Losartan and Nivolumab in Combination with Combination Chemotherapy and SBRT in Treating Patients with Localized Pancreatic Cancer
This phase II trial studies how well losartan and nivolumab work in combination with combination chemotherapy and stereotactic body radiation therapy (SBRT) in treating patients with pancreatic cancer that has not spread to other parts of the body. Losartan is a drug that is used to lower blood pressure. Immunotherapy with monoclonal antibodies, such as nivolumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as fluorouracil, oxaliplatin, irinotecan hydrochloride, and leucovorin calcium, 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. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. It is not yet known how well losartan and nivolumab work in combination with combination chemotherapy and stereotactic body radiation therapy in treating patients with localized pancreatic cancer.
- Histologically confirmed localized pancreatic adenocarcinoma; borderline/potentially resectable or locally advanced. * Borderline resectable is defined by the National Comprehensive Cancer Network (NCCN) as tumors with venous involvement of the superior mesenteric vein (SMV)/portal vein demonstrated tumor abutment with or without impingement and narrowing of the lumen, either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection or reconstruction; gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; or tumor abutment of the superior mesenteric artery (SMA) not to exceed greater than 180 degrees of the circumference of the vessel wall. Tumors involving retroperitoneal structures that can be surgically removed (i.e. kidney), will also be included. * Localized is defined as no extrapancreatic disease, no evidence (on computed tomography [CT]) of involvement of the celiac axis or SMA, no evidence (CT or magnetic resonance imaging [MRI]) of occlusion of the SMV or superior mesenteric-portal vein (SMPV) confluence, no evidence of gross peritoneal or distant metastases on staging laparoscopy or laparotomy. * Locally advanced unresectable disease is defined by the NCCN as: Tumors of the head that have greater than 180 degrees of SMA encasement or any celiac abutment, unreconstructable SMV or portal occlusion, or aortic invasion or encasement. Tumors of the body with SMA or celiac encasement of greater than 180 degrees, unreconstructable SMV or portal occlusion, or aortic invasion. Tumors of the tail with SMA or celiac encasement of greater than 180 degrees. Irrespective of location, all tumors with evidence of nodal metastasis outside of the resection field are deemed unresectable.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Baseline systolic blood pressure (SBP) > 100 mm Hg. This is based on the average of two values – separate seated, resting measurements taken five minutes apart. Blood pressure (BP) does not need to be checked in both arms unless a reading is below 110 mm Hg, in which case the other arm can be checked as well. If BP is checked in both arms, the higher value is deemed accurate for calculating the average.
- Absolute neutrophil count >= 1,500/mm^3.
- Platelets >= 100,000/mm^3.
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) if no biliary stenting has been done OR 2.0 x ULN if patient is s/p biliary stenting OR two down trending values.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN OR two down trending values.
- Potassium (not hemolyzed) < 5 mmol/L.
- Creatinine =< 1.5 mg/ dL OR creatinine clearance >= 30 mL/min (as estimated by Cockcroft Gault equation).
- Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months after the last dose of investigational drug.
- Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]).
- Women must not be breastfeeding.
- Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. Women who are not of childbearing potential, i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
- Ability to understand and the willingness to sign a written informed consent document.
- If applicable, must be on a stable dose of dexamethasone 2 mg or less for at least 7 days prior to initiation of treatment.
- NOTE: Patients enrolled to the randomized portion of the study (arms 1 thru 3) may not be already treated on ACE or ARB therapy for hypertension or renal protection (with diabetes) at the time of enrollment. If patients are receiving ACE or ARB therapy, they may ONLY be considered for the exploratory arm, arm 4. Patients must be on ACE/ARB therapy for >= 1 month prior to entering the study on Arm 4.
- Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator), such as significant cardiac or pulmonary morbidity e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months, ongoing infection as manifested by fever.
- Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test (serum or urine) at baseline. (Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential.)
- Any prior chemotherapy, radiation therapy, immunotherapy, or biologic (‘targeted’) therapy for treatment of the patient’s pancreatic tumor.
- Treatment for other invasive carcinomas within the last five years who are at greater than 5% risk of recurrence at time of eligibility screening. Carcinoma in-situ and basal cell carcinoma/ squamous cell carcinoma of the skin are allowed.
- Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.
- Known, existing uncontrolled coagulopathy.
- Prior systemic fluoropyrimidine therapy within the past 10 years. Prior topical fluoropyrimidine use is allowed. Prior unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase (DPD) deficiency.
- Participation in any investigational drug study within 4 weeks preceding the start of study treatment.
- History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance or oral drug intake.
- Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery.
- Concomitant use of cimetidine, as it can decrease the clearance of fluorouracil (5-FU). Another H2-blocker or proton pump inhibitor may be substituted before study entry.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-fluorouracil, irinotecan, oxaliplatin, or losartan.
- Other serious medical conditions that the investigator feels might compromise study participation.
- An active, known or suspected autoimmune disease other than those listed below. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
- A condition requiring systemic treatment with either corticosteroids (> 15 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 15 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
- Known history of active TB (Bacillus tuberculosis).
- Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 5 months for woman and 7 months for men, after the last dose of trial treatment.
- Known history of, or any evidence of active, non-infectious pneumonitis.
- 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.
- History of severe hypersensitivity reaction to any monoclonal antibody.
Locations & Contacts
Contact: Wells A. Messersmith
Contact: Daniel A. Laheru
Contact: Andrea Julie Bullock
Contact: Brian Matthew Wolpin
Contact: Brian Matthew Wolpin
Contact: Theodore Sunki Hong
Contact: Lawrence Scott Blaszkowsky
Contact: Paul Eliezer Oberstein
Contact: Joseph Michael Herman
Trial Objectives and Outline
I. Evaluate the ability of losartan when added to leucovorin calcium, fluorouracil, irinotecan hydrochloride, oxaliplatin (FOLFIRINOX) with or without immunotherapy (nivolumab) to increase the R0 resection rate of borderline resectable or locally advanced pancreatic cancers.
I. Determine if the addition of losartan to FOLFIRINOX followed by stereotactic body radiation therapy (SBRT), or combination of losartan and immunotherapy (nivolumab) to SBRT and surgery will improve progression-free survival.
II. Determine if the addition of losartan to FOLFIRINOX followed by SBRT, or combination of losartan and immunotherapy (nivolumab) to SBRT and surgery will improve overall survival.
III. Evaluate pathologic complete response (pCR) at time of surgical resection on each protocol arm.
I. Explore whether the addition of immunotherapy (nivolumab) to FOLFIRINOX followed by SBRT and surgery for patients already on angiotensin-converting enzyme/angiotensin II receptor antagonist (ACE/ARB) therapy is associated with different outcomes compared to the combination of losartan and immunotherapy in patients not exposed to ACE/ARB.
II. Characterize relationships between immune infiltrates and extracellular matrix (ECM).
III. Explore the ability of pancreatic organoids to predict the clinical outcomes of individual patients including response and survival.
IV. Explore the ability of blood-based biomarkers (circulating tumor-derived deoxyribonucleic acid [ctDNA], circulating tumor cells [CTCs], exosomes) to detect pancreatic cancer before and after surgery.
V. Explore the impact of FOLFIRINOX, ACE/ARB and immunotherapy on systemic and tumor metabolites.
VI. Determine if losartan changes the pancreatic tumor micro-environment.
VII. Understand the potential effects of immunotherapy on the gut microbiome via serial, self-collected stool collections.
OUTLINE: Patients are randomized to 1 of 3 arms. Patients already receiving an ACE/ARB will be assigned directly to arm 4.
CHEMOTHERAPY: Patients receive oxaliplatin intravenously (IV) over 120 minutes on day 1, irinotecan hydrochloride IV over 90 minutes on day 1, leucovorin calcium IV over 2 hours, and fluorouracil IV over 2-4 minutes on day 1 followed by continuous infusion over 46-48 hours. Treatment repeats every 14 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
SBRT: Beginning 2-6 week after chemotherapy, patients undergo SBRT over 5 or 6 days.
SURGERY: Patients may undergo surgery 28-56 days after SBRT.
CHEMOTHERAPY: Patients receive oxaliplatin, irinotecan hydrochloride, leucovorin calcium, and fluorouracil and in Arm 1. Patients also receive losartan orally (PO) once daily (QD) on days 1-14. Treatment repeats every 14 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
SBRT: Beginning 2-6 weeks after chemotherapy, patients undergo SBRT and receive losartan PO for 5 or 6 days.
SURGERY: Patients may undergo surgery 28-56 days after SBRT. Patients then receive losartan PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.
CHEMOTHERAPY: Patients receive oxaliplatin, irinotecan hydrochloride, leucovorin calcium, and fluorouracil and in Arm 1. Patients also receive losartan PO QD on days 1-14. Treatment repeats every 14 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
SBRT: Beginning 2-6 weeks after chemotherapy, patients undergo SBRT and receive nivolumab IV over 30 minutes and losartan PO for 5 or 6 days.
SURGERY: Patients may undergo surgery 28-56 days after SBRT. Patients then receive nivolumab IV over 30 minutes every 2 weeks and losartan PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.
CHEMOTHERAPY: Patients receive oxaliplatin, irinotecan hydrochloride, leucovorin calcium, and fluorouracil and in Arm 1.
SBRT: Beginning 2-6 weeks after chemotherapy, patients undergo SBRT and receive nivolumab IV over 30 minutes for 5 or 6 days.
SURGERY: Patients may undergo surgery 28-56 days after SBRT. Patients then receive nivolumab IV over 30 minutes every 2 weeks for up to 6 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 5 years.
Trial Phase & Type
Dana-Farber Harvard Cancer Center
Theodore Sunki Hong
Secondary IDs NCI-2018-02378
Clinicaltrials.gov ID NCT03563248