Infigratinib for the Treatment of Advanced or Metastatic Solid Tumors in Patients With FGFR Gene Mutations
Infigratinib for the Treatment of Advanced or Metastatic Solid Tumors in Patients With FGFR Gene Mutations
This phase II trial studies how well infigratinib works in treating solid tumors that have
 spread to other places in the body (advanced or metastatic) in patients with FGFR gene
 mutations such as FGFR1-3 gene fusions or other FGFR genetic alterations. Mutations are any
 changes in the genetic material (DNA) of a cell. FGFR proteins are involved in cell division,
 cell maturation, formation of new blood vessels, wound healing, and bone growth, development,
 and maintenance. FGFR mutations can cause the FGFR protein to become over-active in diseases
 such as cancer. Infigratinib may stop the growth of tumor cells by blocking FGFR proteins in
 these tumors.
PRIMARY OBJECTIVES:

 I. To evaluate the efficacy of single agent infigratinib in patients with advanced or
 metastatic solid tumors of any histologic classification with FGFR1-3 gene
 fusions/translocations or other FGFR genetic alterations (with and without prior therapy with
 different FGFR inhibitor).

 II. To understand response rate and potential for infigratinib to benefit patients who have
 FGFR alterations including point mutations, insertions/deletions and amplifications in
 different solid tumor types.

 SECONDARY OBJECTIVES:

 I. To further evaluate the efficacy of single agent infigratinib. II. To characterize the
 safety and tolerability of single agent infigratinib. II. To evaluate benefit of infigratinib
 in patients who have received one prior FGFR inhibitor.

 EXPLORATORY OBJECTIVES:

 I. To detect biomarkers of resistance to infigratinib treatment through tumor sequencing.

 II. To develop a circulating tumor deoxyribonucleic acid (DNA) (ctDNA) or liquid biopsy assay
 optimized for monitoring response to infigratinib and detecting emerging resistance mutations
 to infigratinib.

 OUTLINE:

 Patients receive infigratinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every
 28 days in the absence of disease progression or unacceptable toxicity.

 Patients who complete study treatment for any reason other than disease progression are
 followed for 30 days, every 8 weeks until disease progression, and then every 4 months for 1
 year. All other patients are followed for 30 days, and then every 4 months for 1 year.
Inclusion Criteria:

 -  Patients with histologically or cytologically confirmed advanced or metastatic solid
 tumors of any histologic classification at the time of diagnosis

 -  Written documentation of local or central Clinical Laboratory Improvement Act
 (CLIA)-certified laboratory determination of FGFR gene fusions/translocations or
 activating mutations

 -  The study is open to solid tumors in the following cohorts:

 -  Cohort 1: Solid tumor patients with FGFR1-3 fusion/translocation (n=10) who have
 progressed on or are intolerant to standard of care (SOC) therapies and received
 treatment with a different FGFR inhibitor. Cholangiocarcinoma patients are
 permitted in this cohort

 -  Cohort 2: Solid tumor patients with FGFR1-3 fusion/translocation (n, up to 30)
 who have progressed on or are intolerant to SOC therapies. Prior therapy with a
 different FGFR inhibitor is not permitted. Cholangiocarcinoma patients are
 excluded from this cohort (there are multiple competing studies and opportunities
 for patients to get treatment in other trials)

 -  Cohort 3: Solid tumor patients with genetic alterations such as point mutations,
 insertions/deletions, or amplifications in any FGFR gene family member (n=10).
 Prior therapy with a different FGFR inhibitor is not permitted.
 Cholangiocarcinoma patients are permitted in this cohort

 -  Evidence of measurable or evaluable disease according to Response Evaluation Criteria
 in Solid Tumors (RECIST) version 1.1

 -  Patients must have received at least one prior SOC regimen for advanced/metastatic
 cancer. Patient should have had evidence of progressive disease following their prior
 regimen, or if prior treatment was discontinued due to toxicity must have continued
 evidence of measurable or evaluable disease. Patients who have received prior
 treatment with an alternate FGFR inhibitor are still eligible for the study

 -  Patients with primary central nervous system (CNS) cancer or CNS metastases are
 excluded (because it is unclear how much CNS penetration the drug has). However,
 asymptomatic patients with history of successfully treated CNS metastases with surgery
 or radiation and follow up imaging showing stability, can be eligible

 -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (patients with ECOG
 performance status of 2 may be considered on a case-by-case basis after discussion
 with QED Therapeutics)

 -  Able to read and/or understand the details of the study and provide written evidence
 of informed consent as approved by Institutional Review Board (IRB)/Ethics Committee
 (EC)

 -  Recovery from adverse events of previous systemic anti-cancer therapies to baseline or
 grade 1, except for:

 -  Alopecia

 -  Stable neuropathy of =< grade 2 due to prior cancer therapy

 -  Able to swallow and retain oral medication

 -  Willing and able to comply with scheduled visits, treatment plan and laboratory tests

 Exclusion Criteria:

 -  Patients who have therapies available that are known to confer a clinical benefit will
 be excluded from the study

 -  Neurological symptoms related to underlying disease requiring increasing doses of
 corticosteroids. Note: Steroid use for management of CNS tumors is allowed but must be
 at a stable dose for at least 2 weeks preceding study entry

 -  History of another primary malignancy except adequately treated in situ carcinoma of
 the cervix or non-melanoma carcinoma of the skin or any other curatively treated
 malignancy that is not expected to require treatment for recurrence during the course
 of the study or affect survival

 -  Any other medical condition that would, in the investigator's judgment, prevent the
 patient's participation in the clinical study due to safety concerns or compliance
 with clinical study procedures

 -  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

 -  History and/or current evidence of extensive tissue calcification including, but not
 limited to, the soft tissue, kidneys, intestine, myocardium and lung with the
 exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, and
 asymptomatic coronary calcification

 -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
 alter the absorption of oral infigratinib (e.g., ulcerative diseases, uncontrolled
 nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)

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

 -  Treatment with any of the following anti-cancer therapies prior to the first dose of
 infigratinib within the stated timeframes:

 -  Cyclical chemotherapy (intravenous) within a period of time that is shorter than
 the cycle length used for that treatment (e.g., 6 weeks for nitrosourea,
 mitomycin-C)

 -  Biological therapy (e.g., antibodies - including bevacizumab) within a period of
 time that is =< 5 half-life (t1/2) or =< 4 weeks, whichever is shorter, prior to
 starting study drug

 -  Continuous or intermittent small molecule therapeutics within a period of time
 that is =< 5 t1/2 or =< 4 weeks (whichever is shorter) prior to starting study
 drug

 -  Any other investigational agents within a period of time that is =< 5 t1/2 or
 less than the cycle length used for that treatment or =< 4 weeks (whichever is
 shortest) prior to starting study drug

 -  Wide field radiotherapy (including therapeutic radioisotopes such as strontium
 89) =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to
 starting study drug

 -  Patients who are currently receiving treatment with agents that are known strong
 inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus
 and/or calcium concentration are excluded. Patients are not permitted to receive
 enzyme-inducing anti-epileptic drugs

 -  Consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star
 fruits, pomelos, Seville oranges or products within 7 days prior to first dose

 -  Use of medications that are known to prolong the QT interval and/or are associated
 with a risk of Torsades de Pointes (TdP) 7 days prior to first dose

 -  Use of amiodarone within 90 days prior to first dose

 -  Current use of therapeutic doses of warfarin sodium or any other coumadin-derivative
 anticoagulants. Heparin and/or low molecular weight heparins are allowed

 -  Absolute neutrophil count (ANC) =< 1,000/mm^3 (1.0 x 10^9/L)

 -  Platelets =< 75,000/mm^3 (75 x 10^9/L)

 -  Hemoglobin =< 9.0 g/dL

 -  Total bilirubin >= 1.5 x upper limit of normal (ULN) unless associated with patient's
 primary cancer and/or metastases and with principal investigator's approval

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >= 3 x ULN unless
 associated with patient's primary cancer and/or metastases and with principal
 investigator's approval

 -  Alkaline phosphatase >= 2.5 x ULN unless associated with patient's primary cancer
 and/or metastases and with principal investigator's approval

 -  Calculated or measured creatinine clearance of < 40 mL/min

 -  Calcium-phosphate homeostasis:

 -  Inorganic phosphorus outside of institutional normal limits

 -  Total serum calcium (can be corrected) outside of institutional normal limits

 -  Clinically significant cardiac disease including any of the following:

 -  Congestive heart failure requiring treatment (New York Heart Association [NYHA]
 grade >= 2), left ventricular ejection fraction (LVEF) < 50% as determined by
 multi-gated acquisition (MUGA) scan or echocardiogram (ECHO), or uncontrolled
 hypertension (refer to World Health Organization [WHO] and International Society
 for 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 drug

 -  Corrected QT using Fridericia's formula (QTcF) > 470 msec (males and females)

 -  History of congenital long QT syndrome

 -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
 female after conception and until the termination of gestation, confirmed by a
 positive human chorionic gonadotropin (hCG) laboratory test

 -  Women of child-bearing potential (WOCBP), defined as all women physiologically capable
 of becoming pregnant, unless they are using highly effective methods of contraception
 during dosing 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 patient. 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

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

 -  In case of use of oral contraception women should have been stable on the same
 pill for a minimum of 3 months before taking study treatment. 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
 6 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 while taking drug
 and for 3 months after the last dose of the study drug and should not father a child
 in this period. A condom is required to be used also by vasectomized men as well as
 during intercourse with a male partner in order to prevent delivery of the drug via
 seminal fluid