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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

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ClinicalTrials.gov Identifier: NCT02038673
Recruitment Status : Completed
First Posted : January 16, 2014
Last Update Posted : October 22, 2018
Sponsor:
Collaborator:
Astellas Pharma Global Development, Inc.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: ASP5878 Phase 1

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  (Clinical Trial)
Actual Enrollment : 86 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Phase I Study of Oral ASP5878 at Single and Multiple Doses in Patients With Solid Tumors
Actual Study Start Date : November 5, 2013
Actual Primary Completion Date : July 19, 2017
Actual Study Completion Date : July 19, 2017

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




Primary Outcome Measures :
  1. Dose-escalation part and Expansion part: Safety assessed by Adverse Events (AEs) [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  2. Dose-escalation part and Expansion part:Safety assessed by Vital signs [ Time Frame: Up to 18 months ]
    Blood pressure, pulse rate and body temperature, Until one of the discontinuation criteria is met.

  3. Dose-escalation part and Expansion part:Safety assessed by Body weight [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  4. Dose-escalation part and Expansion part:Safety assessed by Laboratory tests [ Time Frame: Up to 18 months ]
    Hematology, blood biochemistry, blood coagulation tests and urinalysis, until one of the discontinuation criteria is met.

  5. Dose-escalation part and Expansion part:Safety assessed by 12-lead ECGs [ Time Frame: Up to 18 months ]
    ECG: Electrocardiogram, until one of the discontinuation criteria is met.

  6. Dose-escalation part and Expansion part: Ophthalmology [ Time Frame: Up to 18 months ]
    Eyesight, funduscopy, slit lamp microscopy, and Optical Coherence Tomography, until one of the discontinuation criteria is met.

  7. Dose-escalation part and Expansion part: Bone density measurement [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  8. Dose-escalation part and Expansion part: Computed tomography (CT) Imaging assessment [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  9. Expansion part only: Echocardiogram [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.


Secondary Outcome Measures :
  1. Dose-escalation part: Pharmacokinetics (PK) parameter of ASP5878 in plasma: Cmax [ Time Frame: 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

  2. Dose-escalation part:PK parameter of ASP5878 in plasma: tmax [ Time Frame: Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 ]
    tmax: Time of Cmax

  3. Dose-escalation part:PK parameter of ASP5878 in plasma: AUClast [ Time Frame: 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

  4. Dose-escalation part: PK parameter of ASP5878 in plasma: AUCinf [ Time Frame: 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

  5. Dose-escalation part: PK parameter of ASP5878 in plasma: t1/2 [ Time Frame: 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

  6. Dose-escalation part: PK parameter of ASP5878 in plasma: CL/F [ Time Frame: 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

  7. Dose-escalation part: PK parameter of ASP5878 in plasma: Vz/F [ Time Frame: 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

  8. Dose-escalation part: PK parameter of ASP5878 in urine: Ae [ Time Frame: 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

  9. Dose-escalation part: PK parameter of ASP5878 in urine: CLR [ Time Frame: Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 ]
    CLR: Renal clearance

  10. Dose-escalation part: Pharmacodynamic (PD) parameter: Serum FGF23 concentrations [ Time Frame: Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 ]
    FGF: Fibroblast Growth Factor

  11. Dose-escalation part: PD parameter: Serum inorganic phosphorus concentrations [ Time Frame: Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 ]
  12. Dose-escalation part: PD parameter: Serum calcium concentrations [ Time Frame: Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 ]
  13. Dose-escalation part: PD parameter: Serum iPTH concentrations [ Time Frame: Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 ]
    iPTH: Intact Parathyroid Hormone

  14. Dose-escalation part: PD parameter: Serum calcitriol concentrations [ Time Frame: Day 1 at Cycle 0 and Day 5 (5on-2off) or 27 (q.d./b.i.d.) at Cycle 1 ]
  15. Expansion part: PK parameter of ASP5878 in plasma: Cmax [ Time Frame: Day 1 and 5 at Cycle 1 ]
  16. Expansion part: PK parameter of ASP5878 in plasma: tmax [ Time Frame: Day 1 and 5 at Cycle 1 ]
  17. Expansion part: PK parameter of ASP5878 in plasma: AUClast [ Time Frame: Day 1 and 5 at Cycle 1 ]
  18. Expansion part: PK parameter of ASP5878 in plasma: AUCinf [ Time Frame: Day 1 and 5 at Cycle 1 ]
  19. Expansion part: PK parameter of ASP5878 in plasma: t1/2 [ Time Frame: Day 1 and 5 at Cycle 1 ]
  20. Expansion part: PK parameter of ASP5878 in plasma: CL/F [ Time Frame: Day 1 and 5 at Cycle 1 ]
  21. Expansion part: PK parameter of ASP5878 in plasma: Vz/F [ Time Frame: Day 1 and 5 at Cycle 1 ]
  22. Expansion part: PD parameter: Serum FGF19 concentrations [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  23. Expansion part: PD parameter: Serum FGF23 concentrations [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  24. Expansion part: PD parameter: Serum inorganic phosphorus concentrations [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  25. Expansion part: PD parameter: Serum iPTH concentrations [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  26. Expansion part: PD parameter: Serum calcitriol concentrations [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met.

  27. Expansion part: PD parameter: Serum 7α-hydroxy-4-cholesten-3-one [ Time Frame: Up to 18 months ]
    Until one of the discontinuation criteria is met

  28. Expansion part: Overall response [ Time Frame: 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]).

  29. Expansion part: Maximum Shrinkage in Target Lesion [ Time Frame: Up to 18 months ]
    Best percent change from baseline in the sum of diameters of all target lesions.

  30. Expansion part: Progression free survival (PFS) [ Time Frame: 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.

  31. Expansion part: Time to progression (TTP) [ Time Frame: Up to 18 months ]
    Time from the start of the study treatment until Progressive Disease assessed according to RECIST 1.1.

  32. Expansion part: Time to treatment failure (TTF) [ Time Frame: Up to 18 months ]
    Time from the start of the study drug treatment until discontinuation of study drug treatment for any reason.

  33. Expansion part: Overall survival (OS) [ Time Frame: Up to 18 months ]
    Time from randomization to death from any cause.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02038673


  Show 35 Study Locations
Sponsors and Collaborators
Astellas Pharma Inc
Astellas Pharma Global Development, Inc.
Investigators
Study Director: Medical Director Astellas Pharma Inc

Additional Information:
Responsible Party: Astellas Pharma Inc
ClinicalTrials.gov Identifier: NCT02038673     History of Changes
Other Study ID Numbers: 5878-CL-0101
First Posted: January 16, 2014    Key Record Dates
Last Update Posted: October 22, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
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.
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.
URL: https://www.clinicalstudydatarequest.com/

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc:
ASP5878
FGFR 1,2,3 and 4 inhibitor