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BGJ398 for the Treatment of Tumor-Induced Osteomalacia

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ClinicalTrials.gov Identifier: NCT03510455
Recruitment Status : Recruiting
First Posted : April 27, 2018
Last Update Posted : May 29, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) )

Tracking Information
First Submitted Date  ICMJE April 26, 2018
First Posted Date  ICMJE April 27, 2018
Last Update Posted Date May 29, 2019
Actual Study Start Date  ICMJE February 27, 2019
Estimated Primary Completion Date February 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2018)
phosphate and FGF23 (blood) [ Time Frame: blood phosphate and FGF23 - every two weeks X 6 months, then once a month x 3 months ]
To induce complete metabolic response in subjects with tumor-induced osteomalacia (TIO) with BGJ398 as demonstrated by normalization of FGF23 and phosphate homeostasis
Original Primary Outcome Measures  ICMJE
 (submitted: April 26, 2018)
phosphate and FGF23 (blood) [ Time Frame: blood phosphate and FGF23 - every two weeks X 6 months, then once a month x 3 months ]
To induce clinical remission of tumor-induced osteomalacia (TIO) with BGJ398, evidenced by normalization of blood phosphate and FGF23, off study drug.
Change History Complete list of historical versions of study NCT03510455 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: April 26, 2018)
  • FGF23 (intact and C-terminal), Phosphorous, 1, 25 (OH)2 vitamin D; TRP, TmP /GFR [ Time Frame: FGF23, phosphorus, 1,25 (OH) 2 vitamin D, TRP, TmP /GFR - serial blood testing at visit O; labs every 2 weeks X 6 months, then monthly. ]
    Pharmacodynamics of mineral homeostasis response to BGJ398 in TIO
  • Labs (blood/urine), medical history/physical exam/AE assessments, ophthalmology, echocardiography, US kidney [ Time Frame: Lab (blood) - every 2 weeksfor 9 months; adverse event assesment - ongoing; medical history, physical exam, urinary and ophthalmology evaluations - every month for 9 months; echocardiography - month O and 6; US kidney -month O and 6 ]
    Assess safety/tolerability
  • FDG-PET/CT and/or octreotide [ Time Frame: FDG-PET/CT and/or octreotide at screen and/or 6 month visit ]
    Effect on radiographic evidence of TIO, evidenced by change in clinically indicated FDG-PET/CT and/or octreotide scan
  • Standardized muscle strength testing - fatigue symptom inventory, 6-minute walk, sit and stand test, grip strength test, DASH) [ Time Frame: Standardized muscle strength testing - every month for 9months ]
    Effects on muscle strength
  • Standardized measures of Qol (SF-36) [ Time Frame: SF-36 - every month for 9 months ]
    Effects on quality of life
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE BGJ398 for the Treatment of Tumor-Induced Osteomalacia
Official Title  ICMJE BGJ398 for the Treatment of Tumor-Induced Osteomalacia
Brief Summary

Background:

People with tumor-induced osteomalacia (TIO) have small tumors that may cause low blood phosphorus, weak muscles, bone pain, and broken bones. The tumors may be so small they are hard to find or impossible to remove. Researchers want to test a drug that may help treat TIO.

Objective:

To see how the drug BGJ398 affects people with tumor-induced osteomalacia.

Eligibility:

People ages 18-85 who are in NIH protocol 01-D-0184 and have TIO that cannot be found or easily removed

Design:

At every study visit, participants will have:

  • Medical history
  • Physical exam
  • Blood and urine tests
  • Questions about their health and fatigue

At the screening visit, participants will also have a heart and eye tests. They may have other tests to find their tumor.

The baseline visit will be a 1-week stay in the clinic. Participants will have the regular study tests, plus:

  • Their first dose of the study drug capsules
  • Blood and urine collected every 2-4 hours for 24 hours. A thin plastic tube will be inserted in a vein to collect blood.
  • Heart and kidney ultrasounds
  • Activities that test strength
  • 6-minute walk test

Participants will take the study drug for six 1-month cycles. In each cycle, participants will:

  • Take the study drug every day for 3 weeks. Not take it for 1 week.
  • Have 1 visit. Participants will collect their urine for 24 hours and have their blood drawn. Participants will have the regular study tests and repeat some baseline tests.
  • Have blood and urine tests at their local lab.

Participants will have 1 visit at the end of the last cycle and another 3 months later....

Detailed Description

Background:

  • Tumor-induced osteomalacia (TIO) is a rare disorder in which fibroblast growth factor (FGF23)-producing neoplasms cause renal phosphate wasting and skeletal disease.
  • Recent studies have shown that chromosomal translocations causing a fibronectin-FGFR1 (FN1/FGFR1) fusion gene have been identified in 40-60% of these tumors.
  • BGJ398 is an orally bio-available, selective and ATP competitive pan-fibroblast growth factor receptor (FGFR) kinase inhibitor which has demonstrated anti-tumor activity in preclinical, in vitro and in-vivo tumor models harboring FGFR genetic alterations.

Objectives:

To induce complete metabolic response in subjects with tumor-induced osteomalacia (TIO) with BGJ-398 as demonstrated by normalization of FGF23 and phosphate homeostasis.

Eligibility:

Patients may be eligible if they:

  • Are adults 18-85 years with documented evidence of TIO due to a non-localized or unresectable tumor, or metastatic disease, or resectable tumor that cannot be easily removed.
  • Are not taking any exclusionary medications or foods that may interfere with BGJ398.
  • Are not pregnant or nursing and are willing to use contraception (at least two forms of contraception), if able to become pregnant.
  • Have no significant ophthalmologic, gastrointestinal, renal, or hematologic disease.

Design:

  • Phase 2, open-label, non-randomized, single-arm, drug treatment trial.
  • 10 subjects to be studied.
  • Treatment duration 6 months with 3 months off drug follow-up and optional extension phase.
  • Monthly NIH visits with additional labs obtained in between visits.
  • Imaging performed in those with identifiable tumors.
  • Analyses to include repeated measures ANOVA assessing changes in biochemical indices over time in response to BGJ398.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Tumor-Induced Osteomalacia
  • Oncogenic Osteomalacia
Intervention  ICMJE Drug: BGJ398
BGJ398, a pan-fibroblast growth factor receptor (FGFR) kinase inhibitor will be orally administered over six 4-week cycles (3 weeks on drug, 1 week off drug). After the initial dose, escalation/de- escalation of BGJ398 will be based on FGF- 23 blood levels and adjusted according to protocol procedures. The six cycles of BGJ398 will be followed by 3 months off the drug and an optional extension phase.
Study Arms  ICMJE Experimental: Single Arm (TIO Subjects)
Phase 2, open-label, non-randomized, single-arm, drug treatment trial. 10 subjects will be studied. Treatment duration of 6 months with 3 months off drug follow-up and optional extension phase.
Intervention: Drug: BGJ398
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 26, 2018)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2023
Estimated Primary Completion Date February 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

Patients eligible for inclusion in this study have to meet all of the following criteria:

  • Aged 18-85 years
  • Diagnosis of TIO due to a non-localized or unresectable tumor, or metastatic disease or resectable tumor that cannot be removed by minor surgical procedure. This diagnosis will be confirmed prior to enrollment on protocol 01-D-0184. Where clinically indicated, genetic testing to rule-out heritable causes of FGF23 excess will also be performed on 01-D-0184.
  • Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
  • Able to swallow and retain oral medication.
  • Able to provide informed consent

EXCLUSION CRITERIA:

Patients eligible for this study must not meet any of the following criteria:

  • Have another genetic or secondary cause of hypophosphatemia.
  • History of any other malignancy that has not been cured/in remission for 5 years.
  • Patients who previously received treatment with an FGFR inhibitor other than BGJ398.
  • Current evidence of corneal or retinal disorder/keratopathy including, but not limited to: bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjuctivitis, confirmed by ophthalmologic examination
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BGJ398 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
  • Patients who are currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 are prohibited. This includes treatment with enzyme-inducing antiepileptic drugs including carbamazepine, phenytoin, phenobarbital, and primidone.
  • Consumption of grapefruit, grapefruit juice, pomegranates, star fruits, Seville oranges or products within 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.
  • Insufficient bone marrow function defined as all of the following:

    • ANC <1,500/mm^3 [1.0 x 10^9/L] AND
    • Platelets < 75,000/mm^3 [75 x 10^9/L] AND
    • Hemoglobin < 10.0 g/dL
  • Insufficient hepatic and renal function defined as one of the following:

    • Total bilirubin > 1.5x ULN OR
    • AST/SGOT and ALT/SGPT > 2x ULN OR
    • Blood creatinine > 1.5xULN and/or calculated eGFR < 45 ml/min/1.73 m^2 (calculated by CKD-Epi)
  • Clinically significant cardiac disease including any of the following:

    • Congestive heart failure requiring treatment (NY Heart Association grade >= 2),
    • History or presence of clinically significant ventricular arrhythmias, atrial fibrillation, resting bradycardia, or conduction abnormality
    • Unstable angina pectoris or acute myocardial infarction less than or equal to 3 months prior to starting study drug
    • QTcF > 450 msec (males); > 470 msec (females)
    • History of congenital long QT syndrome
  • Recent (less than or equal to 3 months) transient ischemic attack or stroke
  • Patients under age 21 will have a bone age assessed as part of their clinically indicated skeletal survey under 01-D-0184 and will not be offered enrollment if their growth plates are open.
  • 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 hCG laboratory test
  • Women of child-bearing potential, 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 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 subjects on the study the vasectomized male partner should be the sole partner for that subject.
    • 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

        • 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 or 6 months of spontaneous amenorrhea with serum FSH >40 mIU/ml or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
        • 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 in order to prevent delivery of the drug via seminal fluid.
        • Patients with TIO who are currently taking BGJ398 or have been treated with BGJ398 in the past are eligible to participate in this study, provided that they discontinue BGJ398 for 2 weeks prior to the baseline visit.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jamie E Streit (301) 827-1138 jamie.streit@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03510455
Other Study ID Numbers  ICMJE 180086
18-D-0086
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) )
Study Sponsor  ICMJE National Institute of Dental and Craniofacial Research (NIDCR)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Rachel I Gafni, M.D. National Institute of Dental and Craniofacial Research (NIDCR)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date May 23, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP