BGJ398 for the Treatment of Tumor-Induced Osteomalacia

Phase 2

Terminated

Conditions: Oncogenic Osteomalacia
Tumor-Induced Osteomalacia

Interventions: Drug: BGJ398

Registration Number: NCT03510455

Lead Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)

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 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....

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 4

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single Arm (TIO Subjects)	BGJ398	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Complete Metabolic Remission After Stopping BGJ398	Up to 12 weeks after stopping BGJ398	Participants were monitored for up to 12 weeks after stopping BGJ398. A participant was considered to have a complete metabolic remission by achieving both normal blood FGF23 and phosphorus levels in the blood for 12 weeks after stopping BGJ398.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Grade 3 or 4 Adverse Events or Serious Adverse Events	24 week treatment phase followed by 3 month follow up or extension phase	Percentage of patients who incurred grade 3 or 4 adverse events (AEs) or serious adverse events (SAE) or AEs causing dose interruption/reduction
Hand Grip Strength Test	Assessed at baseline and every 4 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	The person is seated, lower extremities flexed at 90 degrees. The individual uses the dominant hand for this activity. The individual sit with shoulder adducted and neutrally rotated elbow flexed at 90 degrees, forearm in neutral position, resting on the arm of a chair. The JAMAR Hand Dynamometer set to the third level position from the inside is used. The examiner lightly supports the readout dial to prevent it from dropping. The patient is asked to "Squeeze as hard as you can....squeeze.....squeeze....relax." Three successive trials is recorded in kilograms. A 10-15 second break occurs to prevent muscle fatigue. Scores are recorded and averaged for the final result. Scores within two standard deviations of the mean are considered within normal limits.
Number of Participants With Complete and Partial Metabolic Response Rate	Every 2 weeks up to 24 weeks	Participants were monitored for metabolic response to BGJ398 every other week. A participant was considered to have a complete metabolic response by achieving both normal c-terminal FGF23 and phosphorus levels at each time point. A participant was considered to have a partial metabolic response by achieving both a decrease of at least 50% in c-terminal FGF23 levels and an increase of at least 50% in phosphorous at each time point
Pinch Test	Assessed at baseline and every 4 weeks for the 24 treatment period, and every 4 weeks in the follow up phase, up to 37 weeks	A lateral pinch is required of the patient, using the dominant hand. The individual is seated, lower extremities flexed at 90 degrees. The examiner stabilizes the patient's wrist as the patient holds the pinch gauge to perform the test. The examiner requests the person to pinch with maximum strength. The peak-hold needle will automatically record the highest force exerted. After the patient uses the Pinch gauge, the examiner records the reading and resets the peak-hold needle to zero before testing again. Three lateral pinch trials are recorded and averaged for the final result.
PROMIS Mobility Score	Assessed at baseline and every 4 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	Assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Mobility bank. Scores are given as T values when compared to a population where the mean is 50 and 1SD is 10. A higher score represents a better outcome (unencumbered mobility)
Blood C-terminal FGF23 Level	Assessed at baseline and every 2 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks
Blood 1,25-(OH)2-Vitamin D Level	Assessed at baseline and every 4 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks
Six-Minute Walk Test	Assessed at baseline and 24 weeks after starting BGJ398	The Six-Minute Walk Test (6MWT), is a self-paced practical test that measures the distance the patient can quickly cover on a flat, hard surface. Each subject was instructed to complete the maximum distance possible in six minutes. Feedback was given in two minute intervals and during the last 30 seconds. Patients were instructed to notify test administrator of leg cramping, pain, nausea, dizziness and shortness of breath. Test administrators counted each lap and upon test completion, the partial distance is measured and added to where the subject stopped.
Tubular Maximum Reabsorption Rate of Phosphate to Glomerular Filtration Rate (TmP/GFR)	Assessed at baseline and every 2 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	Tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was calculated using blood phosphate and creatinine, as well as either 24 hour urine or spot urine samples.
Five Times Sit-to-Stand Test	Assessed at baseline and every 4 weeks during the 24 week treatment period	The Five Times Sit to Stand Test measures an aspect of transfer skill. The test provides a method to quantify functional lower extremity strength and/or identify movement strategies a patient uses to complete transitional movements. The chair is free standing. Patient sits with arms folded across chest and with their back against the chair. A standard chair height 44 cm was used for each patient. Patient stands fully between repetitions of the test, careful to not touch the back of the chair during each repetition. Patient instructions: "I want you to stand up and sit down 5 times as quickly as you can when I say Go." Timing begins at "Go" and ends when the buttocks touches the chair after the 5th repetition. The results are recorded in seconds.
PROMIS Fatigue	Assessed at baseline and every 4 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	Assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue 8A short form. Scores are given as T values when compared to a population where the mean is 50 and 1SD is 10. A higher score represents increased feelings of fatigue.
PROMIS Pain Interference Score	Assessed at baseline and every 4 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	Assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Pain Interference 8A short form. Scores are given as T values when compared to a population where the mean is 50 and 1SD is 10. A higher score represents increased pain interference
Blood Intact FGF23 Levels	Assessed at baseline and every 2 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	Measured Blood Intact FGF23 Levels.
Radiographic Evidence of Tumor-Induced Osteomalacia	Baseline and at 24 weeks	In patients with radiographic evidence of TIO, 18FDG PET scans were performed
The Disabilities of Arm Shoulder and Hand Outcome Measurement (DASH)	Assessed at baseline and every 4 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	The Disabilities of Arm Shoulder and Hand Outcome Measurement (DASH) The minimum score value is 0, maximum is 100, where a higher school represents a worse outcome (significant symptoms/disability)
Blood Alkaline Phosphatase	Assessed at baseline and every 2 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks
Tubular Reabsorption of Phosphate	Assessed at baseline and every 2 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	Tubular Reabsorption of Phosphate was calculated using blood phosphate and creatinine, as well as either 24 hour urine or spot urine samples.
RAND SF-36 Survey Results	Assessed at baseline and every 4 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks	Evaluation using the RAND 36-Item Short Form Survey (SF-36). Results were separated into 8 domains - Physical Functioning, Role limitations due to physical health problems, Role limitations due to emotional problems, Emotional well-being, Energy/fatigue, Social functioning, Bodily Pain, and General health perceptions. The minimum value is 0, the maximum value is 100, which the higher the score, the better the outcome.
Blood Phosphate Levels	Assessed at baseline and every 2 weeks up to 24 weeks during the treatment phase, and every 4 weeks in the follow up phase, up to 37 weeks