BGJ398 for the Treatment of Tumor-Induced Osteomalacia

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.

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.

Drug: BGJ398

BGJ398, a pan-fibroblast growth factor receptor (FGFR) kinase inhibitor will be orally administered over six 4-week cycles (4 weeks on drug continuously). 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.

Plazo: 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.

Plazo: 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

Plazo: 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

Plazo: 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.

Plazo: 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.

Plazo: 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.

Plazo: 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.

Plazo: 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)

Plazo: 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.

Plazo: 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.

Plazo: 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

Plazo: 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)

Plazo: 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.

Plazo: 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

No informado en este registro.

Plazo: 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

No informado en este registro.

Plazo: 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

No informado en este registro.

Plazo: 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

No informado en este registro.

Plazo: 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.

Plazo: 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.

Plazo: Baseline and at 24 weeks

In patients with radiographic evidence of TIO, 18FDG PET scans were performed

BGJ398 for the Treatment of Tumor-Induced Osteomalacia