Details

Details

Title An Open-label Phase 1 Study of Oral ASP5878 at Single and Multiple Doses in Patients with Solid Tumors

IRB API1Y15

CC 041535C

Hospital Main Campus

Phase Phase 1

Disease Solid Tumors

Drug ASP5878

Description

Description

Dose-escalation part

The objectives in the dose-escalation part are to determine the tolerability, safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of oral ASP5878 at single or multiple doses in patients with a solid tumor.

Primary objectives:
  • To determine the tolerability and safety of ASP5878, and to decide the DLT, maximum tolerated dose (MTD), and recommended dose level of ASP5878 for the expansion part.
Secondary objectives:
  • To determine the PK of ASP5878.
  • To determine the PD of ASP5878.
Exploratory objectives:
  • To determine the antitumor activity of ASP5878.

Expansion part:

The objectives of the expansion part are to determine the safety, PK, PD, and efficacy of oral ASP5878 at multiple doses in patients with urothelial carcinoma, hepatocellular carcinoma, or squamous cell lung carcinoma with FGF or FGFR mutation/overexpression.

Primary objective:
  • To determine the safety of ASP5878.
Secondary objectives:
  • To determine the PK of ASP5878.
  • To determine the PD of ASP5878.
  • To determine the antitumor activity of ASP5878.

Inclusion Criteria

Inclusion Criteria

Dose-escalation part:
  1. Patient must provide written informed consent to participate in the study.
  2. Age ≥ 20 years at the time of providing informed consent.
  3. Histologically or cytologically confirmed solid tumor.
  4. Patient 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.
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.13
  6. Predicted life expectancy ≥ 12 weeks in the judgment of the investigator or sub-investigator.
  7. Patient must meet all of the following criteria on the laboratory tests at screening visit.
    • ANC ≥ 1,500/mm3.
    • Platelet count ≥ 75,000/mm3.
    • Hemoglobin ≥ 9 g/dL.
    • Inorganic phosphorus within the reference range.
    • Corrected calcium* LLN to 11.0 mg/dL. * Corrected calcium should be calculated using Payne formula.
    • Direct bilirubin < 1.5 x ULN.
    • AST and ALT < 2.0 x ULN (< 5.0 x ULN for patients with hepatocellular carcinoma or a metastasis to the liver).
    • Creatinine clearance** ≥ 51 mL/min. ** Creatinine clearance will be calculated using Cockcroft-Gault formula.
  8. Patient is able to be hospitalized from the preceding day of initial dosing to the end of Cycle 1.
  9. Patient with hepatocellular carcinoma is classified as Child-Pugh A.14-15
Expansion part:
  1. Institution Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulation (e.g., HIPAA Authorization for U.S. sites) must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
  2. Subject is a male or female subject who is at least 18 years old (20 years old in Japan, Korea, and Taiwan).
  3. Subject has a histologically or cytologically confirmed diagnosis of a urothelial carcinoma, hepatocellular carcinoma or squamous cell lung carcinoma. Imaging diagnosis is acceptable only for hepatocellular carcinoma.
  4. Subject must meet at least one of the following criteria in the judgment of the investigator or sub-investigator:
      Disease progression despite standard therapies or
    • Standard therapies are considered intolerable.
    • In addition the stage of disease is advanced (unresectable or not eligible for loco-regional therapy), metastatic, or recurrent disease.
    Standard therapies for the indications are as follows:
    • Urothelial carcinoma: Systemic chemotherapy (Platinum-based chemotherapy e.g. gemcitabine plus cisplatin, or methotrexate, vinblastine, doxorubicin plus cisplatin)
    • Hepatocellular carcinoma: Systemic therapy (Sorafenib)
    • Squamous cell lung carcinoma: Systemic chemotherapy (Platinum-doublet chemotherapy)
  5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  6. Subject has a predicted life expectancy ≥ 12 weeks in the judgment of the investigator or sub-investigator.
  7. Subject must meet all of the following criteria on the laboratory tests at screening visit.
    • ANC ≥ 1,500/mm3.
    • Platelet count ≥ 75,000/mm3.
    • Hemoglobin ≥ 9 g/dL.
    • Inorganic phosphorus within the reference range.
    • Corrected calcium* LLN to 11.0 mg/dL. * Corrected calcium should be calculated using Payne formula. Corrected calcium LLN is referred to LLN of calcium
    • Direct bilirubin < 1.5 x ULN.
    • AST and ALT < 2.0 x ULN (< 5.0 x ULN for patients with hepatocellular carcinoma or a metastasis to the liver).
    • Creatinine clearance** ≥ 51 mL/min. ** Creatinine clearance will be calculated using Cockcroft-Gault formula.
  8. Subject with hepatocellular carcinoma is classified as Child-Pugh A.
  9. Subject must provide written informed consent to provide archival or fresh tumor tissue samples.
  10. Subject has a measurable lesion based on RECIST version 1.1.
  11. Subject has evidence (based upon central analytical laboratory result#) of at least one of the following gene mutations or overexpression.
    • Urothelial Carcinoma: FGFR3-TACC3 fusion*** or FGFR3 point mutation***(FGFR3-TACC3 fusion will not be used for prospective screening and enrollment of subjects in the United States.)
    • Hepatocellular carcinoma: FGF19 overexpression
    • Squamous cell lung carcinoma: FGFR1 overexpression
    # For subjects in the US, FGF/FGFR testing should only be performed on archival tissue or tissue that is obtained from standard of care procedures. A fresh biopsy should not be performed to obtain tissue solely to evaluate study eligibility.
  12. Subject agrees not to participate in another intervention study while on treatment.
  13. Female subject must be either:

    Of non-child bearing potential:

    • Post-menopausal (defined as at least 1 year without any menses) prior to Screening, or
    • Documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening

    Or if of childbearing potential:

    • Agree not to try to become pregnant during the study and for 3 months after the final study drug administration
    • Must have a negative urine pregnancy test at Screening and
    • Must use two forms of birth control* (at least one of which must be a barrier method) starting at Screening and throughout the study period and for up to 3 months after last dose of the study drug

  14. Female subject must not be breastfeeding at Screening or during the study period, and for 3 months after the last dose of the study drug.
  15. Female subject must not donate ova starting at Screening and throughout the study period, and for 3 months after last dose of the study drug.
  16. Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control* (one of which must be a barrier method) starting at Screening and throughout the study period and for 90 days after the final study drug administration.
  17. Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration.*Acceptable forms of birth control include:
    • Established use of oral, injected or implanted hormonal methods of 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/ suppository (required in United States only)
    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps)(Japan, Korea, and Taiwan only)
    • Ogino method is acceptable in Japan only
Exclusion Criteria

Exclusion Criteria

Dose-escalation part:
  1. Patient 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).
  2. Patient 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 patient who received mitomycin C or nitrosourea within 6 weeks prior to the planned first day of study drug dosing).
  3. 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.
  4. Patient who received blood transfusions, hemopoietic factors, calcium, vitamin D, diuretics or continuous systemic corticosteroids (oral or intravenous) within 2 weeks prior to the planned first day of study drug dosing.
  5. Patient who were treated with other investigational drug or medical device within 4 weeks prior to the planned first day of study drug dosing.
  6. Prior use of an investigational drug that selectively inhibits FGFR (including ASP5878).
  7. History of organ transplantation.
  8. Concurrent or previous interstitial pneumonia.
  9. Corneal disorder ≥ Grade 2 (CTCAE v 4.0-JCOG).
  10. Concurrent severe infection that requires systemic antibiotics or antiviral drugs (except hepatitis virus that caused hepatocellular carcinoma).
  11. Patient with a positive test for human immunodeficiency virus (HIV) infection.
  12. Patient with a positive hepatitis B surface antigen or hepatitis C antibody (except patients with hepatocellular carcinoma).
  13. Current heart disease of Class III or IV New York Heart Association or a history of such heart disease within 6 months prior to the planned first day of study drug dosing.
  14. Prolongation of QTc interval (mean measurement of three ECGs ≥ 481 ms) on electrocardiogram (ECG) at screening visit.
  15. Severe or uncontrolled systemic disorder apart from the primary disease.
  16. Difficulty taking oral medication, any digestive malabsorptive condition, or concurrent disease that affects gastrointestinal function.
  17. Patient with a brain metastasis with symptoms or requiring treatment.
  18. Previous or concurrent serious hypersensitivity to drug.
  19. Female patients who are pregnant or lactating (female patients must have a negative pregnancy test within 7 days prior to the planned first day of study drug dosing, except for hysterectomized or bilaterally ovariectomized women or those with ≥ 1 year after last menstruation).
  20. Patient who cannot agree to use appropriate contraception throughout the investigational period and up to 3 months after the last dose of the study drug. Recommended contraceptive method is use of a condom; however, an intrauterine device is also allowed for use.
  21. Other conditions ineligible for participation in the study in the opinion of investigator or sub-investigator.
  22. Patients with a concurrent or previous parathyroid disorder.
Expansion part:
  1. Subject 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).
  2. Subject 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 patient who received mitomycin C or nitrosourea within 6 weeks prior to the planned first day of study drug dosing).
  3. Subject has 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.
  4. Subject who received calcium, vitamin D, or continuous systemic corticosteroids (oral or intravenous) within 2 weeks prior to the planned first day of study drug dosing.
  5. Subject who were treated with other investigational drug or medical device within 4 weeks prior to the planned first day of study drug dosing.
  6. Subject has a prior use of an investigational drug that selectively inhibits FGFR (including ASP5878).
  7. Subject has a history of organ transplantation.
  8. Subject has a concurrent or previous parathyroid disorder.
  9. Subject has a concurrent or previous interstitial pneumonia.
  10. Subject has a corneal disorder ≥ Grade 2 (CTCAE v 4.0-JCOG).
  11. Subject has concurrent severe infection that requires systemic antibiotics or antiviral drugs (except hepatitis virus).
  12. Subject has bleeding esophageal or gastric varices within 8 weeks prior to the planned first day of study drug dosing or has known esophageal or gastric varices with red color sign. (Subject that has known esophageal or gastric varices who has no red color sign as confirmed by an endoscopy is permitted)
  13. Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection.
  14. Subject withcurrent heart disease of Class III or IV New York Heart Association or a history of such heart disease within 6 months prior to the planned first day of study drug dosing.
  15. Subject with prolongation of QTc interval (mean measurement of three ECGs ≥ 481 ms) on electrocardiogram (ECG) at screening visit.
  16. Subject with severe or uncontrolled systemic disorder apart from the primary disease.
  17. Subject with difficulty taking oral medication, any digestive malabsorptive condition, or concurrent disease that affects gastrointestinal function.
  18. Subject with a brain metastasis with symptoms or requiring treatment.
  19. Subject with previous or concurrent serious hypersensitivity to drug.
  20. Female subject who are pregnant or lactating (female patients must have a negative pregnancy test within 7 days prior to the planned first day of study drug dosing, except for hysterectomized or bilaterally ovariectomized women or those with ≥ 1 year after last menstruation).
  21. Subject with another malignancy with a disease-free interval of < 5 years (except for another urothelial carcinoma); patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed; patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy).
  22. Subject with other conditions ineligible for participation in the study in the opinion of investigator or sub-investigator.