An Open-label Phase I Study of Orally Available Novel Small-molecule Fibroblast Growth Factor Receptors (FGFR) 1,2,3 and 4 Inhibitor, ASP5878 at Single and Multiple Doses in Patients With Solid Tumors

Study Overview
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Brief Summary
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The objectives of this study are to determine the tolerability, safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of oral ASP5878 in participants with solid tumors.

Detailed Description
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This study consists of two parts. In the dose-escalation part, ASP5878 (orally available novel small-molecule FGFR 1,2,3 and 4 inhibitor, multiple dosing once-a-day (q.d.), multiple dosing twice-a-day (b.i.d.) or 5-day on/2-day off dosing twice-a-day (5on-2off)) is administered to participants with solid tumors in an increasing dose manner, and the tolerability, safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of ASP5878 are evaluated in these participants. Cycle 0 consists of 3 days and Cycle 1 and subsequent cycles consist of 28 days each in the dose-escalation part. In the expansion part, 16mg twice-a-day 5-day on/2-day off dose of ASP5878 (5on-2off) is administered to participants with solid tumors and safety, PK, PD and efficacy of ASP5878 are evaluated. The expansion part starts from Cycle 1 and each cycle consists of 28 days.

Official Title
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An Open-label Phase I Study of Oral ASP5878 at Single and Multiple Doses in Patients With Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: ASP5878


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed solid tumor. Participant must meet at least one of the following criteria in the judgment of the investigator or sub-investigator: Disease progression despite standard therapies Progressive disease without any standard therapies established Standard therapies are considered intolerable Eastern Cooperative Oncology Group performance status 0 or 1. Predicted life expectancy ≥ 12 weeks in the judgment of the investigator or sub-investigator. Exclusion Criteria: Participant with ≥ Grade 2 (CTCAE v 4.0-JCOG) persistent symptoms and objective findings due to the toxicity attributable to prior treatment with antitumor effect (except alopecia). Participant who received a prior treatment intended for antitumor effect (medication, surgery, radiotherapy, etc.) within 4 weeks prior to the planned first day of study drug dosing (or participant who received mitomycin C or Nitrosourea within 6 weeks prior to the planned first day of study drug dosing). A major surgical procedure within 4 weeks prior to the planned first day of study drug dosing or a surgical procedure is planned during the course of the study. Participant who were treated with other investigational drug or medical device within 4 weeks prior to the planned first day of study drug dosing. Participant who has a history of organ transplantation. Participant with a brain metastasis with symptoms or requiring treatment.

Ages Eligible for Study
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Minimum Age: 20 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation part 0.5 mg QD<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 1.0 mg QD<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 2.0 mg QD<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 2.0 mg BID<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 4.0 mg BID<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 6.0 mg BID<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 10.0 mg BID<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 20.0 mg BID<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Dose escalation part 16.0 mg BID<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Expansion part Urothelial Carcinoma<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Expansion part Hepatocellular Carcinoma<br>Oral | Drug: ASP5878<br>* oral<br>|
| Experimental: Expansion part Squamous Cell Lung Carcinoma<br>Oral | Drug: ASP5878<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-escalation part and Expansion part: Safety assessed by Adverse Events (AEs) | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Dose-escalation part and Expansion part:Safety assessed by Vital signs | Blood pressure, pulse rate and body temperature, Until one of the discontinuation criteria is met. | Up to 18 months | 
| Dose-escalation part and Expansion part:Safety assessed by Body weight | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Dose-escalation part and Expansion part:Safety assessed by Laboratory tests | Hematology, blood biochemistry, blood coagulation tests and urinalysis, until one of the discontinuation criteria is met. | Up to 18 months | 
| Dose-escalation part and Expansion part:Safety assessed by 12-lead ECGs | ECG: Electrocardiogram, until one of the discontinuation criteria is met. | Up to 18 months | 
| Dose-escalation part and Expansion part: Ophthalmology | Eyesight, funduscopy, slit lamp microscopy, and Optical Coherence Tomography, until one of the discontinuation criteria is met. | Up to 18 months | 
| Dose-escalation part and Expansion part: Bone density measurement | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Dose-escalation part and Expansion part: Computed tomography (CT) Imaging assessment | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Expansion part only: Echocardiogram | Until one of the discontinuation criteria is met. | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-escalation part: Pharmacokinetics (PK) parameter of ASP5878 in plasma: Cmax | Cmax: Maximum concentration, Cycle 0: single dose, Cycle 1: multiple dose after Cycle 0 | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part:PK parameter of ASP5878 in plasma: tmax | tmax: Time of Cmax | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part:PK parameter of ASP5878 in plasma: AUClast | AUClast: Area under the concentration-time curve from the time of dosing extrapolated to the last measurable concentration | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PK parameter of ASP5878 in plasma: AUCinf | AUCinf: Area under the concentration-time curve from the time of dosing extrapolated to time infinity | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PK parameter of ASP5878 in plasma: t1/2 | t1/2: Terminal elimination half-life | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PK parameter of ASP5878 in plasma: CL/F | CL/F: Apparent total systemic clearance | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PK parameter of ASP5878 in plasma: Vz/F | Vz/F: Apparent volume of distribution during the terminal elimination phase | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PK parameter of ASP5878 in urine: Ae | Ae: Amount of ASP5878 excreted into the urine | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PK parameter of ASP5878 in urine: CLR | CLR: Renal clearance | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: Pharmacodynamic (PD) parameter: Serum FGF23 concentrations | FGF: Fibroblast Growth Factor | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PD parameter: Serum inorganic phosphorus concentrations |  | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PD parameter: Serum calcium concentrations |  | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PD parameter: Serum iPTH concentrations | iPTH: Intact Parathyroid Hormone | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Dose-escalation part: PD parameter: Serum calcitriol concentrations |  | Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 | 
| Expansion part: PK parameter of ASP5878 in plasma: Cmax |  | Day 1 and 5 at Cycle 1 | 
| Expansion part: PK parameter of ASP5878 in plasma: tmax |  | Day 1 and 5 at Cycle 1 | 
| Expansion part: PK parameter of ASP5878 in plasma: AUClast |  | Day 1 and 5 at Cycle 1 | 
| Expansion part: PK parameter of ASP5878 in plasma: AUCinf |  | Day 1 and 5 at Cycle 1 | 
| Expansion part: PK parameter of ASP5878 in plasma: t1/2 |  | Day 1 and 5 at Cycle 1 | 
| Expansion part: PK parameter of ASP5878 in plasma: CL/F |  | Day 1 and 5 at Cycle 1 | 
| Expansion part: PK parameter of ASP5878 in plasma: Vz/F |  | Day 1 and 5 at Cycle 1 | 
| Expansion part: PD parameter: Serum FGF19 concentrations | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Expansion part: PD parameter: Serum FGF23 concentrations | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Expansion part: PD parameter: Serum inorganic phosphorus concentrations | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Expansion part: PD parameter: Serum iPTH concentrations | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Expansion part: PD parameter: Serum calcitriol concentrations | Until one of the discontinuation criteria is met. | Up to 18 months | 
| Expansion part: PD parameter: Serum 7α-hydroxy-4-cholesten-3-one | Until one of the discontinuation criteria is met | Up to 18 months | 
| Expansion part: Overall response | Antitumor activity evaluated based on RECIST version 1.1, until one of the discontinuation criteria is met. Antitumor response is rated on a 4-level scale shown below (complete response [CR], partial response [PR], progressive disease [PD] and stable disease [SD]). | Up to 18 months | 
| Expansion part: Maximum Shrinkage in Target Lesion | Best percent change from baseline in the sum of diameters of all target lesions. | Up to 18 months | 
| Expansion part: Progression free survival (PFS) | Time from the start of the study treatment until death from any cause or Progressive Disease assessed according to RECIST 1.1. | Up to 18 months | 
| Expansion part: Time to progression (TTP) | Time from the start of the study treatment until Progressive Disease assessed according to RECIST 1.1. | Up to 18 months | 
| Expansion part: Time to treatment failure (TTF) | Time from the start of the study drug treatment until discontinuation of study drug treatment for any reason. | Up to 18 months | 
| Expansion part: Overall survival (OS) | Time from randomization to death from any cause. | Up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASP5878, FGFR 1,2,3 and 4 inhibitor