| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007113 |
| E.1.2 | Term | Cancer of prostate |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Protocol phase 1:
Phase 1, Single Dose
-To assess the safety and pharmacokinetics (PK) of TAK 448 in patients receiving a single dose of 1 month depot TAK-448
Phase 1, Multiple Dose
-To assess the safety and PK of TAK 448 in patients receiving repeated doses of 1 month depot TAK-448
Protocol phase 2:
-To assess the safety and PK of TAK 448 in patients receiving repeated doses of 1 month depot TAK-448
-To assess the effect of repeated doses of 1 month depot TAK 448 on serum testosterone concentrations |
|
| E.2.2 | Secondary objectives of the trial |
Protocol phase 1:
Phase 1, Single Dose
-In patients not receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy: to assess the effect of single-dose 1 month depot TAK-448 on serum testosterone, serum luteinizing hormone (LH), and serum prostate-specific antigen (PSA) concentrations
Phase 1, Multiple Dose
-In patients naïve to GnRH analog therapy, to assess the effect of repeated doses of 1 month depot TAK 448 on serum testosterone, serum LH, and serum PSA concentrations
Protocol phase 2:
-To assess the effect of repeated doses of 1 month depot TAK 448 on serum PSA concentrations |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Male 40 to 78 years of age, inclusive, in phase 1; no upper age limit for phase 2, if medical entry criteria are otherwise met.
-Histologically confirmed adenocarcinoma of the prostate, having completed primary local treatment at least 6 months prior to screening.
-Screening serum PSA concentration > 2 ng/mL, unless the patient is on concurrent (or intermittent) GnRH analog therapy, in which case no lower limit is applicable (phase 1).
-For single-dose portion only: Either
a.Concurrent GnRH therapy (which may include patients on intermittent GnRH therapy or patients who are otherwise between injections of GnRH analog therapy) with generally indolent or stable disease with PSA DT > 4 months and absolute PSA < 200 ng/mL and, if metastatic disease is present, asymptomatic with only bone scan positive and/or lymph node evidence of metastases. Patients with recurrent local disease will be generally asymptomatic, without bladder, bowel, or obstructive symptoms.
OR
b.If not receiving GnRH therapy, a potential candidate for GnRH at some time in the future (ie, in a period of ‘watchful waiting,’ with generally indolent or stable disease and with PSA DT > 3 months and absolute PSA < 200 ng/mL, and, if metastatic disease, asymptomatic, with only bone scan positive and/or lymph node evidence of metastases). Patients with recurrent local disease will be generally asymptomatic, without bladder, bowel, or obstructive symptoms.
-For the multiple-dose portion only: Evidence of progressive prostate cancer, which, in the opinion of the referring physician and/or study investigator, warrants the initiation of GnRH analog therapy. Such patients may have either elevated or rising PSA at least 6 months following primary local therapy(ies) or have evidence of metastatic disease not previously treated with GnRH analog therapy. Patients are not eligible for inclusion if they are to receive first line hormone therapy as adjuvant/neoadjuvant therapy for local treatment of disease (surgery or radiation) or for primary local tumor control.
-For the phase 2 portion of the study only: Evidence of progressive prostate cancer, which, in the opinion of the referring physician and/or study investigator, warrants the initiation of GnRH analog therapy. Such patients may have either elevated or rising PSA at least 6 months following primary local therapy(ies) or have evidence of metastatic disease not previously treated with first line hormone (GnRH analog) therapy. Patients are not eligible for inclusion if they are to receive first line hormone therapy as adjuvant/neoadjuvant therapy for local treatment of disease (surgery or radiation) or for primary local tumor control.
-Provision of informed consent and, for the phase 1 portion of the study only, willing to participate in a phase 1 trial with no expectation of therapeutic benefit.
-Generally fit medical condition, with no acute or chronic medical conditions, other than prostate cancer, affecting 2 year life expectancy.
a.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
b.New York Heart Association classification 0 to II
c.Serum creatinine < 1.5 ULN
d.If previously diagnosed hypertension, on 2 or fewer agents and with blood pressure adequately or well controlled (systolic < 150 mmHg, diastolic < 95 mmHg)
e.Hemoglobin > 11.0 g/dL
f.Total bilirubin < 1.5 x ULN
g.Generally normal laboratory evaluation, including liver function tests
(alanine aminotransferase [ALT] and aspartate aminotransferase [AST]
within 3 times the ULN, and GGT within 2.5 times the ULN as reported by
the central reference laboratory)
-Ability to understand and comply with protocol requirements.
-Agreement to even if surgically sterilized but not surgically castrated (ie, status postvasectomy):
o Practice effective barrier contraception
o Phase 1, single-dose portion of the study: during the entire study treatment period and through 3 months after the last dose of study drug
o Phase 1, multiple-dose portion of the study: during the entire study treatment period and through 2 months after the last dose of study drug
o Phase 2 portion of the study: during the entire study treatment period through 2 months after the last dose of study drug
OR
o Abstain from heterosexual intercourse
-Suitable venous access for the study-required blood sampling (ie, including PK and pharmacodynamic sampling).
-For the phase 2 portion of the study only: Patients who have participated in the phase 1, single-dose portion of the study may be eligible to participate in the phase 2 portion of the study if they have completed the phase 1, single-dose portion of the study and meet all other eligibility criteria. Patients will be considered to have completed the phase 1, single-dose portion of the study if they receive 1 dose of study drug and complete the subsequent 3 months of monitoring/testing.
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|
| E.4 | Principal exclusion criteria |
-Advanced or symptomatic metastatic prostate cancer requiring immediate GnRH or additional hormone (CAB) therapy or requiring chemotherapy
-History of surgical castration
-Any history of nonskin cancer, other than prostate cancer, requiring active treatment within the 2 years prior to screening
-Any history of cardiac surgery, within the previous 6 months or any planned elective surgeries, other than skin surgery, during the ensuing 6 months
-Any compromise of bone marrow function that would reduce tolerance to repeated blood draws
-Any history of osteoporosis, unless actively controlled with treatment, or history of vertebral or femoral fracture within the past year
-Any history of seizures or currently on anticonvulsant medications
-Any history of major psychiatric illness (eg, diagnosed psychosis or psychiatric illness requiring hospitalization within the previous year)
-Any history of drug or significant alcohol abuse
-Any participation in clinical trials or receipt of any experimental therapy within 2 months of screening, with the exception of participation in the phase 1 single-dose portion of this study
-Serious infection within 14 days before the first dose of study drug
-Known human immunodeficiency virus (HIV) positive
-Known hepatitis B surface antigen-positive (HBsAg), or known or suspected active hepatitis C infection
-Any of the following cardiovascular conditions or values at the time of screening unless otherwise specified:
o History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of Grade > 2 (CTCAE version 4.03(13)), thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy) within 6 months prior to first dose of study drug. Atrial fibrillation on anticoagulant therapy is not allowed.
o QTc > 500 milliseconds.
o Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that, in the opinion of the investigator, are considered to be clinically significant.
-For the phase 1 and phase 2 portions of the study only, continuous use of systemic or inhaled glucocorticoids (steroids) for more than 2 weeks in the 3 months prior to enrollment (use of nasal steroids is allowed)
-For the phase 1, multiple-dose and the phase 2 portions of the study only, newly introduced (within the first 3 months) bisphosphonates, calcitonins, or other anti-osteoporotic medications, except calcium and vitamin D supplements; however, prior stable therapy for bone loss/osteoporosis is allowed
In addition, for the phase 1, multiple-dose portion of the study only, patients must not meet any of the following exclusion criteria:
-Prior or current use of a GnRH analog or androgen receptor antagonist hormone therapy
In addition, for the phase 2 portion of the study only, patients must not meet any of the following exclusion criteria:
-Prior or current use of a GnRH analog or androgen receptor antagonist as first line hormone therapy (ie, other than as neoadjuvant/adjuvant use)
-History of rising PSA or disease progression while on a GnRH analog or CAB therapy (ie, rising PSA while on neoadjuvant/adjuvant therapy)
In addition, for the phase 1, multiple-dose portion of the study and the phase 2 portion of the study, patients must not meet any of the following exclusion criteria:
-History of use of GnRH analog or antagonist (as adjuvant or neoadjuvant therapy) within the 6 months prior to screening
-History of known or documented primary failure of GnRH analog therapy
-Screening serum testosterone concentration < 150 ng/dL (5.25 nmol/L)
-For patients who complete the phase 1, single-dose portion of the study and are eligible to participate in the phase 2 portion of the study: a history of any Grade 3 or higher AEs at least possibly related to treatment with TAK-448 or placebo during the 3-month phase 1 treatment and follow-up period
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1 of the protocol:
Single Dose:
-Safety;Pharmacokinetics
Multiple Dose:
-Safety; Endocrine; Pharmacokinetics
Phase 2 of the protocol:
-Safety; Endocrine; Pharmacokinetics |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1 Single Dose: Safety - through out study; Pharmacokinetics - Day 1: Multiple timepoints; Day 2 through Day 29: single timepoint at every visit and last quantifiable concentration.
Phase 1 Multiple dose: Safety - through out the study; Endocrine - Day 1 of each month of therapy; Pharmacokinetics - AUC - at the end of Month 1; Trough plasma - Day 1 of each month and last quantifiable concentration
Phase 2: Safety - through out the study;Endocrine - Day 1 of each month of therapy; Pharmacokinetics - AUC - at the end of Month 1; Trough plasma - Day 1 of each month and last quantifiable concentration |
|
| E.5.2 | Secondary end point(s) |
Phase 1 of the protocol:
Single Dose:
-In patients not on concomitant GnRH therapy,
-Serum testosterone and LH concentrations
-Proportion of patients with serum testosterone concentration below the castrate level (≤50 ng/dL, < 1.74 nmol/L) after 29 days
-Serum PSA concentrations
Multiple Dose:
-Serum PSA concentration at the end of Months 1 and 3 and the End-of-Treatment (EOT) visit
Phase 2 of the protocol:
-Serum PSA concentration at the end of Months 1 and 3 and the End-of-Treatment (EOT) visit |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1 Single dose: After 29 days of therapy
Phase 1 Multiple dose: End of Months 1, 3 and end of study visit
Phase 2: End of Months 1, 3 and end of study visit |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Safety/PK study of depot formulation |
|
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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