Selumetinib + Cisplatin/Gemcitabine for Biliary Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: MEK inhibitors, RAS inhibitors

Disqualifiers: Ampullary carcinoma, Cardiac issues, Eye issues, 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: 1

Duration: 10 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the effectiveness of selumetinib when combined with two standard chemotherapy drugs, cisplatin and gemcitabine, for treating biliary cancer. Researchers are testing various timing schedules for selumetinib to assess whether it shrinks tumors more effectively than standard treatment alone. Individuals with biliary tract or gallbladder cancer that cannot be surgically removed, and who have not received prior chemotherapy, may qualify for this study. 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 protocol does not specify if you must stop taking your current medications. However, if you are taking potent inhibitors or inducers of certain enzymes (CYP3A4/5, CYP2C19, and CYP1A2), you can continue with caution.

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

Research has shown that selumetinib, when combined with the chemotherapy drugs cisplatin and gemcitabine, has been studied for safety and effectiveness. In earlier studies, patients who took selumetinib with other chemotherapy drugs lived for an average of 14.4 months, suggesting that patients can tolerate this drug combination.

Cisplatin and gemcitabine are commonly used to treat biliary cancer and are known to have side effects that most patients can manage. Research indicates that these side effects are generally acceptable.

Considering the effectiveness of these drugs together, selumetinib has already been tested in early trials. Researchers have a good understanding of its safety, especially when combined with cisplatin and gemcitabine. While side effects can still occur, previous patients have found the combination manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they include selumetinib, a MEK inhibitor, which is not part of the standard care for biliary cancer. Standard treatment typically involves chemotherapy combinations like cisplatin and gemcitabine. Selumetinib targets a specific pathway in cancer cells, potentially making the treatment more effective by directly inhibiting cancer cell growth and survival. Additionally, the study explores different dosing strategies, such as continuous and sequential selumetinib administration, which could optimize its effectiveness and reduce side effects compared to traditional chemotherapy. This novel approach could provide a more targeted attack on cancer cells, offering hope for improved outcomes in biliary cancer treatment.

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

Research has shown that selumetinib, when combined with cisplatin and gemcitabine, may help shrink tumors in people with biliary cancer. In this trial, participants will be assigned to different treatment arms to evaluate the effectiveness of these combinations. Some studies have found that this combination can effectively stop cancer cells from growing and dividing, leading to smaller tumors. Using cisplatin and gemcitabine together has been shown to help patients with advanced biliary tract cancer live longer. On average, patients lived about 3.6 months longer than those who only received gemcitabine. Overall, adding selumetinib to cisplatin and gemcitabine might provide a more effective treatment for biliary cancer by helping to shrink tumors and improve survival. ^{1 2 6 7 8}

Who Is on the Research Team?

Jennifer J. Knox, MD, MSc

Principal Investigator

Princess Margaret Cancer Centre

Are You a Good Fit for This Trial?

Adults with advanced biliary or gallbladder cancer who haven't had systemic therapy can join this trial. They should be in a condition to perform daily activities (performance status 0, 1, or 2), have an expected lifespan of over three months, and their blood counts and organ functions must meet certain standards. Pregnant women, those with recent other cancers, severe heart or eye conditions, uncontrolled diseases like hepatitis or HIV are excluded.

Inclusion Criteria

Estimated life expectancy > 3 months

Capable of giving written consent

Acceptable recovery of previous side effects

Exclusion Criteria

Any psychiatric or other disorder likely to impact consent

I have had chemotherapy or a MEK inhibitor for cancer that couldn't be surgically removed.

My condition worsened within 6 months after my last cancer treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-In

Selumetinib is administered orally BID for 5-7 days with a washout period before starting the main treatment

1 week

Treatment

Participants receive Selumetinib orally BID and Cisplatin/Gemcitabine intravenously on a 28-day cycle

10 weeks

Visits on Days 1 and 8 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Gemcitabine
• Selumetinib

Trial Overview This phase II study is testing the effectiveness of Selumetinib combined with Cisplatin/Gemcitabine versus just Cisplatin/Gemcitabine in patients. Selumetinib is taken orally and targets cell growth regulation while both Cisplatin and Gemcitabine are given intravenously to damage DNA in tumor cells.

How Is the Trial Designed?

Group I: Arm C (Standard Care) Experimental Treatment 2 Interventions

Cisplatin/gemcitabine, intravenously, on Days 1 and 8 of every 28 day cycle.

Group II: Arm B (Sequential Dosing) Experimental Treatment 3 Interventions

Run-In: Selumetinib, orally, BID for 5 days (Day -7 to Day -3) with 2 days washout On treatment: Selumetinib, orally, BID from Day 1-5 and 8-19 of every 28 day cycle. Cisplatin/gemcitabine, intravenously, on Days 1 and 8 of every 28 day cycle.

Group III: Arm A (Continuous Dosing) Experimental Treatment 3 Interventions

Run-In: Selumetinib, orally, BID for 7 days (Day -7 to Day -1) On treatment: Selumetinib, orally, BID from Day 1-21 of every 28 day cycle. Cisplatin/gemcitabine, intravenously, on Days 1 and 8 of every 28 day cycle.

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 Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

In a study of 10 patients with unresectable biliary tract cancer, the combination of cisplatin and gemcitabine was found to be a standard treatment, but it resulted in significant hematological toxicities, including grade 3/4 neutropenia in 5 patients and thrombocytopenia in 4 patients.

Despite the observed toxicities, the chemotherapy can be administered safely with close monitoring, as dose adjustments were necessary for 8 patients due to adverse effects, particularly hematological issues and anorexia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial safety and efficacy of cisplatin and gemcitabine combination chemotherapy for unresectable biliary tract cancer. Shibata, Y.[2022]

In a phase 2 trial involving 150 patients with advanced biliary cancers, the addition of cetuximab to standard chemotherapy (gemcitabine and oxaliplatin) did not significantly improve progression-free survival compared to chemotherapy alone, with median progression-free survival of 6.1 months versus 5.5 months, respectively.

While cetuximab was well tolerated, the study found a higher incidence of grade 3-4 adverse events in the cetuximab group, suggesting that the standard chemotherapy regimen should remain the preferred treatment for advanced biliary cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Malka, D., Cervera, P., Foulon, S., 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 a phase I study involving 12 patients with unresectable advanced biliary tract cancer, the combination of gemcitabine, cisplatin, and oral S-1 was found to be safe, with no dose-limiting toxicities reported.

The recommended doses of S-1 were established at 80, 100, and 120 mg per day based on patient body surface area, and one patient even achieved conversion to curative surgery, indicating potential efficacy of the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer. Uwagawa, T., Sakamoto, T., Abe, K., et al.[2022]

In a Phase 2 trial involving 51 patients with advanced biliary tract cancer, adding the MEK inhibitor selumetinib to standard chemotherapy (Cisplatin and gemcitabine) did not improve tumor size reduction or survival outcomes compared to chemotherapy alone.

Patients receiving selumetinib experienced higher rates of severe toxicities and required more dose reductions of chemotherapy, indicating that the combination may not be safe or effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised, Phase II study of selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer. Doherty, MK., Tam, VC., McNamara, MG., et al.[2023]

Citations

1. ccanewsonline.com ccanewsonline.com/web-exclusives/expanding-treatment-options-for-patients-with-advanced-cholangiocarcinoma

Expanding Treatment Options for Patients with Advanced ... The median overall survival (OS) with first-line treatment of this combination is up to 12 months, and the median OS when gemcitabine and cisplatin is used as a ...

2. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3967-0

Adjuvant treatment of resectable biliary tract ... - BMC Cancer The median overall survival could be prolonged for almost four months from 8.1 months to 11.7 months with the combination regimen.

3. 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.

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

Cisplatin plus Gemcitabine versus Gemcitabine for Biliary ... Patients treated with cisplatin plus gemcitabine lived an average of 3.6 months longer than those treated with gemcitabine alone.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2736816/

Gemcitabine alone or in combination with cisplatin in patients ... We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11994646/

Efficacy and safety of immune checkpoint inhibitors in ... Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0959804915004499

Cisplatin and gemcitabine in patients with advanced biliary ... Safety and feasibility data is also available for the use of this chemotherapy combination in patients with jaundice refractory to biliary stenting due to ...

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 ...