| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic castrate-resistant prostate cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic castrate resistant prostate cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036911 |
| E.1.2 | Term | Prostate cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objective of this phase I/II three-part study is to evaluate the safety, tolerability, pharmacokineticpharmacodynamic (PK-PD) profile, maximum tolerated dose and antitumor activity of once daily dosing with ASP9521 in patients with metastatic castrate resistant prostate cancer (CRPC) whose cancers are resistant to one
or more lines of hormonal treatment/androgen deprivation therapy (stratified into 2 groups: chemotherapy-naïve or post chemotherapy).
Part 1
-to evaluate the safety and tolerability of ASP9521.
Part II
-To evaluate PSA decline of ≥50% from baseline after 12 weeks of daily dosing with ASP9521.
Part III
-To evaluate the PK of single doses of ASP9521 under fed and fasted conditions.
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| E.2.2 | Secondary objectives of the trial |
Part I
-To determine the maximum tolerated dose, if possible.
-To evaluate prostate specific antigen decline of ≥50% from baseline after 12 weeks of daily dosing with ASP9521.
-To evaluate the PK of ASP9521 following single and multiple dose administration.
-To evaluate the pharmacodynamics of ASP9521.
Part II
-To evaluate the safety and tolerability of ASP9521.
-To evaluate the PK of ASP9521 following multiple dose administration.
-To evaluate the PD effect of ASP9521.
-To evaluate the effect of ASP9521 on pain palliation.
-To explore pharmacogenetic differences.
Part III
-To evaluate the safety and tolerability of single doses of ASP9521 under fed and fasted conditions.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient is eligible for the study if all of the following apply:
1. Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations must be obtained from the patient or legally authorized representative prior to any study-related procedures.
2. Male aged 18 years or older. Female sexual partners of male participants in the study must be non-fertile, i.e., surgically sterilized or must practice an adequate contraceptive method to prevent pregnancies. Adequate contraceptive methods are defined as: sexual abstinence from the day of partner’s dosing until 3 months after the last dose; the use of a condom in addition to having their partner use another acceptable method (oral or injectable hormonal contraceptives, contraceptive patch, intra-uterine devices, vaginal hormonal rings, or sterilization by surgery, a vaginal diaphragm or cervical caps) during the study and for up to 3 months after the last dose; patient’s sexual partner is of non-child bearing potential i.e., post-menopausal, surgically sterilized (e.g., tubal ligation), or hysterectomy in medical history.
3. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.
4. Metastatic disease documented by 2 or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI.
5. Ongoing androgen deprivation with LHRH agonist/antagonist therapy or bilateral orchiectomy. For patients who have not had an orchiectomy, there must be a plan to maintain effective LHRH agonist/antagonist therapy for the duration of the study.
6. Serum testosterone <1.7 nmol/L (50 ng/dL) at screening.
7. Patients receiving bisphosphonates or other approved bone targeting therapy must have been on stable doses for at least 4 weeks prior to screening.
8. Progressive disease at study entry defined as one or more of the following 3 criteria occurring in the setting of castrate levels of testosterone:
● PSA progression defined by a minimum of 2 rising PSA levels with an interval of >1 week between each determination. The PSA value at screening should be >2 ng/mL.
● Soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST). Measurable disease is not required for entry. Lymph nodes >20 mm are considered measurable disease.
● Bone disease progression defined by at least 2 new lesions on bone scan.
9. Life expectancy of >6 months according to the investigator’s judgment.
The following inclusion criteria must be fulfilled by chemotherapy-naïve patients:
10. Eastern Cooperative Oncology Group (ECOG) scores of 0 to 1.
11. Asymptomatic or controlled symptomatic patients with metastatic CRPC who have failed one or more lines of hormonal treatment/androgen deprivation therapy but have not received chemotherapy or have refused chemotherapy.
12. No prior chemotherapy for prostate cancer.
13. Anti-androgen withdrawal patients receiving an anti androgen as part of primary androgen ablation must demonstrate disease progression following discontinuation of anti-androgen (>4 weeks since last flutamide dose or >6 weeks since last bicalutamide or nilutamide dose).
The following inclusion criteria must be fulfilled by post chemotherapy patients:
14. ECOG scores of 0 to 2.
15. No more than 2 prior regimens of chemotherapy for prostate cancer, of which one is docetaxel-based to have been received at least 4 weeks prior to screening.
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| E.4 | Principal exclusion criteria |
Patients will be excluded from participation in the study if any of the following apply:
1. Concomitant treatment with the following is prohibited according to stratification as chemotherapy-naïve or post-chemotherapy patients:
● Chemotherapy-naïve patients:
● All chemotherapeutic agents.
● All biologic agents (except for sipuleucel T [Provenge®]), or other agents with anti-tumor activity against prostate cancer, including 5 alpha reductase inhibitors, androgens (e.g., testosterone), cytoproterone acetate and all other progestational agents, estrogens, and flutamide within 4 weeks prior to day of first dose of ASP9521.
● Bicalutamide or nilutamide within 6 weeks prior to day of first dose of ASP9521.
● Treatment with estramustine.
● Ketoconazole for treatment of prostate cancer.
● Treatment with abiraterone.
● Post-chemotherapy patients:
● All biologic agents (except for sipuleucel T [Provenge®]), or other agents with anti-tumor activity against prostate cancer, including 5 alpha reductase inhibitors, androgens (e.g., testosterone), progestational agents, estrogens, flutamide within 4 weeks prior to day of first dose of ASP9521.
● Bicalutamide or nilutamide within 6 weeks prior to day of first dose of ASP9521.
● Ketoconazole for treatment of prostate cancer.
● Treatment with abiraterone.
2. Use of herbal products that may have hormonal anti prostate cancer activity and/or are known to decrease PSA levels or Prednisolone > 10 mg (or an equivalent) for the treatment of prostate cancer within 4 weeks of day of first dose of ASP9521, or plans to initiate the above within the study period.
3. Radiation therapy for treatment of the prostate within 3 months prior to screening.
4. Radiation therapy for the treatment of metastases within 3 weeks (if single fraction of radiotherapy then within 2 weeks) and radionuclide therapy for the treatment of metastases within 4 weeks prior to screening.
5. Major surgery within 2 months prior to screening.
6. Known or suspected intracerebral disease or brain metastasis.
7. History of another malignancy within the previous 5 years other than curatively treated non-melanomatous skin cancer.
8. Gastrointestinal disorder affecting absorption (e.g., gastrectomy or active peptic ulcer disease).
9. Any of the following significant ophthalmological abnormalities:
a. Abnormal intraocular pressure (IOP).
b. Abnormal fundus, like age-related macular degeneration (AMD) or other retinal damage
10. Significant cardiovascular disease including:
● Myocardial infarction within 6 months prior to screening.
● Uncontrolled angina within 3 months prior to screening.
● Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥45%.
● History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes).
● History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
● Uncontrolled hypertension as indicated by a resting systolic blood pressure (BP) >170 mmHg or diastolic BP >105 mmHg at screening.
11. Concurrent disease or any clinically significant abnormality following the investigator’s review of the pre-study physical examination, 12-lead electrocardiogram (ECG) and clinical laboratory tests, which in the judgment of the investigator would interfere with the patient’s participation in this study or evaluation of study results.
12. Absolute neutrophil count <1,500/µL, platelet count <100,000/µL, and hemoglobin <5.6 mmol/L (9 g/dL) at screening; (NOTE: patients must not have received any growth factors or blood transfusions within 7 days of the hematologic laboratory values obtained at screening).
13. Total bilirubin >1.5 times the upper limit of normal (ULN) at screening. This will not apply to patients with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly uncongugated in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with the sponsor.
14. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times ULN or >5 times ULN in the presence of liver metastases at screening.
15. Creatinine >177 µmol/L (2 mg/dL) at screening.
16. Known or suspected hypersensitivity to ASP9521, or any components of the formulation used.
17. Use of an investigational agent within 4 weeks prior to treatment allocation or a period required by local regulation, whichever is longer.
18. Prior use, or participation in a clinical study, of an investigational agent that blocks androgen synthesis or targets the androgen receptor (like MDV3100 and TAK700). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
-Safety and tolerability will be assessed in all patients by descriptive analysis.
-The primary efficacy endpoint will be the proportion of patients in the full analysis set showing PSA decline of >50% from baseline at week 12, by dose and patient group (i.e., chemotherapy-native versus post chemotherapy patients)
-The ASP9521 pharmacokinetics after single dose.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety variables- frequency and severity of AEs, clinical laboratory tests, physical examinations, vital signs, 12-lead and Holter ECGs will be collected as stated in protocol schedule of assessment. Adverse events will be collected from the time of signed informed consent, and will be assessed each time the patient visits the clinic.
The time point of evaluation of the primary efficacy endpoint is at the week 13 visit.
The ASP9521 pharmacokinetics after single dose.
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint will be determined in all study parts, based on the proportion of patients showing RECIST objective response (partial or complete response) will be reported by dose and patient group. In Part I, it will be done on the safety analysis set. In the expanded dose levels of Part I+II and in Part III, it will be calculated on the per protocol set and the full analysis set. The 95% CI will be reported in the Part I+II analysis.
In addition in all parts PK and PD will be analyzed.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for secondary endpoints are given in the protocol. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study is defined as last patient's last visit.
When sponsor is aware of information regarding quality,efficacy,and safety of the drug,and other information that may affect proper trial conduct,the sponsor may discontinue the study and send a written notice of the discontinuation with the reasons to the investigator. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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