Pevonedistat + Chemotherapy for Bile Duct Cancer

Recruiting at 505 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

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well pevonedistat alone or in combination with chemotherapy (paclitaxel and carboplatin) works in treating patients with bile duct cancer of the liver. Pevonedistat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as paclitaxel and carboplatin, 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. 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 paclitaxel and carboplatin.

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.

What data supports the effectiveness of the drug Pevonedistat + Chemotherapy for Bile Duct Cancer?

Research shows that nab-paclitaxel, a component of the treatment, has shown promise in treating advanced cholangiocarcinoma (bile duct cancer) when combined with other drugs, with some patients experiencing disease control and extended survival. ^{1 2 3 4 5}

Is the combination of Pevonedistat, Paclitaxel, and Carboplatin safe for humans?

Paclitaxel and Carboplatin have been used together in various cancer treatments and are generally safe with manageable side effects. Common side effects include low blood cell counts, nausea, hair loss, and nerve damage, but these are typically manageable with medical support. ^{6 7 8 9 10}

What makes the drug Pevonedistat + Chemotherapy unique for bile duct cancer?

Pevonedistat combined with chemotherapy is unique because it includes Pevonedistat, a novel drug that may enhance the effectiveness of traditional chemotherapy agents like carboplatin and paclitaxel, offering a new approach for treating bile duct cancer, which currently lacks many effective treatment options. ^{1 2 11 12 13}

Research Team

Dustin A Deming

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

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

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 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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

References

1. Switzerland 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). [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Albumin-bound paclitaxel as new treatment for metastatic cholangiocarcinoma: A case report. [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

A multicenter phase II trial with irinotecan plus oxaliplatin as first-line treatment for inoperable/metastatic cancer of the biliary tract. [2018]

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

Phase I study of weekly palliative chemotherapy with low-dose third-line paclitaxel for biliary tract cancer. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin as first-line chemotherapy for advanced breast cancer. [2015]

7. China pubmed.ncbi.nlm.nih.gov

[Combination chemotherapy with paclitaxel and carboplatin in the treatment of advanced non-small cell lung cancer]. [2010]

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

The clinical development of paclitaxel and the paclitaxel/carboplatin combination. [2019]

9. Germany 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. [2022]

10. United States 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. [2015]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Chemotherapy and targeted therapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. [2022]

12. 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]

13. France pubmed.ncbi.nlm.nih.gov

[Therapeutic advances in the management of biliary tract carcinoma]. [2022]