E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Castration-Resistant Prostate Cancer (CRPC) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060862 |
E.1.2 | Term | Prostate cancer |
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 |
Part A: • To assess the safety and tolerability (incidence and severity of adverse events [AEs]) of the combination of AT13387 and abiraterone acetate and to select the most promising treatment regimen for the combination in subjects with castration-resistant prostate cancer (CRPC) who are no longer responding to treatment with abiraterone acetate alone, based on the overall assessment of safety and antitumor activity. Part B: • To assess and compare the antitumor activity (response rate per the Prostate Cancer Working Group 2 [PCWG2] recommendations) between single-agent AT13387 and the combination of AT13387 plus abiraterone acetate in subjects who are no longer responding to treatment with abiraterone acetate alone. |
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E.2.2 | Secondary objectives of the trial |
Part A: • To assess pharmacokinetic interactions between AT13387 and abiraterone; • To assess progression-free survival (PFS) per PCWG2 recommendations and overall survival (OS); and • To assess the androgen receptor (AR) depletion in circulating tumor cells (CTCs) and/or tumor tissue. Part B: • To assess and compare the safety of AT13387 alone and in combination with abiraterone acetate in CRPC; • To assess and compare pharmacodynamic markers of AR depletion and other client protein depletion in CTCs and/or tumor tissue in the 2 arms; and • To assess and compare PFS and OS in the 2 arms. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria will be eligible to participate in the study: 1. Have a histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology; Subjects who meet all of the following criteria will be eligible to participate in the study: 1. Have a histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology; 2. Have received prior castration by orchiectomy and/or LHRH agonist with or without antiandrogen and documented serum testosterone <50 ng/dL; 3. Males >18 years of age; 4. Have Eastern Cooperative Oncology Group (ECOG) performance Status ≤2; 5. Have not had androgen receptor (AR) antagonist treatment in the 6 weeks prior to the first dose of study drug; 6. Have been receiving abiraterone acetate therapy with a steroid for ≥1 month. Only subjects tolerating abiraterone acetate 1000 mg at screening will be eligible to participate in the study; 7. Have documented disease progression on abiraterone acetate defined by 1 or more of the following criteria: • PSA progression according to PCWG2 criteria with 3 consecutive rising PSA measurements, all collected at least 1 week apart; • Radiographic progression in soft tissue or bone by modified RECIST 1.1 for subjects with measurable disease; or • Bone disease progression defined by 2 or more new lesions on 2 consecutive bone scans in the absence of falling PSA; 8. Have CTC count >5 cells/7.5 mL at baseline (for Part A only); 9. Have adequate bone marrow function, defined as absolute neutrophil count >1.5 K/μL and platelet count >100 K/μL; 10. Have adequate hepatic function, defined as bilirubin ≤1.5 × ULN, ALT and aspartate transaminase (AST) ≤2.5 × ULN (ALT and AST ≤5 × ULN, if liver metastases are present); 11. Have adequate renal function, defined as creatinine ≤1.25 × ULN or creatinine clearance >50 mL/min; 12. Must be willing to provide pre-existing diagnostic or resected tumor samples, such as formalin-fixed, paraffin-embedded sections or slides, if this material exists. If pre-existing samples are not available, a sample must be obtained during screening; 13. Subjects and their female partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months following the last dose of study drug. Effective contraception includes methods such as oral contraceptives, double-barrier method (condom plus spermicide or diaphragm) or abstaining from sexual intercourse; and 14. Must be willing and able to provide written informed consent and comply with the protocol and study procedures. |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be excluded from the study: 1. Prior anti-cancer treatment with any HSP90 inhibitor or histone deacetylase (HDAC) inhibitor compound; 2. Have received chemotherapy within 4 weeks prior to the first dose of study drug; 3. Prior prostate surgery or radiotherapy within 4 weeks from the first dose of study drug and single fraction radiotherapy within 2 weeks prior to the first dose of study drug; 4. Hypersensitivity to AT13387 or other components of the drug product; 5. Treatment with any investigational drug within 4 weeks prior to the first dose of study drug; 6. Poor medical risk because of other systemic diseases or active uncontrolled infections; 7. Presence of a life-threatening illness, medical condition, organ system dysfunction, or other factors which, in the Investigator’s opinion, could compromise the subject’s safety, interfere with the metabolism of AT13387, or compromise the integrity of the study outcomes; 8. Abnormal LVEF (<50%) on echocardiogram (ECHO) or multigated acquisition (MUGA) scan; history of ischemic cardiac event, including myocardial infarction within 3 months of study entry, congestive cardiac failure of ≥Grade 3 severity according to New York Heart Association (NYHA) functional classification; history of long QTc syndrome or ventricular arrhythmias; or screening QTcF >450 msec after correction of any electrolyte imbalance and confirmation of QTc by triplicate measurement; 9. Prior malignancy except for adequately treated basal cell or squamous cell carcinoma of the skin, or superficial bladder cancer, or other cancer from which the subject has been disease-free for at least 3 years; 10. Known symptomatic brain or CNS involvement such as a result of cord compression; 11. Contraindication to the use of corticosteroids or history of pituitary or adrenal dysfunction; 12. Prior dose reductions of abiraterone acetate as a result of increased transaminases; or 13. Known history of human immunodeficiency virus (HIV) or seropositive test for hepatitis C virus or hepatitis B virus. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A: The co-primary endpoints for the comparison between the 2 AT13387 regimens are as follows: • Incidence and severity of AEs and DLTs using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4 to assess safety and • Response rate assessed based on achieving any one or more of the following: o Complete response (CR) with disappearance of target lesions or partial response (PR) with 30% decrease in change of sum of longest diameters of target lesions according to modified RECIST 1.1. o PSA response defined as ≥50% decrease in PSA at 12 weeks according to PCWG2 criteria in the absence of skeletal and extraskeletal progression. PSA decline must be confirmed to be sustained by a second PSA value obtained 4 or more weeks later. o Conversion of CTC count defined as decline in CTC count from ≥5 cells/7.5 mL of blood to <5 cells/7.5 mL of blood, or a 30% decrease in CTC count from baseline in the absence of skeletal or extraskeletal progression.
Part B: The primary endpoint for Part B is response rate assessed as in Part A. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
In Part A, a total of 14 evaluable subjects will be randomized to each regimen at the MTD. The absence of at least 1 response in 14 subjects in any of the arms will indicate an antitumor activity in that arm of <20% with 95% confidence; that arm will not proceed to Part B evaluation. |
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E.5.2 | Secondary end point(s) |
Part A: • Pharmacokinetic parameters (maximum concentration [Cmax], area under the curve [AUC], and other secondary pharmacokinetic parameters) of AT13387 and abiraterone; • Depletion of AR and other client proteins in CTCs and/or in tumor tissue to assess biological activity and pharmacodynamics; • PFS (progression defined per PCWG2 recommendations); and • OS.
Part B: • Clinical Benefit Rate: CR + PR + stable disease (SD) ≥24 weeks; • Incidence and severity of AEs using NCI CTCAE version 4; |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of Stage 2 (35 subjects per arm), at least 7 responses should be observed in either arm to declare positive antitumor activity in that arm. If both arms succeed in Stage 2, a total of at least 56 subjects per arm will be randomized in order to compare antitumor activity between the 2 arms. |
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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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.6.13.1 | Other scope of the trial description |
exploratory objective is to identify potential biomarkers for predicting antitumor activity |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |