Clinical Trials /

Infigratinib Before Surgery for the Treatment of Upper Tract Urothelial Cancer

NCT04228042

Description:

This phase I/II 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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Infigratinib Before Surgery for the Treatment of Upper Tract Urothelial Cancer
  • Official Title: Tolerability and Activity of Neoadjuvant Infigratinib, an Inhibitor of FGFR, in Upper Tract Urothelial Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2019-0557
  • SECONDARY ID: NCI-2019-08197
  • SECONDARY ID: 2019-0557
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04228042

Conditions

  • Renal Pelvis and Ureter Urothelial Carcinoma

Interventions

DrugSynonymsArms
Infigratinib3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea, BGJ-398, BGJ398Treatment (infigratinib, surgery)

Purpose

This phase I/II 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.

      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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (infigratinib, surgery)ExperimentalPatients 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.
  • Infigratinib

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)

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate the tolerability of infigratinib in patients with low-grade and high-grade platinum ineligible UTUC.
Time Frame:Up to cycle 2 of infigratinib treatment (each cycle is 28 days)
Safety Issue:
Description:Will estimate proportion of patients who are not able to complete treatment (discontinuation) due to excessive toxicity along with the 90% exact confidence interval.

Secondary Outcome Measures

Measure:Objective response
Time Frame:After 2 cycles treatment of infigratinib (each cycle is 28 days)
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

January 10, 2020