BGJ398 for the Treatment of Tumor-Induced Osteomalacia

Study Overview
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Brief Summary
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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
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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.

Official Title
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BGJ398 for the Treatment of Tumor-Induced Osteomalacia

Conditions
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Oncogenic Osteomalacia, Tumor-Induced Osteomalacia

Intervention / Treatment
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* Drug: BGJ398


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm (TIO Subjects)<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Metabolic Remission 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. | Up to 12 weeks after stopping BGJ398 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete and Partial Metabolic Response Rate | 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 | Every 2 weeks up to 24 weeks | 
| Number of Participants With Grade 3 or 4 Adverse Events or Serious Adverse Events | Percentage of patients who incurred grade 3 or 4 adverse events (AEs) or serious adverse events (SAE) or AEs causing dose interruption/reduction | 24 week treatment phase followed by 3 month follow up or extension phase | 
| Six-Minute Walk Test | 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. | Assessed at baseline and 24 weeks after starting BGJ398 | 
| Hand Grip Strength Test | 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. | 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 | 
| Pinch Test | 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. | 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 | 
| Five Times Sit-to-Stand Test | 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. | Assessed at baseline and every 4 weeks during the 24 week treatment period | 
| The Disabilities of Arm Shoulder and Hand Outcome Measurement (DASH) | 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) | 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 | 
| RAND SF-36 Survey Results | 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. | 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 | 
| PROMIS Fatigue | 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. | 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 | 
| PROMIS Pain Interference Score | 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 | 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 | 
| PROMIS Mobility Score | 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) | 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 | 
| Blood Intact FGF23 Levels | Measured 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 | 
| 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 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 | 
| 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 | 
| 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 | Tubular Reabsorption of Phosphate was calculated using blood phosphate and creatinine, as well as either 24 hour urine or spot urine samples. | 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) | 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. | 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 | 
| Radiographic Evidence of Tumor-Induced Osteomalacia | In patients with radiographic evidence of TIO, 18FDG PET scans were performed | Baseline and at 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypophosphatemia, FGF-23, Fibroblast Growth Factor (FGF23)