Liposomal Irinotecan, Fluorouracil, Leucovorin Calcium, and Rucaparib in Treating Patients With Metastatic 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 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.

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