BGJ398 for the Treatment of Tumor-Induced Osteomalacia

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 4 weeks.
* 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....

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.

Eligibility Criteria:
* 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.