Clinical Trials /

Losartan and Nivolumab in Combination With FOLFIRINOX and SBRT in Localized Pancreatic Cancer

NCT03563248

Description:

This research study is studying a combination of interventions as a possible treatment for pancreatic tumor. The interventions involved in this study are: - FOLFIRINOX which is made up of 4 different drugs: - 5-Fluorouracil (5-FU) - Oxaliplatin - Irinotecan - Leucovorin - Losartan - Nivolumab - Radiation Therapy - Surgery

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Losartan and Nivolumab in Combination With FOLFIRINOX and SBRT in Localized Pancreatic Cancer
  • Official Title: A Randomized Phase 2 Study of Losartan and Nivolumab in Combination With FOLFIRINOX and SBRT in Localized Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: 18-179
  • NCT ID: NCT03563248

Conditions

  • Pancreatic Cancer

Interventions

DrugSynonymsArms
FOLFIRINOXFOLFIRINOX: SBRT: Surgery
LosartanFOLFIRINOX+Losartan:SBRT+Losartan:Surgery
NivolumabFOLFIRINOX+Losartan:SBRT+Nivolumab+Losartan:Sur

Purpose

This research study is studying a combination of interventions as a possible treatment for pancreatic tumor. The interventions involved in this study are: - FOLFIRINOX which is made up of 4 different drugs: - 5-Fluorouracil (5-FU) - Oxaliplatin - Irinotecan - Leucovorin - Losartan - Nivolumab - Radiation Therapy - Surgery

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational intervention to learn whether the intervention works
      in treating a specific disease. "Investigational" means that the intervention is being
      studied.

      The FDA (the U.S. Food and Drug Administration) has approved FOLFIRINOX as a treatment option
      for this disease.

      The FDA has not approved losartan or nivolumab for this specific disease but they have been
      approved for other uses.

      FOLFIRINOX is a combination of 4 chemotherapy agents that may help shrink your tumor before
      surgery. Losartan is a drug that is used to lower blood pressure. Nivolumab is an antibody (a
      cell that attaches to other cells to fight off infection) that may cause programmed cell
      death of cancer cells. Radiation therapy is believed to increase the likelihood of response
      of immunotherapy (the prevention/treatment of a disease through an immune response).
    

Trial Arms

NameTypeDescriptionInterventions
FOLFIRINOX: SBRT: SurgeryActive ComparatorThe FOLFIRINOX regimen will be administered intravenously. Treatment will be every 14 days +3/ -1 at physician discretion SBRT should be administered 2-6 weeks after completing chemotherapy All participants will undergo an attempt at definitive surgical resection following SBRT
  • FOLFIRINOX
FOLFIRINOX+Losartan:SBRT+Losartan:SurgeryExperimentalThe FOLFIRINOX regimen will be administered intravenously. Treatment will be every 14 days +3/ -1 at physician discretion Losartan will be administered orally as a tablet to be taken by the patient at home every day SBRT should be administered 2-6 weeks after completing chemotherapy All participants will undergo an attempt at definitive surgical resection following SBRT
  • FOLFIRINOX
  • Losartan
FOLFIRINOX+Losartan:SBRT+Nivolumab+Losartan:SurExperimentalThe FOLFIRINOX regimen will be administered intravenously. Treatment will be every 14 days +3/ -1 at physician discretion Losartan will be administered orally as a tablet to be taken by the patient at home every day SBRT should be administered 2-6 weeks after completing chemotherapy Participants will receive nivolumab during SBRT All participants will undergo an attempt at definitive surgical resection following SBRT
  • FOLFIRINOX
  • Losartan
  • Nivolumab
FOLFIRINOX x 8 : SBRT + Nivolumab : SurgeryExperimentalThe FOLFIRINOX regimen will be administered intravenously. Treatment will be every 14 days +3/ -1 at physician discretion SBRT should be administered 2-6 weeks after completing chemotherapy Participants will receive nivolumab during SBRT All participants will undergo an attempt at definitive surgical resection following SBRT
  • FOLFIRINOX
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed localized pancreatic adenocarcinoma; borderline/potentially
             resectable or locally advanced.

          -  Borderline resectable is defined by the NCCN as tumors with venous involvement of the
             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 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 CT) of involvement
             of the celiac axis or SMA, no evidence (CT or MRI) of occlusion of the SMV or 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.

          -  Age > 18 years

          -  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. 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.

          -  Normal organ and marrow function as defined below:

               -  absolute neutrophil count ≥ 1,500/mm3

               -  platelets ≥ 100,000/mm3

               -  total bilirubin ≤ 1.5 x institutional upper limit of normal if no biliary
                  stenting has been done OR 2.0 x upper limit of normal if patient is s/p biliary
                  stenting OR two down trending values

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal

               -  Potassium (not hemolyzed) < 5 mmol/L

               -  creatinine ≤ 1.5 mg/ dL OR

               -  creatinine clearance ≥ 30 mL/min (as estimated by Cockcroft Gault Equation)

          -  (140 - age [yrs]) (body wt [kg])

          -  Creatinine clearance for males = ————————————

          -  (72) (serum creatinine [mg/dL])

          -  Creatinine clearance for females = 0.85 x male value

          -  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 HCG) within 24 hours prior to the
             start of nivolumab

          -  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, ie, 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 7 days prior
             to initiation of treatment

        Exclusion Criteria:

          -  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.

          -  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 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 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 (eg,
             contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of participants with R0 resection
Time Frame:Up to 8 months after baseline
Safety Issue:
Description:R0 resection is defined as microscopically negative margins determined by histopathologic assessment of the resection specimen. The R0 resection rate will be analyzed among all eligible patients, including those not resected due to early progression, death or off-study.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:From randomization until the time of progression or death, up to approximately 6 years
Safety Issue:
Description:Progression-free survival is defined as the time from the date of randomization (or registration on Arm 4) to first objective documentation of progressive disease (distant or local) or death. Disease status is evaluated using RECIST (Response Evaluation Criteria in Solid Tumors). Disease progression is defined as having at least a 20% increase in the sum of the longest diameter (LD) of target lesion, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure:Overall survival
Time Frame:From randomization until the time of death, up to approximately 6 years
Safety Issue:
Description:Overall Survival (OS) is defined as the time from randomization (or registration on Arm 4) to death due to any cause, or censored at date last known alive.
Measure:Pathologic complete response
Time Frame:Up to 8 months after baseline
Safety Issue:
Description:The proportion of participants that achieved a pathologic complete response. Pathologic complete response is defined as the disappearance of all target lesions, as confirmed by a pathologist evaluating the tissue samples removed during surgery.
Measure:Number of participants with treatment related serious adverse events
Time Frame:From the start of treatment until 30 days after the end of treatment, up to approximately 14 months
Safety Issue:
Description:Adverse events are assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse events are considered to be related to treatment if the Investigator deems them to be either possibly, probably, or definitely related to treatment.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Pancreatic Cancer

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