Pevonedistat + Chemotherapy for Bile Duct Cancer

Not currently recruiting at 514 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4/5 inducers, BCRP inhibitors

Disqualifiers: Pregnancy, CNS involvement, 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: Unknown

Duration: 21 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called pevonedistat (also known as MLN4924), both alone and with chemotherapy, to evaluate its effectiveness for bile duct cancer that cannot be removed or has spread. Researchers aim to determine if pevonedistat can halt cancer cell growth or shrink tumors, particularly when combined with chemotherapy drugs paclitaxel and carboplatin. Individuals with bile duct cancer in the liver who have previously tried certain treatments might be suitable candidates. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs that affect liver enzymes, like phenytoin or St. John's wort. It's important to discuss your current medications with the study team to ensure there are no interactions.

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

Research has shown that pevonedistat is generally safe in clinical trials. Some studies have found it can cause side effects, but these are usually manageable. When used alone, pevonedistat has demonstrated expected effects without causing serious problems for most patients.

The combination of pevonedistat with the chemotherapy drugs paclitaxel and carboplatin, which are well-known and commonly used in cancer treatments, is being studied to ensure safety. These chemotherapy drugs are generally considered safe, with common side effects like nausea and tiredness, which are often manageable.

Overall, studies suggest that both pevonedistat alone and with chemotherapy are reasonably safe for patients, with side effects that doctors can usually manage. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for bile duct cancer because they introduce pevonedistat, a novel agent that could offer new hope. Unlike standard chemotherapy options like gemcitabine and cisplatin, pevonedistat targets a unique pathway by inhibiting the NEDD8-activating enzyme, potentially disrupting cancer cell survival. Additionally, when combined with established drugs like carboplatin and paclitaxel, pevonedistat could enhance the effectiveness of chemotherapy, leading to better outcomes. This innovative approach provides a fresh angle in treating a challenging cancer type, making it a promising area of study.

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

Studies suggest that pevonedistat might help treat bile duct cancer by blocking a specific enzyme, making cancer cells more susceptible to damage and death. In other cancer types, pevonedistat has shown promise in slowing disease progression. In this trial, some participants will receive pevonedistat alone, while others will receive it with chemotherapy drugs like paclitaxel and carboplatin. When combined with these chemotherapy drugs, the treatment has shown better results in some cancer studies. Specifically, one study found that this combination controlled the disease in 83.3% of patients, with a median survival of 9.0 months. This suggests that pevonedistat, particularly when combined with chemotherapy, could be effective against bile duct cancer. ^{1 4 5 6 7}

Who Is on the Research Team?

Dustin A Deming

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

Adults with advanced bile duct cancer of the liver, who have tried one chemotherapy regimen without success, can join this trial. They should be in good physical condition (ECOG 0-1), expect to live at least 12 weeks, and have measurable disease. Those with HIV or hepatitis must meet specific criteria. People cannot participate if they're planning surgery soon, are pregnant or breastfeeding, haven't recovered from previous treatments' side effects (except hair loss), or have certain heart conditions.

Inclusion Criteria

I am HIV positive with a CD4 count >= 350, undetectable viral load, on modern HIV meds without ritonavir, and no AIDS-defining infections.

I have someone legally authorized to make decisions for me due to my impaired decision-making capacity.

I have a specific liver cancer that has spread or can't be removed and didn't respond well to my first chemotherapy.

Exclusion Criteria

As part of enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if a new medication need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

I have not had major surgery in the last 14 days.

I am taking medication that affects liver enzymes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive pevonedistat alone or in combination with paclitaxel and carboplatin. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days after the last dose, then every 3 months for the first year and every 6 months for years 2-3.

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Paclitaxel
• Pevonedistat

Trial Overview The trial is testing Pevonedistat alone and combined with chemotherapy drugs Paclitaxel and Carboplatin for treating liver bile duct cancer. The goal is to see how well these treatments shrink the cancer compared to current methods.

How Is the Trial Designed?

Group I: Arm B (pevonedistat, paclitaxel, carboplatin) Experimental Treatment 3 Interventions

Patients receive pevonedistat IV over 1 hour on days 1, 3, and 5, paclitaxel IV over 3 hours on day 1, and carboplatin IV over 15-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Starting cycle 5, patients may receive pevonedistat monotherapy at the discretion of treating physician.

Group II: Arm A (pevonedistat) Experimental Treatment 1 Intervention

Patients receive pevonedistat IV over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A phase I clinical trial of low-dose paclitaxel (PTX) as third-line palliative chemotherapy for patients with unresectable biliary tract cancer showed it was well-tolerated, with no severe adverse events (grade 3 or 4) reported.

The treatment resulted in a disease control rate of 83.3% and a median overall survival of 9.0 months, indicating that low-dose PTX is both safe and effective for patients who have not responded to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of weekly palliative chemotherapy with low-dose third-line paclitaxel for biliary tract cancer. Tajima, H., Ohta, T., Shinbashi, H., et al.[2020]

In a multicenter phase II study involving 50 patients with advanced ovarian cancer who had previously undergone platinum-based chemotherapy, the combination of paclitaxel and carboplatin showed an overall response rate of 43%, indicating its efficacy in this patient population.

The treatment was generally safe, with myelosuppression being the most common severe side effect, but only one case of neutropenic fever was reported, suggesting that this regimen can be administered safely to outpatients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the combination paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens phase II study. Pujade-Lauraine, E., Guastalla, JP., Weber, B., et al.[2015]

In a phase II pilot study involving 10 patients with advanced cholangiocarcinoma who were ineligible for cisplatin therapy, the combination of nab-paclitaxel and gemcitabine showed a promising overall response rate of 50% and a disease control rate of 90%.

The treatment demonstrated a median progression-free survival of 5.7 months and a median overall survival of 7.8 months, with no new safety concerns identified, indicating that this regimen is both effective and safe for patients who cannot tolerate standard cisplatin-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Nab-Paclitaxel and Gemcitabine as First-Line Therapy in Patients with Cholangiocarcinoma Ineligible for Cisplatin-Based Chemotherapy (NACHO). Virchow, I., Treckmann, JW., Prasnikar, N., 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]

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 phase II study involving 66 patients with advanced breast cancer, the combination of paclitaxel and carboplatin resulted in a total response rate of 53%, with 12% achieving a complete response and 41% a partial response.

The treatment was generally well-tolerated, with manageable toxicities, allowing for outpatient administration, and a median time to progression of 8.9 months, indicating significant activity against advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin as first-line chemotherapy for advanced breast cancer. Fountzilas, G., Athanassiades, A., Papadimitriou, V., et al.[2015]

In a study of patients with advanced non-small cell lung cancer receiving carboplatin and nanoparticle albumin-bound paclitaxel, 55% experienced treatment suspension, primarily due to neutropenia (65.2%) and infections (24.2%).

Baseline liver dysfunction, age 65 or older, and a performance status of 2 were identified as significant risk factors for treatment suspension, highlighting the need for careful monitoring in these patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of risk factors associated with carboplatin and nab-paclitaxel treatment suspension in patients with non-small cell lung cancer. Saito, Y., Takekuma, Y., Shinagawa, N., et al.[2022]

Nab-paclitaxel, a solvent-free chemotherapy drug, showed promising clinical and serological responses in a 63-year-old patient with advanced cholangiocarcinoma after other treatments failed, indicating its potential efficacy for this aggressive cancer.

The case suggests that nab-paclitaxel could be a viable second-line treatment option for cholangiocarcinoma, warranting further investigation in combination with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Albumin-bound paclitaxel as new treatment for metastatic cholangiocarcinoma: A case report. Martin Huertas, R., Fuentes-Mateos, R., Serrano Domingo, JJ., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04175912

NCT04175912 | Testing the Combination of Pevonedistat ... This study may help the study doctors find out how well pevonedistat shrinks bile duct cancer of the liver when given alone and when in combination with ...

2. consultqd.clevelandclinic.org consultqd.clevelandclinic.org/exploring-novel-therapeutic-avenues-in-advanced-cholangiocarcinoma-lessons-from-the-ea2187-trial

Exploring Treatment for Cholangiocarcinoma - Consult QD Pevonedistat aims to block the NEDD8-activating enzyme, essentially making the cancer cells more vulnerable to DNA damage and tumor cell death. ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10773064/

Deciphering the role of neddylation in tumor ... - PubMed Central This compound has shown promise in preclinical studies of numerous cancer types, including lymphoma, leukemia, and solid tumors, owing to its capacity to induce ...

4. mdpi.com mdpi.com/2218-273X/14/7/738

The Double-Edged Effects of MLN4924: Rethinking Anti- ... Surprisingly, an increasing number of studies have offered proof that MLN4924 not only inhibits cancer development and progression but also promotes cancer ...

5. withpower.com withpower.com/trial/phase-3-carcinoma-hepatocellular-2020-c6945

Pevonedistat + Chemotherapy for Bile Duct Cancer The treatment resulted in a disease control rate of 83.3% and a median overall survival of 9.0 months, indicating that low-dose PTX is both safe and effective ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04175912/

Clinical Trial: NCT04175912 This study may help the study doctors find out how well pevonedistat shrinks bile duct cancer of the liver when given alone and when in ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5694347/

Phase I Study of the Novel Investigational NEDD8-activating ... Conclusions. Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence ...