FOLFIRINOX in Combination with Elraglusib and/or Losartan for the Treatment of Untreated Metastatic Pancreatic Cancer
This phase II trial tests whether FOLFIRINOX with or without elraglusib and/or losartan works to shrink tumors in patients with pancreatic cancer that has spread to other parts of the body (metastatic) that has not had any prior treatment (untreated). FOLFIRINOX is a combination of 4 chemotherapy drugs, fluorouracil, irinotecan, leucovorin, and oxaliplatin. Chemotherapy drugs, such as fluorouracil, irinotecan, leucovorin, and oxaliplatin, 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. Elraglusib may help standard of care chemotherapy drugs regain effectiveness or work better by blocking an enzyme called GSK-3beta. The GSK-3beta enzyme helps cancer cells to grow and to become resistant to chemotherapy drugs. Losartan may help prevent cancer cells from becoming resistant to chemotherapy by suppressing TGF-beta function. Giving elraglusib and/or losartan may help slow the rate or prevent the ability of cancer becoming resistant to FOLFIRINOX.
Inclusion Criteria
- Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma without prior therapy for pancreatic adenocarcinoma
- Participants must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 14 days prior to the date of registration)
- Platelets >= 100,000/mcL (within 14 days prior to the date of registration)
- Total bilirubin =< 1.5 institutional upper limit of normal (ULN) if no biliary stenting has been done OR 2.0 x ULN if patient is status post biliary stenting or two downward trending values (within 14 days prior to the date of registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN (within 14 days prior to the date of registration)
- Creatinine =< 1.5 mg/dL OR creatinine clearance >= 30 mL/min (as estimated by Cockcroft Gault Equation) (within 14 days prior to the date of registration)
- Prior treatment with angiotensin receptor blocker (ARB) for hypertension is allowed. If the patient is randomized to a non-losartan containing treatment arm, the patient must be changed to a antihypertensive medication that is not in the class of angiotensin receptor blocker (ARB)
- Participants with known history of human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy within 6 months are eligible for this trial
- Participants with known history of chronic hepatitis B virus (HBV) infection on suppressive therapy, if indicated
- Participants with known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment are eligible even if they do not have an undetectable HCV viral load
- Participants with known treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
- Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
- Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better
- The effects of treatment are harmful on the developing human fetus are unknown. For this reason, all patients of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 9 months after completion of modified (m)FOLFIRINOX administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Any prior chemotherapy, radiation therapy, immunotherapy, biologic (‘targeted’) therapy or investigational therapy for pancreas adenocarcinoma. No prior adjuvant or neoadjuvant therapy for localized pancreatic adenocarcinoma is allowed
- Patients with known deleterious or suspected deleterious germline or somatic BRCA-mutated pancreatic cancer
- Patients with known TRK (tropomyosin receptor kinase) fusion-positive cancers
- Patients with known deficient mismatch/microsatellite unstable or high tumor mutation burden cancers
- Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery
- Participation in any investigational drug study within 4 weeks preceding the start of study treatment
- Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
- The investigator(s) must state a medical or scientific reason if participants who have brain metastases will be excluded from the study
- History of allergic reactions attributed to compounds of similar chemical composition to elraglusib, losartan, 5-fluorouracil, irinotecan and oxaliplatin not amenable to institutional chemotherapy desensitization protocol. Prior topical fluoropyrimidine use is allowed
- Patients with cardiac ventricular arrhythmias requiring antiarrhythmic therapy, or atrioventricular heart block (due to 5FU administration)
- Known, existing uncontrolled coagulopathy. Concomitant treatment with full dose warfarin (coumadin) is NOT allowed. Patients may receive low molecular weight heparin (LMWH) (such as enoxaparin and dalteparin) and direct oral anticoagulant (DOAC) for management of deep venous thrombosis (DVT)
- Concomitant use of cimetidine, as it can decrease clearance of 5FU. Another H2-blocker or proton pump inhibitor may be substituted before study entry
- Patients taking strong inhibitors of CYP2C19, CYP3A4, and CYP1A2 or strong inducers of CYP3A4 should only be entered into the study protocol if deemed by the investigator to be in their best interest and with study medical coordinator agreement
- Participants with uncontrolled intercurrent illness
- Participants with uncontrolled seizures, central nervous system disorders or psychiatric illness/social situations that would limit compliance with study requirements
- Known history of active TB (Mycobacterium Tuberculosis)
- Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed. Coronavirus disease (COVID) non-live vaccines are allowed
- Patients with known history of UGT1A1 gene polymorphism
Additional locations may be listed on ClinicalTrials.gov for NCT05077800.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. Progression-free survival (PFS) in patients with untreated metastatic pancreas adenocarcinoma (mPAC).
SECONDARY OBJECTIVES:
I. Overall survival (OS).
II. Median time of maintenance therapy (mMT).
III. Objective response rate.
EXPLORATORY OBJECTIVES:
I. Evaluate relationship between dynamic changes in pancreatic adenocarcinoma (PAC) molecular phenotype and spatial cellular organization in response to glycogen synthase kinase-3beta (GSK-3beta) and/or transforming growth factor-beta (TGF-beta) inhibition with clinical outcome in patients treated with FOLFIRINOX, elraglusib and losartan.
II. Characterize alterations in metabolic profile associated with epidermal-mesenchymal transition (EMT) plasticity in response to FOLFIRINOX, losartan and elraglusib.
III. Evaluate the kinetics of circulating tumor deoxyribonucleic acid (ctDNA) quantity in relationship to EMT plasticity and disease burden on 2-dimensional imaging in response to FOLFIRINOX, losartan and elraglusib therapy.
IV. Evaluate the kinetics of circulating tumor cell (CTC) quantity in relationship to EMT plasticity and disease burden on 2-dimensional imaging in response to FOLFIRINOX, losartan and elraglusib therapy.
V. Evaluate how GSK-3 beta and/or TGF-beta inhibition by elraglusib and losartan respectively,
VI. Alters tumor spatial organization of tumor cell and CAF phenotypes to regulate EMT and immune response in the context of FOLFIRINOX exposure.
VII. Characterize the kinetics of tumor associated macrophage trafficking in response to FOLFIRINOX, losartan and elraglusib therapy.
OUTLINE: Patients are randomized to 1 of 4 arms.
ARM I:
COMPLETE THERAPY: FOLFIRINOX: Patients receive oxaliplatin intravenously (IV) over 2 hours on day 1, irinotecan IV over 30 minutes on day 1, leucovorin IV over 2 hours on day 1, and fluorouracil IV over 46 hours on day 1-3. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive fluorouracil IV over 46 hours on days 1-3. Cycles repeats every 14 days until disease progression, when patients will restart complete therapy.
ARM II:
COMPLETE THERAPY: Patients receive FOLFIRINOX as in Arm I and losartan orally (PO) once daily (QD) on days 1-14. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive fluorouracil IV over 46 hours on days 1-3 and losartan PO QD on days 1-14. Cycles repeats every 14 days until disease progression, when patients will restart complete therapy.
ARM III:
COMPLETE THERAPY: Patients receive FOLFIRINOX as in Arm I and elraglusib IV over 90 minutes on days 1 and 8. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive fluorouracil IV over 46 hours on days 1-3 and elraglusib IV over 90 minutes on days 1 and 8. Cycles repeats every 14 days until disease progression, when patients will restart complete therapy.
ARM IV:
COMPLETE THERAPY: Patients receive FOLFIRINOX as in Arm I, elraglusib IV over 90 minutes on days 1 and 8, and losartan PO QD on days 1-14. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive fluorouracil IV over 46 hours on days 1-3, elraglusib IV over 90 minutes on days 1 and 8, and losartan PO QD on days 1-14. Cycles repeats every 14 days until disease progression, when patients will restart complete therapy.
Additionally, patients undergo biopsy at baseline and at progression and CT or MRI and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months for up to 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorColin Dexter Weekes
- Primary ID21-350
- Secondary IDsNCI-2021-13832
- ClinicalTrials.gov IDNCT05077800