9-ING-41 Plus Retifanlimab and Gemcitabine/Nab-Paclitaxel in Patients With Advanced Pancreatic Adenocarcinoma

Given the role of GSK-3β in immune regulation, the combination of GSK-3β inhibition with PD 1 inhibition may be expected to provide synergistic anti-tumor efficacy. The excellent safety profile of 9-ING-41, along with preclinical and clinical evidence of anti-tumor activity in pancreatic cancer, provides a strong rationale to evaluate the efficacy of 9-ING-41 in combination with a PD 1 inhibitor plus standard chemotherapy (gemcitabine/nab-paclitaxel) as frontline therapy for patients with advanced PDAC.

The combination of 9-ING-41 and retifanlimab with gemcitabine/nab-paclitaxel has not previously been administered to human subjects. In the 1801 study, 9-ING- 41 has been administered in combination with various chemotherapy regimens including gemcitabine/nab-paclitaxel, with one 9-ING-41-related SAE (transient visual change) documented to date. Retifanlimab alone has been well-tolerated when administered for up to 2 years in patients with anal cancer. Overall, based on previous nonclinical and clinical experience, both of these agents appear to have an acceptable safety profile and do not appear to have significant overlapping toxicities. However, it is possible that when they are administered together and in combination with gemcitabine/nab-paclitaxel, more frequent or severe AEs, or new AEs not previously observed with any of these agents administered alone, may occur.

It is not known if administration of 9-ING-41 and retifanlimab will act synergistically to provide increased anti-tumor activity compared to gemcitabine/nab-paclitaxel alone. Subjects in this study should not expect to benefit directly by their participation in the study. The data collected in this study may benefit future cancer patients.

• 9-ING-41 (Drug): 9-ING-41 is a small molecule potent selective GSK-3β inhibitor
• Retifanlimab (Drug), also known as INCMGA00012: Humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes human PD-1.
• Gemcitabine (Drug): cytotoxic chemotherapy agent
• Abraxane (Drug): cytotoxic chemotherapy agent

Primary outcomes

• Disease Control Rate (DCR) [Up to approximately 11 months from baseline]: Percentage of patients with stable disease (SD), Complete Response (CR), or Partial Response (PR) for ≥16 weeks during treatment. Per RECIST v1.1, (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

Secondary outcomes

• Best Response [Up to 12 months (from enrollment)]: Number of patients with Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) per RECIST v1.1 Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
• Overall Response Rate (ORR) [Up to 12 months (from enrollment)]: Percentage of patients with Complete Response (CR) or Partial Response (PR) per RECIST v1.1 Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
• Adverse Events and Serious Adverse Events [Up to 12 months (from enrollment)]: Number of participants with overall treatment-related adverse events (AE) and/or serious adverse events (SAE) at least possibly related as assessed by CTCAE v5.0.
• Duration of Response (DOR) [Up to 12 months (from enrollment)]: Time from documentation of tumor response to disease progression. Per RECISIT v1.1, Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
• Progression-free Survival (PFS) [Up to 12 months (from enrollment)]: Time from study enrollment until objective tumor progression or death. Per RECISIT v1.1, Progressive Disease (PD) is ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.
• Overall Survival (OS) [Up to 24 months]: Time patients are alive from study enrollment to death from any cause.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Voluntarily written informed consent and willingness/ability to comply with the protocol requirements
* Has pathologically confirmed advanced, recurrent, or metastatic pancreatic cancer AND is previously untreated with systemic agents in the advanced/metastatic setting.
* Must have at least 1 measurable lesion per RECIST v1.1. Lesions that are radiated should not count as target lesions unless there is evidence of growth post radiation on a subsequent scan prior to trial enrollment.
* Must have available archived tumor tissue at study entry (metastatic tissue preferred to primary tissue)
* Adequate bone marrow function: absolute neutrophil count (ANC) ≥ 1000/mL; hemoglobin ≥ 8.5 g/dL, platelets ≥ 100,000/mL.
* Adequate liver function: transaminases (aspartate aminotransferase/ alanine aminotransferase, AST/ALT) and alkaline phosphatase ≤ 2.5 x ULN (≤ 5 X the upper limit of normal (ULN) in the setting of liver metastasis or infiltration with malignant cells); bilirubin ≤ 1.5 x ULN.
* Adequate renal function: creatinine clearance CrCl > 60 mL/min measured or calculated by Cockcroft- Gault (C-G) equation (estimated glomerular filtration rate \[eGFR\] can also be used in place of CrCl).
* Serum amylase and lipase ≤ 1.5 x ULN
* Eastern Co-operative Oncology Group (ECOG) performance status (PS) 0 - 1
* 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 - 7 days Surgery with general anesthesia - 7 days Surgery with local anesthesia - 7 days

Exclusion Criteria:

* Is pregnant or lactating.
* Is known to be hypersensitive to any of the components or metabolites of 9-ING-41 or to the excipients used in its formulation, or known sensitivity to one of the chemotherapeutic agents or to the PD-1 inhibitor.
* History of receiving prior treatment with any anti-PD-1, PD-L1 or PD-L2 agent.
* Has endocrine or acinar pancreatic carcinoma.
* Has not recovered from clinically significant toxicities as a result of prior anticancer therapy, except alopecia, anemia not requiring transfusion support and infertility. Recovery is defined as ≤ Grade 1 or baseline severity per Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (v5.0).
* Has significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, or stroke within 6 months of the first dose of 9-ING-41, or cardiac arrhythmia requiring medical treatment detected at screening.
* Has had a myocardial infarction within 12 weeks of the first dose of 9-ING-41 or has electrocardiogram (ECG) abnormalities that are deemed medically relevant by the investigator or study medical coordinator.
* Has symptomatic rapidly progressive brain metastases or leptomeningeal involvement as assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI). Patients with stable brain metastases or leptomeningeal disease or slowly progressive disease are eligible provided that they have not required new treatments for this disease in a 28-day period before the first dose of study drug, and anticonvulsants and steroids are at a stable dose for a period of 14 days prior to the first dose of study drug.
* Has had major surgery (not including placement of central lines) within 7 days prior to study entry or is planned to have major surgery during the course of the study (major surgery may be defined as any invasive operative procedure in which an extensive resection is performed, e.g., a body cavity is entered, organs are removed, or normal anatomy is altered).
* Has any medical and/or social condition that, in the opinion of the investigator would preclude study participation.
* Has received an investigational anti-cancer drug in the 14-day period before the first dose of study drug (or within 5 half-lives if longer) or is currently participating in another interventional clinical trial.
* Has a current malignancy other than pancreatic cancer.
* Known immunodeficiency syndrome or active autoimmune disease or requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent).
* Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis.
* Palliative radiation therapy administered within 1 week of first dose of study treatment or radiation therapy that is > 30 Gy within 6 months of the first dose of study treatment.
* Has received systemic antibiotics ≤ 7 days prior to the first dose of study drug.
* History of organ transplant, including allogeneic stem cell transplantation.
* Known hypersensitivity to another monoclonal antibody that cannot be controlled with standard measures (eg, antihistamines and corticosteroids).
* Known allergy or hypersensitivity to any component of retifanlimab or formulation components.
* Has received a live vaccine within 28 days of the planned start of study drug.

Participant flow

Outcome results

• Disease Control Rate (DCR) (Primary), Number, percentage of patients: 9-ING-41 Plus Retifanlimab Plus Gem/Abraxane 100
• Best Response (Secondary), Count of participants, Participants: 9-ING-41 Plus Retifanlimab Plus Gem/Abraxane 0
• Overall Response Rate (ORR) (Secondary), Number, percentage of patients: 9-ING-41 Plus Retifanlimab Plus Gem/Abraxane 33
• Adverse Events and Serious Adverse Events (Secondary), Number, participants: 9-ING-41 Plus Retifanlimab Plus Gem/Abraxane 2
• Duration of Response (DOR) (Secondary), Median, months: 9-ING-41 Plus Retifanlimab Plus Gem/Abraxane 5.273 (4.862 to 5.684)
• Progression-free Survival (PFS) (Secondary), Median, months: 9-ING-41 Plus Retifanlimab Plus Gem/Abraxane 6.785481 (4.970569 to 8.69)
• Overall Survival (OS) (Secondary), Median, months: 9-ING-41 Plus Retifanlimab Plus Gem/Abraxane 10.72596 (6.965337 to 20.40549)

Adverse events

Time frame: Adverse Events data collected for up to 12 months. All-Cause Mortality data collected for up to 24 months

Serious adverse events by term

Other adverse events by term

• Results publication: Shaw G, Cavalcante L, Giles FJ, Taylor A. Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells. J Hematol Oncol. 2022 Sep 14;15(1):134. doi: 10.1186/s13045-022-01352-x. PMID 36104795

• Study Protocol and Statistical Analysis Plan (PDF, 2023-02-04)

• Anwaar Saeed, MD, Principal investigator, University of Pittsburgh