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

57 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Selumetinib, Cisplatin, and Gemcitabine for treating biliary cancer?

Research shows that combining Selumetinib with Cisplatin and Gemcitabine may enhance treatment effectiveness for advanced biliary tract cancer. Selumetinib, when used with these chemotherapy drugs, has shown potential benefits in clinical trials, suggesting it could improve outcomes for patients with this type of cancer. ^{1 2 3 4 5}

Is the combination of Selumetinib, Cisplatin, and Gemcitabine safe for humans?

The combination of Cisplatin and Gemcitabine is generally safe but can cause significant side effects like low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and loss of appetite (anorexia). Selumetinib has been studied with these drugs, and while it shows promise, careful monitoring for these side effects is important. ^{1 2 6 7 8}

What makes the drug combination of Selumetinib, Cisplatin, and Gemcitabine unique for biliary cancer?

This treatment is unique because it combines Selumetinib, a MEK inhibitor that works inside cells to block specific pathways, with the standard chemotherapy drugs Cisplatin and Gemcitabine, potentially enhancing their effectiveness against advanced biliary tract cancer. ^{1 2 3 4 7}

What is the purpose of this trial?

This is a phase II study (the second stage of testing a new drug or new drug combinations) to see how useful two different schedules of study drug selumetinib with cisplatin and gemcitabine are compared to cisplatin and gemticabine alone in patients with biliary cancer. Selumetinib, an oral drug which plays an important role in the regulation of cell growth (MEK 1/2 inhibitor) has been shown to shrink tumours in patients with biliary cancer and other types of human cancers. Selumetinib has also been shown to shrink tumours when given in combination with cisplatin and gemcitabine in research studies done in animals and in some patients with biliary tract cancer. Cisplatin and gemcitabine are intravenous drugs that work by damaging DNA in tumor cells so that they are unable to grow and divide.

Research Team

Jennifer J. Knox, MD, MSc

Principal Investigator

Princess Margaret Cancer Centre

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

References

1. England 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. [2023]

2. England pubmed.ncbi.nlm.nih.gov

A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study. [2022]

3. England 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. [2022]

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

Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study. [2022]

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

Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Phase I trial of S-1 every other day in combination with gemcitabine/cisplatin for inoperable biliary tract cancer. [2022]