Pan FGFR Kinase Inhibitor BGJ398 and Combination Chemotherapy in Treating Patients With Untreated Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To determine dose-limiting toxicity, the maximum tolerated dose and recommended phase II
dose of BGJ398 (pan FGFR kinase inhibitor BGJ398) administered in combination with modified
(m)FOLFIRINOX (fluorouracil, irinotecan hydrochloride and oxaliplatin) in patients with
advanced pancreatic and colorectal cancer patients. (Phase Ib)

II. To determine the 6-month overall survival rate of patients with treatment-naïve
metastatic pancreatic ductal adenocarcinoma treated with BGJ398 plus mFOLFIRINOX. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetic profile of BGJ398, fluorouracil, oxaliplatin, irinotecan
(irinotecan hydrochloride) and their metabolites when administered in combination and
explore for drug-drug interactions. (Phase Ib)

II. To determine the 1-year overall survival rate, response rate, progression free survival
and cancer antigen (CA)19-9 changes in treatment-naïve metastatic pancreatic cancer patients
treated with BGJ398 plus mFOLFIRINOX. (Phase II)

III. To determine the safety and tolerability of BGJ398 in combination with mFOLFIRINOX in
the study population.

IV. To explore plasma and tumor biomarkers associated with efficacy to the study
combination.

OUTLINE: This is a phase Ib, dose-escalation study of pan FGFR kinase inhibitor BGJ398
followed by a phase II study.

Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV
over 90 minutes, and fluorouracil IV continuously over 46 hours on days 1 and 15. Patients
also receive pan FGFR kinase inhibitor BGJ398 orally (PO) once daily (QD) on days 8-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days and then every 4
months for up to 2 years.

Inclusion Criteria:

- Phase Ib: Histologically or cytologically confirmed adenocarcinoma of the pancreas,
colon or rectum which disease is advanced (defined as not surgically curable) or
metastatic in whom combination treatment using fluorouracil, oxaliplatin and
irinotecan is a rational option

- All patients must consent to provide archival tumor samples; non-availability of
evaluable tumor samples does not exclude patient from the study

- Phase II: Patients with histologically or cytologically confirmed metastatic
pancreatic ductal adenocarcinoma that have not received systemic chemotherapy for
advanced or metastatic disease; the definitive diagnosis of metastatic pancreatic
adenocarcinoma will be made by integrating the histopathological data within the
context of the clinical and radiographic data

- Phase II: The initial 20 patients must have evaluable baseline tumor samples;
evaluable samples are defined as those obtained by core biopsy or surgical resection
and amendable to histological analysis; samples obtained by fine needle aspiration
biopsy are not considered evaluable; patients who do not have evaluable archival
tumor samples must consent to a tumor core biopsy prior to starting study treatment
and, patients who consent to the baseline tumor biopsy will be eligible to receive
study treatment irrespective of whether the samples obtained are evaluable

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

- Phase Ib: Have evaluable disease per Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 criteria

- Phase II: Have at least 1 metastatic lesion other than the primary pancreatic tumor
that is evaluable per RECIST 1.1 criteria; lesions previously irradiated are not
considered evaluable

- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (International System of Units
[SI] units 1.5 x 10^9/L)

- Platelets >= 100,000 cells/mm^3 (SI units 100 x 10^9/L)

- Hemoglobin >= 9.0 g/dL (SI units 90 g/L)

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3 x
ULN; in patients with known hepatic involvement, AST and ALT =< 5 x ULN are allowed

- Serum creatinine =< 1.5 x ULN or estimated creatinine clearance >= 60 mL/min by the
Cockcroft-Gault equation

- International normalized ratio (INR) =< 1.5

- Inorganic phosphorus =< ULN

- Ionized calcium =< ULN

- Ability to swallow and retain oral medication

- Participant or legal representative must understand the investigational nature of
this study and sign an Independent Ethics Committee/Institutional Review Board
approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Phase II: Patient who recurs with metastatic disease =< 6 months of completing
adjuvant chemotherapy after curative-intent surgical resection is not eligible;
patients who recur with metastatic disease > 6 months after completion of adjuvant
chemotherapy are eligible

- Phase II: Patients that previously received systemic chemotherapy for metastatic or
advanced pancreatic adenocarcinoma are not eligible

- Phase II: Diagnosis of any second malignancy within the last 3 years except for
adequately treated basal cell carcinoma, or squamous cell skin carcinoma or in-situ
cervical carcinoma

- Patients with clinically significant ascites requiring paracentesis on 2 or more
occasions within 4 weeks prior to start of study treatment

- Known hypersensitivity to BGJ398, fluorouracil, oxaliplatin, irinotecan or to any of
the excipients

- Homozygous UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 (i.e. 7
TA repeats) gene alleles; the UGT1A1 test should be conducted per local institutional
practice

- Palliative radiation treatment (e.g., pain control, bony lesions at risk of fracture)
completed =< 2 weeks of starting study treatment; patient will be eligible if
palliative radiotherapy is completed > 2 weeks from the start of study treatment and
has recovered from radiotherapy toxicities

- Pulmonary embolus or thrombosis of the deep venous system (deep vein thrombosis
[DVT]) within 2 weeks of starting study treatment; patients who had a history of
thromboembolic disease should be stable on therapeutic anticoagulation using low
molecular weight (LMW) heparin for at least 2 weeks prior to the start of study
treatment; use of warfarin (or derivatives) is not allowed at the start of study
treatment

- Patients with known symptomatic brain metastases requiring steroids and/or
antiepileptic therapy; patients with previously diagnosed brain metastases are
eligible if they have completed their treatment and have recovered from the acute
effects of radiation therapy or surgery prior to the start of study treatment, and
have discontinued corticosteroid treatment for these metastases for at least 4 weeks
and are neurologically stable; patients with leptomeningeal involvement are excluded

- Current evidence of corneal or retinal disorder/keratopathy including but not limited
to bullous/band keratopathy, corneal abrasion, inflammation/ulceration,
keratoconjunctivitis, confirmed by ophthalmologic examination

- Prior FGFR inhibitor therapy

- History or current evidence of:

- Tissue calcification including, but not limited to, the soft tissue, kidneys,
intestines, myocardium and lung with the exception of calcified lymph nodes and
asymptomatic coronary calcification

- Endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid
disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis etc

- Patients who are currently receiving or consuming

- Medications that are known strong inducers or inhibitors of cytochrome P450,
family 3, subfamily A, polypeptide 4 (CYP3A4) =< 14 days of starting study
treatment

• Medications with a known risk of prolonging the QT interval or inducing
Torsades de Pointes =< 7 days prior to start of study treatment

- Amiodarone =< 180 days prior to start of study treatment

- Grapefruit, grapefruit juice, pomegranates, star fruits, Seville oranges or
products =< 7 days prior to start of study treatment

- Warfarin (or derivatives)

- Uncontrolled intercurrent illness including, but not limited to,

- Ongoing or active infection

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Clinically significant cardiac disease including any of the following:

- Congestive heart failure requiring treatment (New York Heart Association
grade >= 2), left ventricular ejection fraction (LVEF) < 50% as determined
by multi gated acquisition scan (MUGA) scan or echocardiogram

- Uncontrolled hypertension (defined as systolic blood pressure [BP] >= 160
mmHg OR diastolic BP >= 100 mmHg despite maximal anti-hypertensive
medications: refer to World Health Organization [WHO]-International Society
of Hypertension [ISH] guidelines)

- History or presence of clinically significant ventricular arrhythmias,
atrial fibrillation, resting bradycardia, or conduction abnormality

- Unstable angina pectoris or acute myocardial infarction < 3 months prior to
starting study treatment

- Corrected QT using the Fredericia's formula (QTcF) > 450 msec (males); >
470 msec (females)

- History of congenital long QT syndrome

- Known (historical) positive human immunodeficiency virus (HIV) serology, active
hepatitis B, or active hepatitis C infection

- Major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or
significant traumatic injury =< 4 weeks and minor procedures (including percutaneous
biopsies, placement of vascular access device, laparoscopy +/- biopsy) =< 1 week
prior to starting study treatment; patients who have minor procedure(s) > 1 week
prior to starting study treatment and have recovered from side effects of such
procedure are eligible

- Unwilling or unable to follow protocol requirements

- Any condition which in the Investigator's opinion deems the participant an unsuitable
candidate to receive study drug

- Received an investigational agent within 30 days prior to enrollment

- Pregnant or nursing women; a negative pregnancy test (serum or urine) =< 3 days prior
to starting study treatment

- Women of child-bearing potential (defined as all women physiologically capable of
becoming pregnant) unless they are using highly effective methods of contraception
during study treatment and for 3 months following the discontinuation of study
treatment; highly effective contraception methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of
the subject); periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study
treatment; in case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment

- Male sterilization (at least 6 months prior to screening); for female patients
on the study the vasectomized male partner should be the sole partner for that
patient

- Combination of the following (a+b or a+c, or b+c):

- Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy
(failure rate < 1%), for example hormone vaginal ring or transdermal
hormone contraception

- Placement of an intrauterine device (IUD) or intrauterine system (IUS).

- Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository; oral contraceptives (OC), injected or implanted hormonal
methods are not allowed as the sole method of contraception

- Post-menopausal women are allowed to participate in this study; women are considered
post-menopausal and not of child bearing potential if they have had 12 months of
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago;
in the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child
bearing potential

- Sexually active males unless they use a condom during intercourse during and for 3
months after the last dose of the study treatment and should not father a child in
this period; a condom is required to be used also by vasectomized men in order to
prevent delivery of the drug via seminal fluid