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
- Registration Number
- NCT02038673
- Lead Sponsor
- Astellas Pharma Inc
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 86
-
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.
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Predicted life expectancy ≥ 12 weeks in the judgment of the investigator or sub-investigator.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Dose escalation part 0.5 mg QD ASP5878 Oral Dose escalation part 6.0 mg BID ASP5878 Oral Dose escalation part 2.0 mg BID ASP5878 Oral Dose escalation part 20.0 mg BID ASP5878 Oral Expansion part Urothelial Carcinoma ASP5878 Oral Dose escalation part 1.0 mg QD ASP5878 Oral Dose escalation part 10.0 mg BID ASP5878 Oral Expansion part Hepatocellular Carcinoma ASP5878 Oral Expansion part Squamous Cell Lung Carcinoma ASP5878 Oral Dose escalation part 2.0 mg QD ASP5878 Oral Dose escalation part 4.0 mg BID ASP5878 Oral Dose escalation part 16.0 mg BID ASP5878 Oral
- Primary Outcome Measures
Name Time Method Dose-escalation part and Expansion part:Safety assessed by Body weight Up to 18 months Until one of the discontinuation criteria is met.
Dose-escalation part and Expansion part: Computed tomography (CT) Imaging assessment Up to 18 months Until one of the discontinuation criteria is met.
Dose-escalation part and Expansion part:Safety assessed by Vital signs Up to 18 months Blood pressure, pulse rate and body temperature, Until one of the discontinuation criteria is met.
Dose-escalation part and Expansion part: Ophthalmology Up to 18 months Eyesight, funduscopy, slit lamp microscopy, and Optical Coherence Tomography, until one of the discontinuation criteria is met.
Dose-escalation part and Expansion part:Safety assessed by Laboratory tests Up to 18 months Hematology, blood biochemistry, blood coagulation tests and urinalysis, until one of the discontinuation criteria is met.
Expansion part only: Echocardiogram Up to 18 months Until one of the discontinuation criteria is met.
Dose-escalation part and Expansion part:Safety assessed by 12-lead ECGs Up to 18 months ECG: Electrocardiogram, until one of the discontinuation criteria is met.
Dose-escalation part and Expansion part: Safety assessed by Adverse Events (AEs) Up to 18 months Until one of the discontinuation criteria is met.
Dose-escalation part and Expansion part: Bone density measurement Up to 18 months Until one of the discontinuation criteria is met.
- Secondary Outcome Measures
Name Time Method Dose-escalation part:PK parameter of ASP5878 in plasma: tmax Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 tmax: Time of Cmax
Dose-escalation part:PK parameter of ASP5878 in plasma: AUClast Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 AUClast: Area under the concentration-time curve from the time of dosing extrapolated to the last measurable concentration
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 Expansion part: PK parameter of ASP5878 in plasma: AUCinf 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 FGF23 concentrations Up to 18 months Until one of the discontinuation criteria is met.
Expansion part: PD parameter: Serum iPTH concentrations Up to 18 months Until one of the discontinuation criteria is met.
Expansion part: PD parameter: Serum calcitriol concentrations Up to 18 months Until one of the discontinuation criteria is met.
Dose-escalation part: Pharmacokinetics (PK) parameter of ASP5878 in plasma: Cmax Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 Cmax: Maximum concentration, Cycle 0: single dose, Cycle 1: multiple dose after Cycle 0
Dose-escalation part: PK parameter of ASP5878 in plasma: AUCinf Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 AUCinf: Area under the concentration-time curve from the time of dosing extrapolated to time infinity
Dose-escalation part: PK parameter of ASP5878 in plasma: t1/2 Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 t1/2: Terminal elimination half-life
Dose-escalation part: PK parameter of ASP5878 in urine: Ae Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 Ae: Amount of ASP5878 excreted into the urine
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 calcitriol concentrations Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 Expansion part: Progression free survival (PFS) Up to 18 months Time from the start of the study treatment until death from any cause or Progressive Disease assessed according to RECIST 1.1.
Dose-escalation part: PK parameter of ASP5878 in plasma: CL/F Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 CL/F: Apparent total systemic clearance
Dose-escalation part: PK parameter of ASP5878 in plasma: Vz/F Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 Vz/F: Apparent volume of distribution during the terminal elimination phase
Expansion part: PK parameter of ASP5878 in plasma: Cmax 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: 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: PD parameter: Serum 7α-hydroxy-4-cholesten-3-one Up to 18 months Until one of the discontinuation criteria is met
Expansion part: Overall response Up to 18 months 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 \[SD\]).
Expansion part: Maximum Shrinkage in Target Lesion Up to 18 months Best percent change from baseline in the sum of diameters of all target lesions.
Expansion part: Overall survival (OS) Up to 18 months Time from randomization to death from any cause.
Dose-escalation part: PK parameter of ASP5878 in urine: CLR Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 CLR: Renal clearance
Expansion part: PD parameter: Serum FGF19 concentrations Up to 18 months Until one of the discontinuation criteria is met.
Expansion part: Time to progression (TTP) Up to 18 months Time from the start of the study treatment until Progressive Disease assessed according to RECIST 1.1.
Dose-escalation part: Pharmacodynamic (PD) parameter: Serum FGF23 concentrations Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 FGF: Fibroblast Growth Factor
Dose-escalation part: PD parameter: Serum iPTH concentrations Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 iPTH: Intact Parathyroid Hormone
Expansion part: PK parameter of ASP5878 in plasma: tmax Day 1 and 5 at Cycle 1 Expansion part: PD parameter: Serum inorganic phosphorus concentrations Up to 18 months Until one of the discontinuation criteria is met.
Expansion part: Time to treatment failure (TTF) Up to 18 months Time from the start of the study drug treatment until discontinuation of study drug treatment for any reason.
Trial Locations
- Locations (35)
Site US404
🇺🇸Cleveland, Ohio, United States
Site US406
🇺🇸Spartanburg, South Carolina, United States
Site US410
🇺🇸Fairfax, Virginia, United States
Site JP108
🇯🇵Fukuoka, Japan
Site JP122
🇯🇵Chiba, Japan
Site US402
🇺🇸Orange, California, United States
Site US401
🇺🇸New York, New York, United States
Site US403
🇺🇸Seattle, Washington, United States
Site JP115
🇯🇵Fukuoka, Japan
Site JP120
🇯🇵Fukuoka, Japan
Site JP116
🇯🇵Hokkaido, Japan
Site JP113
🇯🇵Hyogo, Japan
Site JP111
🇯🇵Ishikawa, Japan
Site JP103
🇯🇵Ibaraki, Japan
Site JP119
🇯🇵Kanagawa, Japan
Site JP101
🇯🇵Kyoto, Japan
Site JP112
🇯🇵Nagoya, Japan
Site JP109
🇯🇵Miyagi, Japan
Site JP110
🇯🇵Miyagi, Japan
Site JP121
🇯🇵Okayama, Japan
Site JP104
🇯🇵Osaka, Japan
Site JP106
🇯🇵Osaka, Japan
Site JP117
🇯🇵Niigata, Japan
Site JP118
🇯🇵Osaka, Japan
Site JP102
🇯🇵Tokyo, Japan
Site JP124
🇯🇵Shizuoka, Japan
Site KR203
🇰🇷Seoul, Korea, Republic of
Site JP123
🇯🇵Tokyo, Japan
Site KR202
🇰🇷Gyeonggi-do, Korea, Republic of
Site KR201
🇰🇷Seoul, Korea, Republic of
Site KR204
🇰🇷Seoul, Korea, Republic of
Site TW302
🇨🇳Tainan, Taiwan
Site TW303
🇨🇳Taipei, Taiwan
Site TW301
🇨🇳Taipei, Taiwan
Site JP107
🇯🇵Tokyo, Japan