Clinical Trials /

Liposomal Irinotecan, Fluorouracil, Leucovorin Calcium, and Rucaparib in Treating Patients With Metastatic Pancreatic, Colorectal, Gastroesophageal, or Biliary Cancer

NCT03337087

Description:

This phase I/II trial studies the side effects and best dose of liposomal irinotecan and rucaparib when given together with fluorouracil and leucovorin calcium and to see how well they work in treating patients with pancreatic, colorectal, gastroesophageal, or biliary cancer that has spread to other places in the body. Drugs used in chemotherapy, such as liposomal irinotecan, fluorouracil, leucovorin calcium, and rucaparib, 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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Bile Duct Adenocarcinoma
  • Colorectal Adenocarcinoma
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Liposomal Irinotecan, Fluorouracil, Leucovorin Calcium, and Rucaparib in Treating Patients With Metastatic Pancreatic, Colorectal, Gastroesophageal, or Biliary Cancer
  • Official Title: Phase I/Ib Study of Irinotecan Liposome (Nal-IRI), Fluorouracil, Leucovorin, and Rucaparib in the Treatment of Select Gastrointestinal Metastatic Malignancies Followed by a Phase II Study of First Line Treatment of Selected Patients With Metastatic Adenocarcinoma of the Pancreas With Genomic Markers (Signature) of Homologous Recombination Deficiency (HRD)

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-GI-1603
  • SECONDARY ID: NCI-2017-01976
  • SECONDARY ID: ACCRU-GI-1603
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03337087

Conditions

  • Biliary System Disorder
  • BRCA1 Gene Mutation
  • BRCA2 Gene Mutation
  • Gastroesophageal Junction Adenocarcinoma
  • Homologous Recombination Deficiency
  • Metastatic Pancreatic Adenocarcinoma
  • PALB2 Gene Mutation
  • Stage IV Colorectal Cancer AJCC v7
  • Stage IV Pancreatic Cancer AJCC v6 and v7
  • Stage IVA Colorectal Cancer AJCC v7
  • Stage IVB Colorectal Cancer AJCC v7

Interventions

DrugSynonymsArms
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Treatment (nal-IRI, leucovorin, fluorouracil, rucaparib)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, citrovorum factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinTreatment (nal-IRI, leucovorin, fluorouracil, rucaparib)
Liposomal IrinotecanIrinotecan Liposome, MM-398, nal-IRI, Nanoliposomal Irinotecan, Nanoparticle Liposome Formulation of Irinotecan, Onivyde, PEP02Treatment (nal-IRI, leucovorin, fluorouracil, rucaparib)
Rucaparib6H-Pyrrolo(4,3,2-ef)(2)benzazepin-6-one, 8-Fluoro-1,3,4,5-tetrahydro-2-(4-((methylamino)methyl)phenyl)-, 8-Fluoro-2-(4-((methylamino)methyl)phenyl)-1,3,4,5-tetrahydro-6H-azepino(5,4,3-cd)indol-6-oneTreatment (nal-IRI, leucovorin, fluorouracil, rucaparib)

Purpose

This phase I/II trial studies the side effects and best dose of liposomal irinotecan and rucaparib and when given together with fluorouracil and leucovorin calcium and to see how well they work in treating patients with pancreatic, colorectal, gastroesophageal, or biliary cancer that has spread to other places in the body. Drugs used in chemotherapy, such as liposomal irinotecan, fluorouracil, leucovorin calcium, and rucaparib, 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the recommended dose level for the phase Ib and phase II trial of liposomal
      irinotecan (nal-IRI) and fluorouracil (5-FU) with rucaparib (MFR) in patients with metastatic
      disease from pancreatic cancer (up to 2 lines of prior therapy), colorectal cancer (up to 3
      lines of prior therapy), gastroesophageal cancer (up to 1 line of prior therapy) and biliary
      tract cancer (with 1 line of prior therapy allowed). (Phase I) II. To assess, in a
      preliminary fashion, antitumor efficacy, in terms of objective response, of the recommended
      dose level of combination of nal-IRI and 5-FU with rucaparib in patients with metastatic
      disease from pancreatic cancer (up to 1 line of prior therapy in the metastatic setting) and
      gastroesophageal cancer (with 1 line of prior therapy in the metastatic setting). (Phase Ib)
      III. To estimate the proportion of evaluable patients who reach complete response
      (CR)/partial response (PR) =< 32 weeks after registration among patients with metastatic
      adenocarcinoma of the pancreas with genomic markers (signature) of homologous recombination
      deficiency (HRD), specifically BRCA1, BRCA2, and PALB2 mutation, treated with the combination
      of nal-IRI and 5FU/leucovorin calcium (LV) with rucaparib (MFR). (Phase II)

      SECONDARY OBJECTIVES:

      I. To estimate the progression-free survival (PFS) and overall survival (OS) for patients
      with metastatic adenocarcinoma of the pancreas with genomic markers (signature) of homologous
      recombination deficiency (HRD), specifically BRCA1, BRCA2, and PALB2 mutation, treated with
      the combination of nal-IRI and 5-FU/LV with rucaparib (MFR). (Phase II) II. To assess the
      toxicity of the combination of nal-IRI and 5-FU/LV with rucaparib in patients with metastatic
      adenocarcinoma of the pancreas with genomic markers (signature) of homologous recombination
      deficiency (HRD), specifically BRCA1/2 and PALB2 mutation. (Phase II)

      TERTIARY OBJECTIVES:

      I. To evaluate the role of genomic markers (signature) of HRD, mutation other than BRCA1,
      BRCA2, and PALB2 as predictive biomarkers of response to MFR.

      II. To evaluate BRCA1, BRCA2, and PALB2 mutations as predictive biomarker of response to MFR.

      OUTLINE: This is phase I, dose-escalation study of liposomal irinotecan and rucaparib and
      followed by a phase II study.

      Patients receive liposomal irinotecan intravenously (IV) over 90 minutes, leucovorin calcium
      IV, and fluorouracil IV over 46 hours on days 1 and 15. Patients also receive rucaparib
      orally (PO) twice daily (BID) on days 4-13 and 18-27. Courses repeat every 28 days in the
      absence of disease progression or unaccepted toxicity.

      After completion of study treatment, patients are followed up for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nal-IRI, leucovorin, fluorouracil, rucaparib)ExperimentalPatients receive liposomal irinotecan IV over 90 minutes, leucovorin calcium IV, and fluorouracil IV over 46 hours on days 1 and 15. Patients also receive rucaparib PO BID on days 4-13 and 18-27. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
  • Fluorouracil
  • Leucovorin Calcium
  • Liposomal Irinotecan
  • Rucaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Phase I only: Histologic confirmation of pancreatic, colorectal, gastroesophageal or
             biliary adenocarcinoma, as follows:

               -  Patients with metastatic disease from pancreatic cancer who received no more than
                  2 lines of prior therapy in the metastatic setting

               -  Patients with metastatic disease from colorectal cancer who received no more than
                  3 lines of prior therapy in the metastatic setting

               -  Patients with metastatic disease from gastroesophageal cancer who received no
                  more than 1 line of prior therapy in the metastatic setting

               -  Patients with metastatic disease from biliary tract cancer who received no more
                  than 1 line of prior therapy in the metastatic setting

               -  NOTE: No prior exposure to irinotecan in the metastatic setting will be allowed
                  except in the phase I dose escalation portion and in colon cancer patients only;
                  in pancreas cancer, exposure to irinotecan is only allowed in the neoadjuvant
                  setting and no progressive disease < 3 months from last dose of irinotecan

          -  Phase Ib only: Histologic confirmation of pancreatic or gastroesophageal
             adenocarcinoma, as follows:

               -  Patients with metastatic disease from pancreatic cancer who received no more than
                  1 line of prior therapy in the metastatic setting

               -  Patients with metastatic disease from gastroesophageal cancer who received no
                  more than 1 line of prior therapy in the metastatic setting

               -  NOTE: No prior exposure to any irinotecan in the metastatic setting will be
                  allowed

          -  Phase II only: Patients with metastatic adenocarcinoma of the pancreas with genomic
             markers (signature) of homologous recombination deficiency (HRD) or BRCA1 or BRCA2 or
             PALB2 mutation, or HRD (non-BRCA, non-PALB) who have not received any systemic therapy
             in the metastatic setting

               -  NOTE: In pancreatic cancer: exposure to irinotecan is only allowed in the
                  neoadjuvant setting and no progressive disease < 3 months from last dose of
                  irinotecan

          -  Metastatic colorectal, pancreatic, gastroesophageal or biliary tract adenocarcinoma
             not amenable to curative resection

          -  Measurable disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

          -  Obtained =< 21 days prior to registration: Absolute neutrophil count (ANC) >=
             1500/mm^3

          -  Obtained =< 21 days prior to registration: Platelet count >= 100,000/mm^3

          -  Obtained =< 21 days prior to registration: Hemoglobin > 9.0 g/dL

          -  Obtained =< 21 days prior to registration: Total bilirubin =< institutional upper
             limit of normal (ULN)

          -  Obtained =< 21 days prior to registration: Aspartate transaminase (AST) =< 3 x ULN, =<
             5.0 x ULN for patients with metastatic disease to the liver

          -  Obtained =< 21 days prior to registration: Aminotransferase (ALT) =< 3.0 x ULN, =< 5.0
             x ULN for patients with metastatic disease to the liver

          -  Obtained =< 21 days prior to registration: Creatinine =< 1.0 mg/dL or creatinine
             clearance >= 45 ml/min using the Cockcroft-Gault formula

          -  Negative serum or urine pregnancy test done =< 7 days prior to registration and
             repeated prior to dosing on day 1 of each cycle, for individuals of childbearing
             potential only; NOTE: Individuals are considered to be of childbearing potential
             unless one of the following applies:

               -  Is postmenopausal, defined as no menses for at least 12 months without an
                  alternative medical cause; a high follicle-stimulating hormone (FSH) level
                  consistently in the postmenopausal range (30 mIU/mL or higher) may be used to
                  confirm a postmenopausal state in women not using hormonal contraception or
                  hormonal replacement therapy; however, in the absence of 12 months of amenorrhea,
                  a single FSH measurement is insufficient to confirm a postmenopausal state: or

               -  Considered to be permanently sterile; permanent sterilization includes
                  hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy

          -  Provide informed written consent

          -  Willing to return to enrolling institution for follow-up (during the Active Monitoring
             Phase of the study)

               -  Note: During the active monitoring phase of a study (i.e., active treatment and
                  observation), participants must be willing to return to the consenting
                  institution for follow-up

          -  Willing to provide tissue and blood samples for mandatory correlative research
             purposes

          -  Individuals of reproductive potential and their partners willing to practice total
             abstinence or use a highly effective method of contraception (failure rate < 1% per
             year) during treatment and for 6 months following the last dose of rucaparib; the
             following are allowable only:

               -  Ongoing use of progesterone-only injectable or implantable contraceptives (eg,
                  Depo Provera, Implanon, Nexplanon)

               -  Placement of an intrauterine device or intrauterine system

               -  Bilateral tubal occlusion

               -  Sterilization, with appropriate post-vasectomy documentation of absence of sperm
                  in ejaculate

               -  True, complete (as opposed to periodic) abstinence

        Exclusion Criteria:

          -  Any of the following:

               -  Pregnant individuals

               -  Nursing individuals

               -  Persons of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
             positive and currently receiving antiretroviral therapy

          -  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

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Previous or concurrent cancer that is distinct in primary site or histology from
             cancer of primary site =< 3 years prior to randomization EXCEPT for curatively treated
             cervical cancer in situ, melanoma in situ, non-melanoma skin cancer and superficial
             bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades
             lamina propria)]; Note: All cancer treatments for those distinct in a primary site
             other than cancer of origin must be completed >= 3 years prior to randomization

          -  Received any prior poly ADP-ribose polymerase inhibitor (PARPi) treatment

          -  Corrected QT interval (QTc) prolongation > 480 msec, as calculated by either the
             Bazett or Fridericia formula, as per institutional standard
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of the combination of nal-IRI and 5FU with rucaparib (MFR) (Phase I)
Time Frame:Up to 28 days from start of treatment
Safety Issue:
Description:The Maximum Tolerated Dose (MTD) will be based on the assessment of dose-limiting toxicities (DLT) during the first cycle of treatment only (i.e., 1 cycle of therapy = 28 days) and will be defined as the dose at which fewer than one-third of patients experience a DLT to study treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with the next higher dose having at least 2 out of 3 or 2 out of 6 patients encountering DLT. Three patients will be treated at each dose level, and can be enrolled simultaneously. If one DLT is encountered, an additional 3 patients will be added to that dose level. If at any point two DLTs are encountered within a given dose level, then the MTD has been exceeded and if only three patients have been treated at the next lower dose three more patients are treated at the next lower dose. The number of patients who developed DLTs are reported here by dose level.

Secondary Outcome Measures

Measure:Overall survival (Phase II)
Time Frame:Time from registration to death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier.
Measure:Progression-free survival (Phase II)
Time Frame:Time from registration to the earliest date documentation of disease progression or death due to any cause, assessed up to 3 years
Safety Issue:
Description:The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse events (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. The overall adverse event rates for grade 3 or higher adverse events will be compared using Chi-square or Fisher?s exact tests between the two treatment groups.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Academic and Community Cancer Research United

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