of severe hematologic toxicity, suggesting that gemcitabine plus cisplatin could be a safe option for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Thongprasert, S., Napapan, S., Charoentum, 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 Phase I trial established the maximally tolerated doses (MTD) for two drug combinations: everolimus plus gemcitabine and the three-drug regimen including cisplatin, with both regimens being generally well tolerated despite hematologic dose-limiting toxicities (DLTs).

The trial showed promising efficacy, with complete responses in two patients and partial responses in three others, suggesting that the three-drug combination could be a viable option for future studies in specific cancers like cholangiocarcinoma and gallbladder carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. Costello, BA., Borad, MJ., Qi, Y., et al.[2022]

Adding durvalumab to gemcitabine and cisplatin for advanced biliary tract cancer resulted in only a modest increase in quality-adjusted life years (0.12 QALY) but came with a high incremental cost, leading to an incremental cost-effectiveness ratio (ICER) of $159,644.70/QALY with charity assistance and $696,571.11/QALY without, both exceeding the willingness-to-pay threshold in China.

The analysis indicated that durvalumab would only become cost-effective if its price dropped by over 94.2%, highlighting that the high cost of durvalumab significantly impacts its economic viability as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of adding durvalumab to chemotherapy as first-line treatment for advanced biliary tract cancer based on the TOPAZ-1 trial. Zhao, Q., Xie, R., Zhong, W., 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]

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. Japan pubmed.ncbi.nlm.nih.gov

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience]. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM). [2022]

5. England pubmed.ncbi.nlm.nih.gov

Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. [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. United States pubmed.ncbi.nlm.nih.gov

Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of adding durvalumab to chemotherapy as first-line treatment for advanced biliary tract cancer based on the TOPAZ-1 trial. [2023]

9. 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]