Immunotherapy + Propranolol + Chemotherapy for Hepatopancreatic Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must be taking: Propranolol

Must not be taking: Immunosuppressants

Disqualifiers: Prior treatment, Cardiovascular disease, Autoimmune, 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: 3

Duration: Up to 2 years

62 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for advanced pancreatic, liver, and biliary tract cancers. Researchers are testing the effectiveness of immunotherapy drugs (durvalumab and tremelimumab) combined with propranolol, with or without chemotherapy, in slowing cancer progression. The goal is to determine if this combination surpasses current treatments in effectiveness. Individuals with a confirmed diagnosis of advanced pancreatic, hepatocellular, or biliary tract cancer, who have not received prior palliative systemic treatment, might be suitable for the trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that current use of immunosuppressive medication is an exclusion criterion, except for certain types like intranasal or inhaled steroids. It's best to discuss your specific medications with the trial team.

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

Research shows that the treatment combinations in this trial have been studied for safety in various cancers. For biliary tract cancer, the combination of durvalumab with gemcitabine and cisplatin has proven to be safe and generally well-tolerated, as expected for these treatments. Studies report that patients usually handle these treatments well, without any unexpected side effects.

For pancreatic cancer, research on durvalumab and tremelimumab, when used with gemcitabine and nab-paclitaxel, indicates that the combination is generally safe. Patients have shown a manageable safety profile, and similar results have appeared in other cancers.

In liver cancer, durvalumab and tremelimumab have undergone extensive study. Some serious side effects were noted, with a small number of fatal reactions reported. However, these outcomes are rare, and the overall safety is considered acceptable.

Propranolol, a drug often used for heart conditions, is included in the combinations. It has a long history of safe use, though its role in cancer treatment is still being explored. Overall, past research shows that the treatments in this trial are generally well-tolerated, but monitoring for side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for hepatopancreatic cancer because they combine immunotherapy with traditional chemotherapy and the beta-blocker propranolol, aiming to enhance the body’s immune response against cancer cells. Unlike standard treatments like surgery, chemotherapy, or radiation, this approach uses Durvalumab and Tremelimumab to boost the immune system directly. Additionally, propranolol is thought to reduce stress-related hormones that may aid cancer growth. This multi-faceted strategy not only targets the cancer cells more effectively but also potentially limits the cancer's ability to spread, offering a novel approach compared to current options.

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

Research has shown that adding durvalumab to chemotherapy can greatly improve outcomes for patients with biliary tract cancer. In this trial, participants with biliary tract cancer will receive durvalumab combined with gemcitabine, cisplatin, and continuous propranolol, with tremelimumab administered on day 1 of cycle 1. Studies have found that this combination doubles the survival rate over three years.

For pancreatic cancer, participants in this trial will receive durvalumab with tremelimumab, gemcitabine, nab-paclitaxel, and continuous propranolol. Early results suggest that this combination offers a significant survival advantage.

In liver cancer, participants will receive durvalumab and tremelimumab with continuous propranolol. This combination has shown a major survival benefit and has received FDA approval for this type of cancer. Researchers aim to determine if adding propranolol can enhance these positive effects for all the cancers studied in this trial. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

Adults with advanced pancreatic, liver, or biliary tract cancers who have measurable disease and a life expectancy of at least 12 weeks. They must not have received prior systemic treatment for their cancer, be able to consent to the trial, use effective birth control if applicable, and meet specific health criteria including organ function tests.

Inclusion Criteria

Measurable disease must be present according to RECIST criteria V1.1

Body Weight >30kg

I am able to understand and agree to the study's requirements.

Exclusion Criteria

I have had pneumonitis treated with steroids.

Other severe acute or chronic medical conditions including inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study

I am not pregnant or breastfeeding and agree to use birth control during and after treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Durvalumab every 3-4 weeks, Tremelimumab on day 1 of cycle 1, and continuous propranolol, with chemotherapy as applicable

Up to 2 years

Visits every 3-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Durvalumab
• Gemcitabine
• Nab paclitaxel
• Propranolol
• Tremelimumab

Trial Overview

The study is testing Durvalumab and Tremelimumab in combination with Propranolol and chemotherapy (Nab paclitaxel + Gemcitabine or Cisplatin) for treating advanced hepatopancreaticobiliary tumors. The drugs are given on different schedules depending on the type of cancer being treated.

How Is the Trial Designed?

Group I: Pancreatic Cancer Experimental Treatment 5 Interventions

Durvalumab will be administered once every 4 weeks, in combination with gemcitabine + nab-paclitaxel (day 1/8/15) and continuous propranolol. Tremelimumab will be given on day 1 of cycle 1, which may be repeated at the time of progression in eligible patients.

Group II: Hepatocellular Cancer Experimental Treatment 3 Interventions

Durvalumab will be administered once every 4 weeks in combination with continuous propranolol. Tremelimumab will be given on day 1 of cycle 1, which may be repeated at the time of progression in eligible patients.

Group III: Biliary Tract Cancer Experimental Treatment 5 Interventions

Durvalumab will be administered once every 3 weeks, in combination with cisplatin + gemcitabine (day 1/8) and continuous propranolol. Tremelimumab will be given on day 1 of cycle 1, which may be repeated at the time of progression in eligible patients.

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?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Published Research Related to This Trial

A study of 5465 patients with advanced pancreatic cancer in Ontario showed that the introduction of new chemotherapy regimens, GEMNAB and FOLFIRINOX, significantly improved overall survival rates over time, with median survival increasing from 5.6 months to 7.6 months between 2008 and 2018.

FOLFIRINOX was found to provide better overall survival compared to GEMNAB, particularly in younger and healthier patients, while GEMNAB still showed improved survival compared to the older standard treatment, gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. Raphael, MJ., Raskin, W., Habbous, S., et al.[2023]

The combination of ipilimumab and gemcitabine was found to be safe and tolerable for treating advanced pancreatic ductal adenocarcinoma (PDAC), with a maximum tolerated dose established at ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2.

Despite the safety of the regimen, the overall response rate was only 14%, indicating that adding ipilimumab does not significantly enhance the effectiveness compared to gemcitabine alone in advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. Kamath, SD., Kalyan, A., Kircher, S., et al.[2022]

Cis-dichlorodiammineplatinum(II) can cause serious side effects such as nephrotoxicity, gastrointestinal issues (like nausea and vomiting), and myelosuppression, highlighting the need for careful monitoring during treatment.

Other potential side effects include ototoxicity (which can lead to hearing loss), anaphylactic reactions, and peripheral neuropathies, indicating that while the drug may be effective, its safety profile requires close attention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic effects of cis-dichlorodiammineplatinum(II) in man. Von Hoff, DD., Schilsky, R., Reichert, CM., et al.[2022]

Cisplatin, carboplatin, and oxaliplatin, while structurally similar, have different therapeutic uses and efficacy profiles; for example, carboplatin is less effective than cisplatin for certain cancers but comparable in others like ovarian cancer.

Oxaliplatin is particularly effective for colorectal cancer when combined with 5-fluorouracil and folinic acid, marking it as a significant advancement in treatment options for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Platinum compounds: metabolism, toxicity and supportive strategies]. Lipp, HP., Hartmann, JT.[2013]

The combination of tremelimumab and durvalumab (T300 + D) showed the highest overall survival rate (18.7 months) and objective response rate (24.0%) among patients with unresectable hepatocellular carcinoma, indicating its potential as an effective treatment option.

All treatment regimens were generally well-tolerated, but T300 + D had the most favorable safety profile, with a significant association between early CD8+ lymphocyte expansion and treatment response, suggesting a promising mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. Kelley, RK., Sangro, B., Harris, W., et al.[2022]

In a study of 1102 patients with metastatic pancreatic cancer, FOLFIRINOX treatment resulted in a median overall survival of 9.27 months, significantly longer than the 6.87 months observed with gemcitabine plus nab-paclitaxel (P < 0.001).

Patients receiving FOLFIRINOX also experienced 17.3% fewer posttreatment hospitalizations and 20% lower posttreatment costs compared to those treated with gemcitabine plus nab-paclitaxel, indicating better safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma. Klein-Brill, A., Amar-Farkash, S., Lawrence, G., et al.[2023]

In a study of 735 women treated with carboplatin for gynecological cancers, 10.2% experienced hypersensitivity reactions, with the incidence increasing significantly over the years from 0.88% in 2006 to 5.42% in 2013.

Risk factors for these reactions included advanced disease stage, specific cancer histologies, presence of malignant ascites, and a history of other drug allergies, suggesting that careful monitoring and potential preventive measures, like adjusting infusion rates and using desensitization protocols, could help manage these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk Factors of Hypersensitivity to Carboplatin in Patients with Gynecologic Malignancies. Tai, YH., Tai, YJ., Hsu, HC., et al.[2020]

The phase III POSEIDON trial demonstrated that a three-drug regimen combining the CTLA4 inhibitor tremelimumab, the PD-L1 inhibitor durvalumab, and chemotherapy significantly improves progression-free survival and overall survival in patients with metastatic non-small cell lung cancer compared to chemotherapy alone.

This study suggests that targeting multiple immune pathways with this combination therapy may enhance treatment effectiveness for lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-Drug Regimen Bests Chemo in NSCLC. [2022]

In the CASPIAN study involving 805 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of durvalumab and platinum-etoposide significantly improved overall survival compared to platinum-etoposide alone, with a median survival of 12.9 months versus 10.5 months.

However, adding tremelimumab to durvalumab and platinum-etoposide did not provide a significant survival benefit, indicating that durvalumab plus platinum-etoposide should be considered the new standard of care for first-line treatment of ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Goldman, JW., Dvorkin, M., Chen, Y., et al.[2021]

This phase II study aims to evaluate the effectiveness of combining durvalumab and tremelimumab with neoadjuvant chemotherapy in improving progression-free survival (PFS) in patients with advanced-stage ovarian cancer, specifically those with stage IIIC/IV epithelial ovarian cancer.

The study will involve 24 patients and will assess immune biomarkers and changes in the tumor microenvironment through serial biopsies, with the primary goal of achieving a 12-month PFS rate, while also monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in advanced-stage ovarian cancer: a Korean Gynecologic Oncology Group Study (KGOG 3046), TRU-D. Lee, JY., Kim, JW., Lim, MC., et al.[2020]

Since the approval of sorafenib in 2007, multiple new treatments for unresectable hepatocellular carcinoma have emerged, including lenvatinib and the combination of atezolizumab plus bevacizumab, enhancing options for patients.

Recent studies presented at the 2022 ASCO Gastrointestinal Cancers Symposium indicate that the combination of durvalumab and tremelimumab may significantly improve overall survival compared to sorafenib, marking a potential shift in treatment strategies for both advanced and intermediate-stage hepatocellular carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New treatment paradigm with systemic therapy in intermediate-stage hepatocellular carcinoma. Kudo, M.[2023]

Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a very low 5-year survival rate, but systemic treatments, particularly combination chemotherapies like FOLFIRINOX and nab-paclitaxel with gemcitabine, can help control symptoms and extend life.

Emerging genomic classifications of PDAC may lead to new targeted therapies and immunotherapies, although these approaches are still largely in the experimental stage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic pancreatic ductal adenocarcinoma: diagnosis and treatment with a view to the future. Pokorny, AMJ., Chin, VT., Nagrial, AM., et al.[2019]

In a study of 88 patients with advanced pancreatic adenocarcinoma, chemotherapy regimens using cisplatin, capecitabine, and gemcitabine with either epirubicin or docetaxel showed a median overall survival of 8.5 months, indicating similar effectiveness to more commonly used treatments.

The study also found that these regimens had manageable toxicity levels, with 21.6% experiencing grade 4 neutropenia and 10.2% having febrile neutropenia, suggesting they could be viable alternatives in settings with limited access to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes of cisplatin, capecitabine, and gemcitabine with either epirubicin (PEXG) or docetaxel (PDXG) as first-line palliative treatment in metastatic or unresectable locally advanced pancreatic adenocarcinoma. Hitchen, N., Waldron, NR., Deva, S., et al.[2023]

A phase I trial involving 33 patients tested the combination of cisplatin and carboplatin, revealing that while the combination is feasible, it can lead to unexpectedly severe thrombocytopenia (low platelet count) when using specific doses, particularly 280 mg/m2 carboplatin with 25 mg/m2 cisplatin.

Despite the risk of thrombocytopenia, the combination therapy showed promising responses in tumors known to be responsive to platinum-based treatments, suggesting that further investigation into this combination is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platinum analogue combination chemotherapy: cisplatin and carboplatin--a phase I trial with pharmacokinetic assessment of the effect of cisplatin administration on carboplatin excretion. Trump, DL., Grem, JL., Tutsch, KD., et al.[2017]

Platinum-containing chemotherapy agents, widely used for various cancers, have led to an increase in hypersensitivity reactions, which can include symptoms like skin rash and abdominal cramping, and can even result in severe cardiovascular and respiratory complications.

Management strategies for these hypersensitivity reactions include discontinuing the chemotherapy, using premedication, extending infusion times, and desensitization protocols, highlighting the need for careful monitoring and individualized treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review. Makrilia, N., Syrigou, E., Kaklamanos, I., et al.[2022]

Citations

1.

imfinzihcp.com

imfinzihcp.com/hcc/unresectable/efficacy.html

Efficacy

IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11107832/

Evaluating the Therapeutic Potential of Durvalumab in ...

Patient-reported outcomes for the phase 3 TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. J ...

3.

cdn.clinicaltrials.gov

cdn.clinicaltrials.gov/large-docs/35/NCT03875235/SAP_004.pdf

A Phase III Randomized, Double-Blind, Placebo-Controlled ...

durvalumab + Gemcitabine/Cisplatin is superior to placebo + Gemcitabine/Cisplatin in the. TOPAZ-1 study. One could have extensive follow-up ...

4.

astrazeneca.com

astrazeneca.com/media-centre/press-releases/2024/imfinzi-plus-chemotherapy-doubled-overall-survival-rate-at-three-years-for-patients-with-advanced-biliary-tract-cancer-in-topaz-1-phase-iii-trial.html

Imfinzi plus chemotherapy doubled overall survival rate at ...

The latest data from TOPAZ-1 show that twice as many patients with advanced biliary tract cancer were still alive at three years with durvalumab and ...

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10667376/

Durvalumab: A Review in Advanced Biliary Tract Cancer

The median overall survival of patients with advanced biliary tract cancer receiving gemcitabine plus cisplatin is ≈ 10–12 months, and ...

6.

imfinzihcp.com

imfinzihcp.com/hcc/unresectable/qol.html

Patient-Reported Outcomes

Discover patient-reported outcomes from the HIMALAYA study, such as quality of life and symptom scales for patients with unresectable HCC ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39301763/

Efficacy, safety and differential outcomes of immune- ...

Immuno-chemotherapy in patients with BTC was feasible, effective and safe in a real-life scenario. Our results were comparable to the phase ...

8.

imfinzihcp.com

imfinzihcp.com/biliary-tract-cancers/real-world-evidence.html

real-world evidence data

Discover real-world evidence and data for IMFINZI® (durvalumab) in patients with locally advanced or metastatic biliary tract cancer.