9-ING-41 + Retifanlimab + Chemotherapy for Pancreatic Cancer

(RiLEY Trial)

Overseen By Amy Rose, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Anwaar Saeed

Must not be taking: Anti-PD-1 agents

Disqualifiers: Pregnancy, Cardiovascular impairment, Brain metastases, others

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

Compensation: Varies

Number of Visits: 14

Duration: Up to 24 months

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must not be receiving any other investigational medicinal product and should not have received systemic antibiotics within 7 days prior to the first dose of the study drug.

What data supports the effectiveness of the drug combination 9-ING-41 and Retifanlimab for pancreatic cancer?

The research shows that combining chemotherapy with immunotherapy drugs like anti-PD1 antibodies (similar to Retifanlimab) has provided clinical benefits in pancreatic cancer patients, suggesting potential effectiveness for this combination. ^{1 2 3 4 5}

What safety information is available for 9-ING-41, Retifanlimab, and chemotherapy in humans?

Immune checkpoint inhibitors, like Retifanlimab, can cause side effects such as diarrhea, liver inflammation, and pancreas inflammation. These side effects have been observed in treatments for various cancers, not just pancreatic cancer. ^{6 7 8 9 10}

How is the drug 9-ING-41 + Retifanlimab + Chemotherapy different from other pancreatic cancer treatments?

The combination of 9-ING-41 and Retifanlimab with chemotherapy is unique because it includes 9-ING-41, which is a novel drug that may work differently from standard chemotherapy by targeting specific pathways in cancer cells, and Retifanlimab, an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells. This approach is different from traditional treatments that primarily rely on chemotherapy alone. ^{2 4 11 12 13}

What is the purpose of this trial?

This is a study of the combination of 9 ING-41 (elraglusib) and retifanlimab plus mFOLFIRINOX in patients with pancreatic cancer without prior systemic therapy for advanced disease. The safety lead-in cohort will consist of 6 patients, followed by dose de-escalation if necessary, based on safety assessments. After evaluating the safety and tolerability at the initial dose level, the study will proceed to an expansion cohort at the determined safe dose level, with the total maximum enrollment not exceeding 12 patients for the entire study.

Research Team

Anwaar Saeed, MD

Principal Investigator

UPMC Hillman Cancer Center

Eligibility Criteria

This trial is for patients with advanced pancreatic adenocarcinoma who haven't had systemic therapy before. It's a small study, starting with 6 people to check safety, and may include up to 12 participants after initial assessments.

Inclusion Criteria

I can provide a tissue sample for the study, either from previous surgery or a new biopsy.

Has received the final dose of any of the following treatments/procedures within the specified minimum intervals before first dose of study drug: Focal radiation therapy, Surgery with general anesthesia, Surgery with local anesthesia, May have received treatment with fluorouracil or gemcitabine as a radiation sensitizer in the adjuvant setting if the treatment was received at least 6 months before study enrollment, May have received neoadjuvant chemotherapy with FOLFIRINOX if given at least 6 months before study enrollment, May have received prior cytotoxic doses of systemic chemotherapy in the adjuvant setting if given at least 6 months before study enrollment, Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 hours of first study therapy, Male patients with partners of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 6 months after discontinuation of study treatment and use appropriate barrier contraception or true abstinence, Must not be receiving any other investigational medicinal product.

My blood, liver, kidney tests are normal, and I can do all my daily activities.

Exclusion Criteria

Has any medical and/or social condition that, in the opinion of the investigator would preclude study participation.

Known hypersensitivity to another monoclonal antibody that cannot be controlled with standard measures.

Is pregnant or lactating.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 9-ING-41, retifanlimab, and mFOLFIRINOX chemotherapy

Up to 24 months

IV infusions every 14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for progression-free survival and overall survival

Up to 42 months

Treatment Details

Interventions

• 9-ING-41
• Retifanlimab

Trial Overview The trial tests a combination of the drug elraglusib (9-ING-41) and retifanlimab with modified FOLFIRINOX chemotherapy. The focus is on finding a safe dose level through an initial cohort and then expanding to more patients if it's deemed safe.

Participant Groups

Group I: Retifanlimab + 9-ING-41 + Chemotherapy Experimental Treatment 3 Interventions

1. Chemotherapy: oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, irinotecan 150 mg/m2 IV, and 5-FU continuous IV infusion 2400 mg/m2 over 46 hours every 14 days 2. Retifanlimab: IV at 500 mg on day 1 of every other cycle (Cycles 1, 3, 5, etc) 3.9-ING-41: IV at 9.3 mg/kg twice weekly (days 1, 3, 8 and 11) for the first 4 cycles, then weekly (days 1 and 8) thereafter

Who Is Running the Clinical Trial?

Anwaar Saeed

Lead Sponsor

Trials

5

Recruited

240+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Actuate Therapeutics Inc.

Industry Sponsor

Trials

10

Recruited

580+

Findings from Research

In a phase 3 study involving 800 patients with metastatic pancreatic cancer, ganitumab combined with gemcitabine did not improve overall survival (OS) compared to gemcitabine alone, with median OS of 7.2 months for placebo and similar results for both ganitumab doses (7.0 and 7.1 months).

The combination treatment showed manageable safety with no unexpected toxicities, but circulating biomarkers did not indicate any treatment effect on OS or progression-free survival (PFS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Fuchs, CS., Azevedo, S., Okusaka, T., et al.[2022]

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 meta-analysis of 53 trials involving 6581 patients revealed that combined immune checkpoint inhibitors (ICIs) lead to significant gastrointestinal adverse events, with diarrhea occurring in 25.4% of patients, hepatitis in nearly 13%, and pancreatitis in about 7.5%.

The study highlights a high incidence of both mild and severe gastrointestinal adverse events associated with combined ICI treatments, indicating a need for further research to understand these effects and their impact on patient treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal treatment-related adverse events of combined immune checkpoint inhibitors: a meta-analysis. Karna, R., S Deliwala, S., Ramgopal, B., et al.[2023]

In a case series of seven patients treated with immune checkpoint inhibitors (ICIs), two developed diabetic ketoacidosis (DKA) and five experienced pancreatitis, highlighting the potential for serious pancreatic adverse events associated with ICI therapy.

Pancreatitis was often asymptomatic and could be managed effectively by holding the ICI treatment and administering steroids, with some patients able to safely resume ICI therapy after recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events in patients treated with immune checkpoint inhibitors. Hana, C., Rehman, T., Park, K., et al.[2023]

In a systematic review of 59 randomized controlled trials involving 41,757 patients, immune checkpoint inhibitors (ICIs) were found to be associated with a 0.93% incidence of all-grade pancreatitis and higher rates of pancreatic enzyme elevations, indicating a notable risk of pancreatic adverse events (AEs) during treatment.

The study revealed that PD-1 inhibitors carry a greater risk of pancreatic AEs compared to PD-L1 inhibitors, and patients receiving dual ICI therapy face an even higher risk than those on single ICI therapy, highlighting the need for clinician awareness regarding these potential complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. Zhao, Z., Zhang, W., Pang, L., et al.[2023]

In a study of 184 patients with non-small cell lung cancer treated with immune checkpoint inhibitors, 26.6% developed immune-related adverse events (IRAEs), with certain factors like statin use and previous corticosteroid therapy increasing the risk of IRAEs.

Interestingly, patients who experienced IRAEs had significantly better progression-free survival (41 weeks vs. 9 weeks) and overall survival (89 weeks vs. 28 weeks), suggesting that the occurrence of IRAEs may be linked to improved treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. Serino, M., Freitas, C., Martins, M., et al.[2022]

A multidisciplinary approach using Vedolizumab effectively treated corticosteroid-refractory immune-mediated colitis in a melanoma patient receiving anti-PD-1 therapy, highlighting a potential new treatment strategy for managing immune-related adverse events.

The patient's expression of HLA-B*35 suggests a genetic predisposition to autoimmune reactions, indicating that genotyping may help tailor immunotherapy and manage side effects in high-risk melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autoimmune colitis and neutropenia in adjuvant anti-PD-1 therapy for malignant melanoma: efficacy of Vedolizumab, a case report. d'Apolito, M., Spagnuolo, R., Siciliano, MA., et al.[2022]

The combination of gemcitabine, capecitabine, bevacizumab, and erlotinib showed promising efficacy in treating advanced pancreatic cancer, with 10 partial responses observed among 20 patients and median overall survival of 12.5 months.

The maximum-tolerated dose of capecitabine was determined to be 1,660 mg/m², with a recommended dose of 1,440 mg/m² for further studies, while the treatment was generally well-tolerated with manageable side effects like diarrhea and skin rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose finding and early efficacy study of gemcitabine plus capecitabine in combination with bevacizumab plus erlotinib in advanced pancreatic cancer. Starling, N., Watkins, D., Cunningham, D., et al.[2022]

In a phase I trial involving 50 patients with advanced pancreatic cancer, the combination of nivolumab, nab-paclitaxel, and gemcitabine showed a manageable safety profile, with 48 patients experiencing grade 3/4 treatment-emergent adverse events, but only one dose-limiting toxicity reported.

The treatment resulted in a median overall survival of 9.9 months and an overall response rate of 18%, indicating limited efficacy, which led to the conclusion that further investigation of this combination is not supported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer. Wainberg, ZA., Hochster, HS., Kim, EJ., et al.[2022]

References

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

Sintilimab Plus Modified FOLFIRINOX in Metastatic or Recurrent Pancreatic Cancer: The Randomized Phase II CISPD3 Trial. [2023]

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

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer. [2022]

4. China pubmed.ncbi.nlm.nih.gov

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

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

Two types of biomarker-dependent chemo-immunotherapy for pancreatic cancer? [2023]

6. England pubmed.ncbi.nlm.nih.gov

Gastrointestinal treatment-related adverse events of combined immune checkpoint inhibitors: a meta-analysis. [2023]

7. Australia pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events in patients treated with immune checkpoint inhibitors. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. [2023]

9. Spain pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. [2022]

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

Autoimmune colitis and neutropenia in adjuvant anti-PD-1 therapy for malignant melanoma: efficacy of Vedolizumab, a case report. [2022]

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

Dose finding and early efficacy study of gemcitabine plus capecitabine in combination with bevacizumab plus erlotinib in advanced pancreatic cancer. [2022]

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

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer. [2022]

13. Germany pubmed.ncbi.nlm.nih.gov

Phase II trial of gemcitabine and S-1 for patients with advanced pancreatic cancer. [2022]