Liposomal Irinotecan, Fluorouracil, Leucovorin Calcium, And Rucaparib In Treating Patients With Metastatic Pancreatic, Colorectal, Gastroesophageal, Or Biliary Cancer

Study Overview

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

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 (metastatic). Chemotherapy drugs, such as liposomal irinotecan, fluorouracil, 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. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as rucaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Giving liposomal irinotecan and rucaparib together with fluorouracil and leucovorin calcium may work better in treating patients with pancreatic, colorectal, gastroesophageal, or biliary cancer.

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 disease control rate and further tolerability, of the recommended dose level of combination of nal-IRI and 5-FU with rucaparib in patients with metastatic disease from pancreatic cancer (=< 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 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 with rucaparib (MFR). (Phase II) II. To assess the toxicity of the combination of nal-IRI and 5-FU with rucaparib in patients with metastatic adenocarcinoma of the pancreas with genomic markers (signature) of homologous recombination deficiency (HRD), specifically BRCA1/2 and PALB2 mutations. (Phase II) EXPLORATORY 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. PHASE Ia: 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. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. PHASE Ib/II: Patients receive liposomal irinotecan IV over 90 minutes and fluorouracil IV over 46 hours on days 1 and 15. Patients also receive rucaparib PO BID on days 4-13 and 18-27. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. After completion of study treatment, patients are followed up every 6 months for 3 years.

Metastatic Biliary Tract Carcinoma
Metastatic Colorectal Carcinoma
Metastatic Gastroesophageal Junction Adenocarcinoma
Metastatic Malignant Digestive System Neoplasm
Metastatic Pancreatic Adenocarcinoma
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

DRUG: Fluorouracil
DRUG: Irinotecan Sucrosofate
OTHER: Laboratory Biomarker Analysis
DRUG: Leucovorin Calcium
DRUG: Rucaparib

ACCRU-GI-1603
NCI-2017-01976 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
ACCRU-GI-1603 (OTHER Identifier) (OTHER: Academic and Community Cancer Research United)
P30CA015083 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2017-11-06	Results First Submitted 2024-04-05	Last Update Submitted that met QC Criteria 2024-05-10
First Submitted that Met QC Criteria 2017-11-07	Results First Submitted that Met QC Criteria 2024-05-10	Last Update Posted (ACTUAL) 2024-05-17
First Posted (ACTUAL) 2017-11-08	Results First Posted 2024-05-17	Last Verified 2024-05

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (nal-IRI, leucovorin, fluorouracil, rucaparib) PHASE Ia: Patients 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. Cycles repeat every 28 days in the absence of dis	DRUG: Fluorouracil Given IV DRUG: Irinotecan Sucrosofate Given IV OTHER: Laboratory Biomarker Analysis Correlative studies DRUG: Leucovorin Calcium Given IV DRUG: Rucaparib Given PO

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (nal-IRI, leucovorin, fluorouracil, rucaparib)

PHASE Ia: Patients 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. Cycles repeat every 28 days in the absence of dis

DRUG: Fluorouracil

Given IV

DRUG: Irinotecan Sucrosofate

Given IV

OTHER: Laboratory Biomarker Analysis

Correlative studies

DRUG: Leucovorin Calcium

Given IV

DRUG: Rucaparib

Given PO

Primary Outcome Measures	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (Phase I)	Will be assessed to determine maximum tolerated dose (MTD) of the combination of liposomal irinotecan (nal-IRI) and fluorouracil (5FU) with rucaparib (MFR). MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD.	Up to 28 days from start of treatment

Secondary Outcome Measures	Measure Description	Time Frame

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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: Patients with metastatic adenocarcinoma of the pancreas who have who received no more than 1 line of prior therapy in the metastatic setting

NOTE: Exposure to irinotecan is only allowed in the neoadjuvant setting and no progressive disease < 3 months from last dose of irinotecan
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: Exposure to irinotecan is only allowed in the neoadjuvant setting and no progressive disease < 3 months from last dose of irinotecan
Measurable disease
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
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 (obtained =< 21 days prior to registration)
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
Patients must discontinue prior chemotherapy >= 28 days before registration

Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

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 registration 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 registration
Received any prior poly ADP-ribose polymerase inhibitor (PARPi) treatment. Patients who received prior PARPi treatment in the adjuvant setting with the last dose received more than 12 months prior to registration are allowed to enroll.
Corrected QT interval (QTc) prolongation > 480 msec, as calculated by either the Bazett or Fridericia formula, as per institutional standard
Inability to swallow

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Tanios S Bekaii-Saab, Academic and Community Cancer Research United

Publications

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