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

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

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: ASP5878

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.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan
    • Site JP122
  • Fukuoka, Japan
    • Site JP108
  • Fukuoka, Japan
    • Site JP115
  • Fukuoka, Japan
    • Site JP120
  • Hokkaido, Japan
    • Site JP116
  • Hyogo, Japan
    • Site JP113
  • Ibaraki, Japan
    • Site JP103
  • Ishikawa, Japan
    • Site JP111
  • Kanagawa, Japan
    • Site JP119
  • Kyoto, Japan
    • Site JP101
  • Miyagi, Japan
    • Site JP109
  • Miyagi, Japan
    • Site JP110
  • Nagoya, Japan
    • Site JP112
  • Niigata, Japan
    • Site JP117
  • Okayama, Japan
    • Site JP121
  • Osaka, Japan
    • Site JP104
  • Osaka, Japan
    • Site JP106
  • Osaka, Japan
    • Site JP118
  • Shizuoka, Japan
    • Site JP124
  • Tokyo, Japan
    • Site JP102
  • Tokyo, Japan
    • Site JP107
  • Tokyo, Japan
    • Site JP123
• Korea, Republic of
  • Gyeonggi-do, Korea, Republic of
    • Site KR202
  • Seoul, Korea, Republic of
    • Site KR201
  • Seoul, Korea, Republic of
    • Site KR203
  • Seoul, Korea, Republic of
    • Site KR204
• Taiwan
  • Tainan, Taiwan
    • Site TW302
  • Taipei, Taiwan
    • Site TW301
  • Taipei, Taiwan
    • Site TW303
• United States
  • California
    • Orange, California, United States, 92868
      • Site US402
  • New York
    • New York, New York, United States, 10032
      • Site US401
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Site US404
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Site US406
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Site US410
  • Washington
    • Seattle, Washington, United States, 98109
      • Site US403

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

12

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Collaborators: Astellas Pharma Global Development, Inc.
• Investigators: Study Director: Medical Director, Astellas Pharma Inc

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2013
• Primary Completion (Actual): July 19, 2017
• Study Completion (Actual): July 19, 2017

Study Registration Dates

• First Submitted: January 15, 2014
• First Submitted That Met QC Criteria: January 15, 2014
• First Posted (Estimated): January 16, 2014

Study Record Updates

• Last Update Posted (Actual): October 31, 2024
• Last Update Submitted That Met QC Criteria: October 29, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: ASP5878; FGFR 1,2,3 and 4 inhibitor
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 5878-CL-0101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No