FOLFIRINOX + 9-ING-41 for Pancreatic Cancer

Not currently recruiting at 6 trial locations

Overseen By Colin Weekes, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Colin D. Weekes, M.D., PhD

Must not be taking: Cimetidine, Strong CYP inhibitors

Disqualifiers: Prior chemotherapy, BRCA mutation, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments to determine if they can prevent advanced pancreatic cancer from resisting standard therapies. The study tests various combinations of existing drugs with a new experimental drug, 9-ING-41 (a GSK-3β inhibitor), to identify the most effective option. Individuals diagnosed with metastatic pancreatic cancer who have not yet received treatment may find this trial suitable. 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 must stop taking your current medications, but if you are on an angiotensin receptor blocker (ARB) for high blood pressure and are not assigned to the losartan group, you will need to switch to a different type of blood pressure medication. Also, you cannot take cimetidine and certain other medications that affect liver enzymes.

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

Research shows that the combination of 9-ING-41 with FOLFIRINOX is under careful study for safety. Studies have found that 9-ING-41, also known as elraglusib, when used with other chemotherapy drugs, is generally well-tolerated. Initial data suggest that adding 9-ING-41 to treatment does not cause severe side effects beyond those expected with standard chemotherapy.

For FOLFIRINOX and Losartan, research in patients with pancreatic cancer has shown that this combination is safe. Patients tolerated it well, with side effects similar to those expected from chemotherapy alone.

The trial is also exploring the use of all three treatments together: FOLFIRINOX, 9-ING-41, and Losartan. Early findings from ongoing studies indicate a promising safety profile, but they remain under review.

It is important to note that this trial is in a phase where safety is actively evaluated. This means the treatment has already demonstrated a reasonable level of safety in earlier studies, but researchers continue to monitor it closely to ensure it is safe for more patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about FOLFIRINOX combined with 9-ING-41 and Losartan for pancreatic cancer because it targets the disease in a novel way. FOLFIRINOX, already a standard treatment, is enhanced by 9-ING-41, which is a GSK-3β inhibitor that may help reduce tumor growth. Losartan, typically used for high blood pressure, is included to potentially improve drug delivery to the tumor by altering the tumor's microenvironment. This multi-pronged approach aims to tackle the cancer more effectively than current treatments, offering hope for better outcomes for patients.

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

Research has shown that FOLFIRINOX can extend the lives of people with advanced pancreatic cancer. One study found that patients using FOLFIRINOX lived an average of 11.1 months, compared to 6.8 months for those using gemcitabine. In this trial, participants may receive FOLFIRINOX alone or with other treatments. Studies suggest that 9-ING-41, a type of drug, might enhance the effectiveness of chemotherapy against pancreatic tumors. Early results indicate that combining 9-ING-41 with FOLFIRINOX could improve treatment outcomes. Some participants in this trial will receive this combination. Although adding losartan to FOLFIRINOX did not significantly extend the time patients lived without cancer progression, it did help successfully remove tumors in some cases. This combination of treatments is being studied in this trial to determine if it can prevent the cancer from becoming resistant to standard therapy. ^{1 3 4 6 7}

Who Is on the Research Team?

Colin Weekes, M.D., Ph.D.

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults over 18 with newly diagnosed metastatic pancreatic adenocarcinoma who haven't had treatment for it yet. They must have a certain level of physical fitness and adequate organ function. People with HIV, HBV, or cured HCV can join. Those with controlled brain metastases may be eligible. Pregnant women can't participate unless they use contraception.

Inclusion Criteria

My organs and bone marrow are functioning well.

I have another cancer, but it won't affect this trial's treatment.

I had hepatitis C but have been treated and cured.

Exclusion Criteria

I am not on strong medication that affects liver enzymes CYP2C19, CYP3A4, and CYP1A2.

I have a known UGT1A1 gene variation.

My pancreatic cancer is linked to a harmful BRCA gene mutation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In

Establish the side effects from the study treatment to its safety before beginning the main part of the study

2-4 weeks

1-2 cycles of treatment

Complete Therapy

Participants receive FOLFIRINOX, 9-ING-41, and Losartan for up to 12 cycles

24 weeks

Bi-weekly visits for each cycle

Maintenance Therapy

Participants continue with FOLFIRINOX and other drugs until disease progression

Up to 30 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• 9-ING-41
• FOLFIRINOX
• Losartan

Trial Overview The study tests if the experimental drug 9-ING-41 combined with FOLFIRINOX (a mix of four chemotherapy drugs) and Losartan prevents resistance to standard pancreatic cancer treatment in patients without prior therapy.

How Is the Trial Designed?

Group I: Safety Run-In: FOLFIRINOX + Elraglusib + Losartan Experimental Treatment 3 Interventions

The study will begin with a Safety Run-In phase to establish the side effects from the study treatment to its safety before beginning the main part of the study, six (6) participants will receive 1-2 cycles (each study cycle is 14 days +/- 3 days) of: * FOLFIRINOX * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each study cycle * Irinotecan portion of FOLFIRINOX on Day 1 of each study cycle * Oxaliplatin portion of FOLFIRINOX on Day 1 of each study cycle * Leucovorin portion of FOLFIRINOX on Day 1 of each study cycle The FOLFIRINOX treatment regimen will be given every 14 days +/- 3 days at physician discretion. * Elraglusib on days on days 1, 3, 8, and 11 of every 14-day cycle * Losartan daily of every 14-day cycle.

Group II: FOLFIRNINOX Experimental Treatment 1 Intervention

The study will be conducted in three parts depending on participant disease progression: Complete Therapy, Maintenance Therapy and Complete Therapy Round 2. For initial complete therapy, participants will receive FOLFIRINOX as follows (each study cycle is 14 days +/- 3 days, FOLFIRINOX can be given +/- 3 days): * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each study cycle up to 12 cycles (24 weeks) * Irinotecan portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Oxaliplatin portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Leucovorin portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) For Maintenance therapy, participants will receive FOLFIRINOX as follows: * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each 14 day study cycle until disease progression For Complete Therapy Round 2, participants will repeat initial complete therapy of FOLFIRINOX until further disease progression

Group III: FOLFIRINOX + Losartan Experimental Treatment 2 Interventions

The study will be conducted in three parts depending on participant disease progression: Complete Therapy, Maintenance Therapy and Complete Therapy Round 2. For initial complete therapy (each study cycle is 14 days +/- 3 days): * FOLFIRINOX (+/- 3 days) * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each study cycle up to 12 cycles (24 weeks) * Irinotecan portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Oxaliplatin portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Leucovorin portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Losartan daily up to 12 cycles (24 weeks) For Maintenance therapy: * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each 14 day study cycle until disease progression * Losartan daily until disease progression For Complete Therapy Round 2, participants will repeat initial complete therapy of FOLFIRINOX + Losartan until further disease progression

Group IV: FOLFIRINOX + Elraglusib + Losartan Experimental Treatment 3 Interventions

The study conducted in 3 parts depending on disease progression: Complete Therapy, Maintenance Therapy and Complete Therapy Round 2. For initial complete therapy (each study cycle is 14 days +/- 3 days): * FOLFIRINOX (+/- 3 days) * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each study cycle * Irinotecan portion of FOLFIRINOX on Day 1 of each study cycle * Oxaliplatin portion of FOLFIRINOX on Day 1 of each study cycle * Leucovorin portion of FOLFIRINOX on Day 1 of each study cycle * Elraglusib on days 1, 3, 8, and 11 of every 14-day cycle * Losartan daily For Maintenance therapy: * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each 14 day study cycle until disease progression * Elraglusib on days 1, 3, 8, and 11 of every 14-day cycle until disease progression * Losartan daily until disease progression For Complete Therapy Round 2, participants will repeat initial complete therapy of FOLFIRINOX + Elraglusib + Losartan until further disease progression

Group V: FOLFIRINOX + Elraglusib Experimental Treatment 2 Interventions

The study conducted in 3 parts depending on disease progression: Complete Therapy, Maintenance Therapy and Complete Therapy Round 2 For initial complete therapy (each study cycle is 14 days +/- 3 days): * FOLFIRINOX (+/- 3 days) * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each study cycle up to 12 cycles (24 weeks) * Irinotecan portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Oxaliplatin portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Leucovorin portion of FOLFIRINOX on Day 1 of each study cycle up to 12 cycles (24 weeks) * Elraglusib on days 1, 3, 8, and 11 of every study cycle up to 12 cycles (24 weeks) For Maintenance therapy: * 5Fluorouracil portion of FOLFIRINOX on Days 1-3 of each study cycle until disease progression * Elraglusib on days 1, 3, 8, and 11 of every study cycle until disease progression For Complete Therapy Round 2, repeat of initial complete therapy until further disease progression

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

Approved in European Union as FOLFIRINOX for:

• Advanced pancreatic cancer

Approved in United States as FOLFIRINOX for:

• Metastatic pancreatic cancer

Who Is Running the Clinical Trial?

Colin D. Weekes, M.D., PhD

Lead Sponsor

Trials

2

Recruited

70+

Colin D. Weekes, M.D.

Lead Sponsor

Trials

2

Recruited

70+

Lustgarten Foundation

Collaborator

Trials

27

Recruited

5,500+

Actuate Therapeutics Inc.

Industry Sponsor

Trials

10

Recruited

580+

Published Research Related to This Trial

In a study of 342 patients with metastatic pancreatic cancer, the FOLFIRINOX chemotherapy regimen significantly improved overall survival (11.1 months) compared to gemcitabine (6.8 months), indicating it is a more effective first-line treatment option.

While FOLFIRINOX showed a higher objective response rate (31.6% vs. 9.4% for gemcitabine), it also resulted in more adverse events, including a 5.4% incidence of febrile neutropenia, highlighting the need to balance efficacy with safety in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. Conroy, T., Desseigne, F., Ychou, M., et al.[2023]

In a study of 18 patients with locally advanced pancreatic cancer (LAPC), neoadjuvant therapy using FOLFIRINOX resulted in a promising R0 resection rate of 44%, indicating that a significant portion of patients became eligible for surgical removal of their tumors after treatment.

The treatment showed high efficacy with a 1-year overall survival rate of 100% and a progression-free survival rate of 83%, although it was associated with notable chemotherapy-related toxicities, including neutropenia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. Hosein, PJ., Macintyre, J., Kawamura, C., et al.[2022]

FOLFIRINOX, a combination chemotherapy regimen, has been shown to significantly improve overall survival and progression-free survival in patients with metastatic pancreatic cancer compared to the traditional treatment with gemcitabine, based on results from the PRODIGE 4/ACCORD 11 trial.

While FOLFIRINOX is associated with higher toxicity rates, including febrile neutropenia and diarrhea, its rapid adoption in clinical practice highlights its effectiveness, and further studies are needed to explore its benefits in other treatment settings like second-line therapy and adjuvant chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status on the place of FOLFIRINOX in metastatic pancreatic cancer and future directions. Lambert, A., Gavoille, C., Conroy, T.[2021]

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]

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]

In a study of 289 patients with advanced pancreatic ductal adenocarcinoma, the FOLFOXIRI chemotherapy regimen showed similar overall survival (11.1 months) compared to the standard FOLFIRINOX regimen (11.6 months), indicating no significant therapeutic advantage for FOLFOXIRI.

FOLFOXIRI was associated with a higher incidence of grade 3/4 digestive adverse events (28.7% vs. 19.5% for FOLFIRINOX), suggesting that while it is feasible, it may lead to more severe side effects without improving survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOXIRI vs FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: A population-based cohort study. Vienot, A., Chevalier, H., Bolognini, C., et al.[2020]

Neoadjuvant FOLFIRINOX treatment in patients with borderline resectable pancreatic cancer (BRPC) resulted in a median overall survival of 22.2 months and a high resection rate of 67.8%, indicating its potential effectiveness in this patient group.

The treatment was associated with manageable adverse events, with the most common being neutropenia, diarrhea, and fatigue, but no deaths were reported due to FOLFIRINOX, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis. Janssen, QP., Buettner, S., Suker, M., et al.[2021]

In a study of 69 chemotherapy-naïve patients with metastatic pancreatic cancer, the modified FOLFIRINOX regimen resulted in a median overall survival of 11.2 months and a response rate of 37.7%, indicating its efficacy in this patient population.

The modified regimen demonstrated a better safety profile compared to previous studies, with a 47.8% incidence of grade 3 or higher neutropenia and fewer serious adverse events, suggesting it can be administered without prophylactic pegfilgrastim.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer. Ozaka, M., Ishii, H., Sato, T., et al.[2019]

In a multicenter phase II study involving 31 patients with locally advanced pancreatic cancer (LAPC) and 44 with metastatic pancreatic cancer (MPC), modified FOLFIRINOX showed comparable efficacy to full-dose FOLFIRINOX in MPC, with a response rate of 35.1% and a median overall survival of 10.2 months.

The study found that modified FOLFIRINOX significantly reduced adverse events such as neutropenia, vomiting, and fatigue, while demonstrating notable efficacy in LAPC with a median progression-free survival of 17.8 months and overall survival of 26.6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Stein, SM., James, ES., Deng, Y., et al.[2022]

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-FOLFIRINOX (mFOLFIRINOX) significantly improves safety and tolerability for Chinese patients with locally advanced pancreatic cancer (LAPC), with a response rate of 37.1% and common severe side effects including neutropenia and anemia.

Patients with LAPC who received neoadjuvant therapy with mFOLFIRINOX and subsequently underwent surgery had a median overall survival of 27.7 months, which is significantly better than the 8.9 months seen in patients who had upfront surgery without prior chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population. Li, X., Guo, C., Li, Q., et al.[2023]

In a study of 243 patients with advanced pancreatic adenocarcinoma treated with FOLFIRINOX, the relative dose intensity (RDI) of the treatment agents did not significantly correlate with disease control or objective response, suggesting that dose reductions may not compromise treatment effectiveness.

The median cumulative multi-drug RDI was 80%, and including RDI in predictive models did not enhance the ability to forecast disease control, indicating that oncologists can safely adjust doses without fearing a loss of therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRINOX relative dose intensity and disease control in advanced pancreatic adenocarcinoma. Vary, A., Lebellec, L., Di Fiore, F., et al.[2022]

Citations

1. esmoopen.com esmoopen.com/article/S2059-7029(25)00991-3/fulltext

Phase II study of elraglusib (9-ING-41), a GSK-3β inhibitor ... Elraglusib monotherapy led to an objective response rate (ORR) of 3.2%, median progression-free survival (PFS) of 1.6 months, and median overall ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8301062/

GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its ... Studies show targeting this protein for treatment may overcome resistance to conventional chemotherapy in pancreatic tumors. Early-stage ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40403387/

Phase II study of elraglusib (9-ING-41), a GSK-3β inhibitor ... The purpose of this study was to assess the efficacy and safety of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine/nab-paclitaxel ( ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.578

Phase 2 study of 9-ING-41, a small molecule selective ... 9-ING-41 has significant anti-tumor activity through apoptosis induction, anti-fibrotic activity and NK/T-cell effector stimulation.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03678883

NCT03678883 | 9-ING-41 in Patients with Advanced Cancers The Actuate 1801 Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41, a potent GSK-3β inhibitor, as a single agent and in combination ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06896188

NCT06896188 | 9-ING-41 Combined With Retifanlimab, ... This is a study of the combination of 9 ING-41 (elraglusib) and retifanlimab plus mFOLFIRINOX in patients with pancreatic cancer without prior systemic ...

7. actuatetherapeutics.com actuatetherapeutics.com/press_releases/actuate-announces-completion-of-enrollment-in-a-phase-2-trial-of-elraglusib-in-combination-with-folfirinox-and-losartan-in-patients-with-previously-untreated-metastatic-pancreatic-cancer/

Actuate Announces Completion of Enrollment in a Phase 2 ... Initial Data from this Phase 2 Trial Demonstrates Early Evidence of Clinical Activity of Elraglusib (9-ING-41) in Combination with ...