MK2 Inhibitor + mFOLFIRINOX for Pancreatic Cancer

Overseen By Moh'd Khushman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: CYP3A4 inhibitors, CYP2C8 inducers

Disqualifiers: Other malignancy, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

51 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators hypothesize that MK2 inhibition may improve efficacy of mFOLFIRINOX chemotherapy for patients with pancreatic ductal adenocarcinoma (PDAC).

Do I need to stop my current medications for the trial?

The trial requires that you stop taking strong and moderate CYP3A4 and CYP2C8 inhibitors and inducers, as well as drugs with QT prolonging potential, within 5 half-lives of the agent. If you're on these medications, you may need to stop them before participating.

What data supports the effectiveness of the drug mFOLFIRINOX for pancreatic cancer?

Research shows that modified FOLFIRINOX (mFOLFIRINOX) can be effective as a second-line treatment for patients with metastatic pancreatic cancer, especially after other treatments like gemcitabine and S-1 have failed. Studies indicate it may offer a balance between effectiveness and safety, making it a viable option for patients with good performance status. ^{1 2 3 4 5}

What safety data exists for mFOLFIRINOX in pancreatic cancer treatment?

Modified FOLFIRINOX (mFOLFIRINOX) has been studied for safety in treating pancreatic cancer, showing that it can have significant side effects, but these are generally less severe than the standard FOLFIRINOX regimen. ^{1 2 4 6 7}

What makes the MK2 Inhibitor + mFOLFIRINOX treatment unique for pancreatic cancer?

The MK2 Inhibitor + mFOLFIRINOX treatment is unique because it combines a modified version of the FOLFIRINOX regimen, which is already used for advanced pancreatic cancer, with an MK2 inhibitor, potentially enhancing its effectiveness. This combination aims to improve outcomes by targeting cancer cells more effectively than standard treatments. ^{1 2 4 8 9}

Research Team

Moh'd Khushman

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for individuals with untreated metastatic pancreatic ductal adenocarcinoma. Participants should not have had previous treatments for their condition.

Inclusion Criteria

Ability to understand and willingness to sign an IRB approved written informed consent document.

I agree to use birth control if I can have children or am sexually active with women who can.

Measurable disease by RECIST 1.1.

Exclusion Criteria

I have lung disease that causes symptoms like coughing or shortness of breath.

I cannot swallow pills.

I have taken specific drugs that affect how my body processes other medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive zunsemetinib and mFOLFIRINOX to determine the optimal dose

12 months

Bi-weekly visits for treatment administration

Dose Expansion

Participants receive the determined dose of zunsemetinib and mFOLFIRINOX

12 months

Bi-weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• mFOLFIRINOX
• Zunsemetinib

Trial Overview The study tests the combination of a new drug, Zunsemetinib (MK2 inhibitor), with an existing chemotherapy regimen called mFOLFIRINOX to see if it's more effective in treating pancreatic cancer.

Participant Groups

Group I: Dose expansion phase (zunsemetinib + mFOLFIRNOX) Experimental Treatment 2 Interventions

The dose of zunsemetinib will be determined during the dose escalation phase of the trial. mFOLFIRINOX will be 85 mg/m\^2 of oxaliplatin intravenous (IV) on day 1 of each cycle, 150 mg/m\^2 of irinotecan IV on day 1 of each cycle, 400 mg/m\^2 of leucovorin IV on day 1 of each cycle, and 2400 mg/m\^2 continuous infusion starting on day 1 of each cycle and continuing for 46 hours. Each cycle is 2 weeks in length.

Group II: Dose escalation phase (zunsemetinib + mFOLFIRNOX) Experimental Treatment 2 Interventions

The dose of zunsemetinib will be determined by the dose level assigned and will be taken by mouth either once or twice daily depending on assigned dose level. mFOLFIRINOX will be 85 mg/m\^2 of oxaliplatin intravenous (IV) on day 1 of each cycle, 150 mg/m\^2 of irinotecan IV on day 1 of each cycle, 400 mg/m\^2 of leucovorin IV on day 1 of each cycle, and 2400 mg/m\^2 continuous infusion starting on day 1 of each cycle and continuing for 46 hours. Each cycle is 2 weeks in length.

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

Approved in European Union as mFOLFIRINOX for:

• Pancreatic ductal adenocarcinoma (PDAC)

Approved in United States as mFOLFIRINOX for:

• Advanced pancreatic cancer

Approved in Canada as mFOLFIRINOX for:

• Resectable pancreatic ductal adenocarcinoma

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Aclaris Therapeutics, Inc.

Industry Sponsor

Trials

35

Recruited

4,900+

Findings from Research

The modified FOLFIRINOX (mFOLFIRINOX) regimen demonstrated a high treatment efficacy in patients with locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC), achieving a response rate of 55.2% among 29 evaluable patients.

The treatment was well-tolerated, with only 9 patients experiencing grade 3 or 4 adverse effects, and no patients discontinued treatment due to side effects, indicating a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Modified FOLFIRINOX for advanced pancreatic cancer: a tertiary center experience from China]. Bai, X., Su, R., Ma, T., et al.[2018]

Modified-dose FOLFIRINOX (mFOLFIRINOX) demonstrated comparable efficacy to standard-dose FOLFIRINOX (sFOLFIRINOX) in treating pancreatic cancer, with similar objective response rates and overall survival outcomes among 130 patients studied.

mFOLFIRINOX was associated with significantly lower rates of severe adverse events, such as neutropenia, anorexia, and diarrhea, suggesting it is a safer option for patients who may be concerned about toxicity while maintaining effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of efficacy and safety between standard-dose and modified-dose FOLFIRINOX as a first-line treatment of pancreatic cancer. Kang, H., Jo, JH., Lee, HS., et al.[2022]

Modified FOLFIRINOX (mFOLFIRINOX) showed moderate efficacy in treating locally advanced or metastatic pancreatic cancer, with a response rate of 30.8% and a disease control rate of 69.2% in 13 patients after previous treatments failed.

The treatment was associated with a median overall survival of 176 days and significant adverse effects, including neutropenia in 38.5% of patients, indicating that while mFOLFIRINOX can be beneficial, it also carries risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified FOLFIRINOX for Locally Advanced and Metastatic Pancreatic Cancer Patients Resistant to Gemcitabine and S-1 in Japan: A Single Institutional Experience. Umemura, A., Nitta, H., Sasaki, A., et al.[2022]

In a study of 76 patients with metastatic pancreatic cancer, mFOLFIRINOX treatment resulted in significantly better objective response rates (20.0% vs 0%) and progression-free survival (3.7 months vs 2.1 months) compared to the oral fluoropyrimidine S-1.

While mFOLFIRINOX showed promising treatment outcomes, it also led to more frequent severe side effects, such as grade 3-4 neutropenia and peripheral sensory neuropathy, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with S-1 as second-line chemotherapy in metastatic pancreatic cancer. Ikezawa, K., Kiyota, R., Takada, R., et al.[2022]

In a phase III trial involving 80 patients with metastatic pancreatic adenocarcinoma, modified FOLFIRINOX (mFOLFIRINOX) significantly improved overall survival compared to S-1, with median survival rates of 9.2 months versus 4.9 months, respectively.

While mFOLFIRINOX showed higher efficacy with better response and disease control rates, it also resulted in more severe adverse events, with 56% of patients experiencing grade 3-4 side effects compared to 17% in the S-1 group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified FOLFIRINOX versus S-1 as second-line chemotherapy in gemcitabine-failed metastatic pancreatic cancer patients: A randomised controlled trial (MPACA-3). Go, SI., Lee, SC., Bae, WK., et al.[2022]

Modified FOLFIRINOX shows similar effectiveness in treating metastatic pancreatic adenocarcinoma (MPA) compared to standard FOLFIRINOX, with no significant differences in overall survival or progression-free survival among patients.

While modified FOLFIRINOX had a lower dose reduction rate, it was associated with a slightly higher incidence of severe toxicity, indicating that patient selection may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective comparison of the efficacy and the toxicity of standard and modified FOLFIRINOX regimens in patients with metastatic pancreatic adenocarcinoma. de Jesus, VHF., Camandaroba, MPG., Donadio, MDS., et al.[2023]

In a phase II trial involving 48 patients with gemcitabine-refractory unresectable pancreatic cancer, modified FOLFIRINOX demonstrated promising efficacy with an objective response rate of 18.8% and a disease control rate of 62.5%.

The treatment was associated with manageable safety concerns, primarily neutropenia (64.6% of patients), but most non-hematologic adverse events were mild, indicating that while effective, careful monitoring for hematologic toxicities is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of modified FOLFIRINOX in gemcitabine-refractory pancreatic cancer. Chung, MJ., Kang, H., Kim, HG., et al.[2020]

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]

A nomogram was developed to predict 6-month survival in patients with metastatic and locally advanced pancreatic cancer treated with FOLFIRINOX, based on four key prognostic factors: performance status, liver metastases, baseline carbohydrate antigen 19-9 level, and neutrophil-to-lymphocyte ratio.

The nomogram demonstrated good accuracy in predicting outcomes, with a C index of 0.762 in an independent validation cohort, helping to identify patient subsets with varying prognoses based on the number of poor prognostic features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Validated Nomogram Predicting 6-Month Survival in Pancreatic Cancer Patients Receiving First-Line 5-Fluorouracil, Oxaliplatin, and Irinotecan. Fornaro, L., Leone, F., Vienot, A., et al.[2020]

References

1. China pubmed.ncbi.nlm.nih.gov

[Modified FOLFIRINOX for advanced pancreatic cancer: a tertiary center experience from China]. [2018]

2. China pubmed.ncbi.nlm.nih.gov

Comparison of efficacy and safety between standard-dose and modified-dose FOLFIRINOX as a first-line treatment of pancreatic cancer. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

Modified FOLFIRINOX for Locally Advanced and Metastatic Pancreatic Cancer Patients Resistant to Gemcitabine and S-1 in Japan: A Single Institutional Experience. [2022]

4. Australia pubmed.ncbi.nlm.nih.gov

Efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with S-1 as second-line chemotherapy in metastatic pancreatic cancer. [2022]

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

Modified FOLFIRINOX versus S-1 as second-line chemotherapy in gemcitabine-failed metastatic pancreatic cancer patients: A randomised controlled trial (MPACA-3). [2022]

6. China pubmed.ncbi.nlm.nih.gov

Retrospective comparison of the efficacy and the toxicity of standard and modified FOLFIRINOX regimens in patients with metastatic pancreatic adenocarcinoma. [2023]

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

Multicenter phase II trial of modified FOLFIRINOX in gemcitabine-refractory pancreatic cancer. [2020]

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

Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma. [2023]

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

Validated Nomogram Predicting 6-Month Survival in Pancreatic Cancer Patients Receiving First-Line 5-Fluorouracil, Oxaliplatin, and Irinotecan. [2020]