Infigratinib Before Surgery for the Treatment of Upper Tract Urothelial Cancer

Study Overview
=================
Brief Summary
-----------------
This phase Ib trial studies the side effects of infigratinib before surgery in treating patients with upper tract urothelial cancer. Infigratinib may stop the growth of tumor cells by blocking the activities of a gene called FGFR needed for cell growth. Giving infigratinib before surgery may cause the tumor to shrink, which may make the surgical procedure easier and/or reduce the need for more extensive surgery.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. Evaluate the tolerability of infigratinib in patients with low-grade and high-grade platinum ineligible upper tract urothelial carcinoma (UTUC). SECONDARY OBJECTIVES: I. Assess tolerability in those with GFR 30-49. II. Evaluate the objective response rate (complete response [CR] + partial response [PR]) of infigratinib after 2 cycles in UTUC with and without FGFR3 alterations. III. Correlate tumor tissue FGFR3 alteration (presence/absence, alteration type, and clonal status) with response and occurrence/severity of adverse events (AEs) such as hyperphosphatemia. IV. Evaluate upper tract, bladder and local/distant recurrence within 12 months. V. Evaluate renal function pre-treatment and after two treatments. VI. Evaluate patient-reported quality of life (QOL) outcomes during treatment. EXPLORATORY OBJECTIVES: I. Explore intra-tumor heterogeneity, gene expression profiles, and changes in tumor microenvironment using single cell ribonucleic acid (RNA) sequencing (scRNA-seq) and mass cytometry by time-of-flight (CyTOF) pre and post treatment to identify potential mechanisms of response and/or resistance, and correlation with the occurrence/severity of AEs. II. Explore urinary/upper tract washing FGFR3 alterations as potential biomarker for detection and response. III. Explore cell free deoxyribonucleic acid (cfDNA) for detection of FGFR3 alterations and as a predictor of response. OUTLINE: Patients receive infigratinib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. During weeks 8-9 (at least 48 hours after last dose of infigratinib), patients undergo surgery. After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 1 year after surgery.

Official Title
-----------------
Tolerability and Activity of Neoadjuvant Infigratinib, an Inhibitor of FGFR, in Upper Tract Urothelial Carcinoma

Conditions
-----------------
Renal Pelvis and Ureter Urothelial Carcinoma

Intervention / Treatment
-----------------
* Drug: Infigratinib
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Procedure: Surgical Procedure


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have low grade UTUC undergoing nephroureterectomy or ureterectomy, or high grade UTUC and not eligible for cis-platin neoadjuvant chemotherapy either due to medical comorbidities (e.g., cardiac dysfunction, hearing loss, glomerular filtration rate [GFR] < 50), or based on < 49% risk prediction of non-organ confined disease by clinical nomogram Have adequate biopsy tissue available for mutational analysis, as determined by the study pathologist, prior to enrollment. Any biopsy of index UTUC tissue available within 6 weeks of enrollment may be used Calculated or measured creatinine clearance >= 30 mL/min Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Are 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)/Independent Ethics Committee (IEC) Have recovered from AEs of previous systemic anti-cancer therapies to baseline or grade 1, except for alopecia Are able to swallow and retain oral medication Are willing and able to comply with scheduled visits, treatment plan and laboratory tests If a woman of childbearing potential (WOCBP), must have a negative pregnancy test within 7 days of the first dose of study drug. A woman is not of childbearing potential if she has undergone surgical sterilization (total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 6 weeks before taking study drug) or if she is post-menopausal and has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, spotting, etc., for at least 12 months, with an appropriate clinical profile, and there is no other cause of amenorrhea (e.g., hormonal therapy, prior chemotherapy). WOCBP and males whose sexual partners are WOCBP must agree to use barrier contraception and a second form of highly effective contraception (Clinical Trials Facilitation Group, 2014) while receiving study drug and for 3 months following their last dose of study drug. Alternatively, total abstinence is also considered a highly effective contraception method 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. Sexually active males must 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 during this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid Exclusion Criteria: Have a history of another primary malignancy within 3 years except: Adequately treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin Any other untreated cancer deemed by treating physician to be at low risk for progression during the study period (such as low or intermediate risk prostate cancer) Curatively treated malignancy that is not expected to have recurrence or require treatment during the course of the study Have uncontrolled bladder cancer. Patients with bladder cancer must have bladder cleared of disease by transurethral resection prior to initiating treatment and must not be at need for systemic therapy Have any other medical condition that would, in the investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures Have 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. Subjects with asymptomatic ophthalmologic conditions assessed by the investigator to pose minimal risk for study participation may be enrolled in the study Have a history and/or current evidence of extensive tissue calcification including, but not limited to, the soft tissue, kidneys, intestine, myocardium, vasculature and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, and asymptomatic coronary calcification Have 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) Have current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis etc 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. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges or products containing juice of these fruits within 7 days prior to first dose of study drug Have used medications known to prolong the QT interval and/or are associated with a risk of torsades de pointes (TdP) 7 days prior to first dose of study drug Have used amiodarone within 90 days prior to first dose of study drug Are currently using therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulants or using direct thrombin inhibitors (e.g., argatroban) or factor Xa inhibitors (e.g., rivaroxaban) that are primarily metabolized by CYP3A4. Heparin and/or low molecular weight heparins or direct thrombin inhibitors and/or factor Xa inhibitors that are not metabolized by CYP3A4 (e.g., dabigatran, edoxaban) are allowed Absolute neutrophil count (ANC) < 1,000/mm^3 (1.0 x 10^9/L) Platelets < 100,000/mm^3 (75 x 10^9/L) Hemoglobin < 9.0 g/dL Total bilirubin > 1.5 x upper limit of normal (ULN) (unless documented Gilbert's syndrome) Aspartate aminotransferase (AST)/ serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) > 2.5 x ULN (AST and ALT > 5 x ULN in the presence of liver involvement of cholangiocarcinoma) Calculated or measured creatinine clearance of < 30 mL/min Have amylase or lipase > 2.0 x ULN Have abnormal calcium-phosphate homeostasis: Inorganic phosphorus outside of local normal limits Total corrected serum calcium outside of local normal limits Have 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% or local lower limit of normal as determined by echocardiogram (ECHO), or uncontrolled hypertension Presence of Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 or later grade >= 2 ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction abnormality Unstable angina pectoris or acute myocardial infarction =< 3 months prior to first dose of study drug Corrected QT interval by Fridericia (QTcF) > 470 msec (males and females) Note: If the QTcF is > 470 msec in the first electrocardiography (ECG), a total of 3 ECGs separated by at least 5 minutes should be performed. If the average of these 3 consecutive results for QTcF is =< 470 msec, the subject meets eligibility in this regard Known history of congenital long QT syndrome Have had a recent (=< 3 months) transient ischemic attack or stroke

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (infigratinib, surgery)<br>Patients receive infigratinib PO QD on days 1-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. During weeks 8-9 (at least 48 hours after last dose of infigratinib), patients undergo surgery. | Drug: Infigratinib<br>* Given PO<br>* Other names: BGJ398;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Surgical Procedure<br>* Undergo surgery<br>* Other names: Type of Surgery;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will estimate proportion of patients who are not able to complete treatment (discontinuation) due to excessive toxicity along with the 90% exact confidence interval. Toxicities will be tabulated using frequency and percentage by grade and their relations to treatment. | Up to cycle 2 of infigratinib treatment (1 cycle = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response | Will estimate the objective response rate along with the 90% confidence interval. Fisher's exact test will be used to explore the difference in response between the two cohorts of patients. | After 2 cycles treatment of infigratinib (1 cycle = 28 days) | 
| Circulating cell-free deoxyribonucleic acid (cfDNA) analysis | Wilcoxon rank sum test and Fisher's exact test will be used to explore the association between objective response and cfDNA. | Up to 1 year post surgery | 
| Expression of markers | Wilcoxon rank sum test and Fisher's exact test will be used to explore the association between objective response and expression of markers. | Up to 1 year post surgery | 
| FGFR3 alteration type | Wilcoxon rank sum test and Fisher's exact test will be used to explore the association between objective response and FGFR3 alteration type. | Up to 1 year post surgery | 
| Recurrence | Will be summarized using proportion and 90% confidence interval as a binary outcome, and will also be estimated using the Kaplan-Meier method as a time to event variable. | At 12 months | 
| Changes in patient reported quality of life outcomes | Will be measured using a validated questionnaire (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3). | Baseline up to 1 month postoperative check |