| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Androgen Receptor-Positive Triple Negative Breast Cancer (AR+ TNBC) |
|
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057654 |
| E.1.2 | Term | Breast cancer female |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006198 |
| E.1.2 | Term | Breast cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| 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 |
The primary efficacy objective of this trial is to estimate the CBR at 16 weeks (defined as CR, PR, or SD) (by RECIST 1.1) of GTx-024 18 mg given PO daily in subjects with TNBC and centrally confirmed AR+ status.
Safety objective:
To describe the safety profile of GTx-024 18 mg PO daily in subjects with TNBC and centrally confirmed AR+ as well as in all subjects enrolled and treated.
Pharmacokinetic objective:
To describe the plasma concentrations of GTx-024 and GTx 024
glucuronide at each of the assessed time points. |
|
| E.2.2 | Secondary objectives of the trial |
• Estimate the CBR at 16 weeks (by RECIST 1.1) of GTx 024 18 mg in all subjects enrolled who receive at least one dose of study medication regardless of AR status as determined by the central laboratory
The following secondary efficacy objectives apply to both centrally confirmed AR+ subjects (the evaluable subset of the FAS) as well as to all subjects in the FAS:
• Estimate the objective response rate (ORR; defined as CR or PR) (by RECIST 1.1) of GTx-024 18 mg at 16 weeks
• Estimate the CBR (by RECIST 1.1) of GTx-024 18 mg at 24 weeks
• Estimate the ORR (CR or PR) (by RECIST 1.1) of GTx-024 18 mg at 24 weeks
• Estimate the best overall response rate of GTx 024 18 mg
• Estimate the progression free survival of subjects receiving GTx-024 18 mg
• Estimate the time-to-progression of subjects receiving GTx-024 18 mg
• Estimate duration of response (from documentation of response to disease progression or death) of subjects receiving GTx-024 18 mg
• Estimate overall survival (OS)
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|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Optional: Left over biospecimens (for example, blood and tissue samples) after analyses may be stored for future research uses from subjects who have consented and provided it is not prohibited by local laws and Ethics Committees. No additional samples will be collected except for those listed above. The samples will be stored for up to 10 years and destroyed after that. The samples may undergo genetic tests, tests for biomarkers, and other tests specific for the indication. It is the responsibility of the Investigator, or a person designated by the Investigator (if acceptable under local regulations), to obtain written informed consent from each individual who has consented to have their biospecimens stored for future research. Subjects must receive an explanation that they are completely free to refuse long-term storage of their samples for future research and may withdraw their sample at any time and for any reason during the 10 year storage period of the specimen(s), unless their sample has been retained in a anonymized manner (in which case it can no longer be identified as relating to the subject). |
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| E.3 | Principal inclusion criteria |
Subject Inclusion Criteria: Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Able and willing to give voluntary, written and signed, informed consent;
2. Women ≥ 18 years of age;
3. Women with TNBC who have received at least one but no more than two prior chemotherapy regimens for the treatment of advanced or metastatic TNBC;
4. Confirmation of AR+ (defined as ≥ 10% nuclear AR staining by immunohistochemistry [IHC]) TNBC in either the primary or metastatic lesion, assessed prior to the start of or during the screening period by a local laboratory or by medical history;
5. TNBC confirmed by medical history as: human epidermal growth factor receptor 2 [HER2]-negative (confirmed by IHC 0, 1+ regardless of fluorescence in situ hybridization [FISH] ratio; IHC 2+ with FISH ratio lower than 2.0 or HER2 gene copy less than 6.0; FISH ratio of 0, indicating gene deletion, when positive and negative in situ hybridization [ISH] controls are present); estrogen receptor (ER) negative (confirmed as ER expression less than or equal to 1% positive tumor nuclei); progesterone receptor negative (confirmed as progesterone receptor expression less than or equal to 1% positive tumor nuclei);
6. Availability of paraffin embedded or formalin fixed tumor tissue; OR, a minimum of 10 and up to 20 slides of archived tumor tissue or new biopsy, if archived tissue is unavailable, for central laboratory confirmation of AR status and molecular subtyping. Metastatic tumor tissue is preferred when possible;
7. Subjects must have either measurable disease or bone only non-measurable disease according to RECIST 1.1;
8. Subjects with bone metastases should be treated with intravenous bisphosphonates or subcutaneous denosumab (or investigator preferred standard of care) prior to and/or during the trial, unless there is a contraindication or subject intolerance to these therapies. For subjects who are normocalcemic, therapy can be initiated at the time the subject initiates study drug;
9. Eastern Cooperative Oncology Group (ECOG) performance status3 0 or 1 at the time of screening and enrollment;
10. Negative serum pregnancy test in women of childbearing potential (premenopausal or less than 12 months of amenorrhea post-menopause, and who have not undergone surgical sterilization), no more than 7 days before the first dose of study treatment;
11. For women of childbearing potential who are sexually active, agreement to use a highly effective, non hormonal form of contraception during and for at least 6 months after completion of study treatment; OR, a fertile male partner willing and able to use effective non-hormonal means of contraception (barrier method of contraception in conjunction with spermicidal jelly, or surgical sterilization) during and for at least 6 months after completion of study treatment;
12. Adequate organ function as shown by:
● Absolute neutrophil count ≥ 1,000 cells/mm3
● Platelet count ≥ 100,000 cells/mm3
● Hemoglobin ≥ 9 g/dL
● Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 Upper Limit of the Normal range (ULN) (or ≤ 5 if hepatic metastases are present)
● Total serum bilirubin ≤ 2.0 × ULN (unless the subject has documented Gilbert Syndrome)
● Alkaline phosphatase levels ≤ 2.5 × ULN (≤ 5 × ULN in subjects with liver metastasis)
● Serum creatinine ≤ 2.0 mg/dL or 177 μmol/L
● International normalized ratio (INR) or activated partial thromboplastin time (aPTT) < 1.5 × ULN (unless on anticoagulant treatment at screening);
13. Able to swallow capsules;
14. Any toxicity from prior chemotherapy has resolved or is Grade 1 (NCI-CTCAE, Version 4.0).
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|
| E.4 | Principal exclusion criteria |
Subject Exclusion Criteria: Subjects eligible for this study must not meet any of the following criteria:
1. Life expectancy < 4 months;
2. Subjects with radiographic evidence of central nervous system (CNS) metastases as assessed by computerized tomography (CT) or magnetic resonance imaging (MRI) that are not well controlled (symptomatic or requiring control with continuous corticosteroid therapy [e.g., dexamethasone]). Note: Subjects with CNS metastases are permitted to participate in the study if the CNS metastases are medically well controlled prior to screening (as assessed by the Investigator) after receiving local therapy (irradiation, surgery, etc.);
3. Radiotherapy within 14 days prior to first dose of study treatment;
4. Have, in the judgment of the Investigator, a clinically significant concurrent illness or psychological, familial, sociological, geographical, or other concomitant condition that would not permit adequate follow-up and compliance with the study protocol;
5. Positive hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection at screening;
6. Positive human immunodeficiency virus (HIV) infection at screening;
7. Prior treatment with any anti-androgens, including but not limited to, enzalutamide and bicalutamide;
8. Major surgery within 28 days of the first dose of study treatment;
9. Be currently taking or have previously taken testosterone, methyltestosterone, oxandrolone (Oxandrin®), oxymetholone, danazol, fluoxymesterone (Halotestin®), testosterone-like agents (such as dehydroepiandrosterone, androstenedione, and other androgenic compounds, including herbals), or anti androgens;
10. Treatment with any of the following hormone replacement therapies, unless discontinued at least 28 days prior to the first dose of study treatment:
● Estrogens
● Megesterol acetate;
11. Treatment with any investigational agent within 28 days before the first dose of study treatment;
12. Another active cancer (excluding adequately treated basal cell carcinoma or cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or melanoma in situ). Prior history of other cancer is allowed as long as there is no active disease within the prior 5 years;
13. Subject has a concomitant medical condition that precludes adequate study treatment compliance or assessment, or increases subject risk, in the opinion of the Investigator, such as but not limited to:
● Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTCB (corrected according to Bazett’s formula) interval > 470 msec; serious uncontrolled cardiac arrhythmia grade II or higher according to NYHA; uncontrolled hypertension (systolic > 150 and/or diastolic > 100 mm Hg)
● Acute and chronic active infectious disorders and non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy
● Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome);
14. Current treatment with intravenous bisphosphonate or denosumab with elevated serum calcium corrected for albumin or ionized calcium levels outside institutional normal limits at screening;
15. History of non-compliance to medical regimens;
16. Subjects unwilling to or unable to comply with the protocol procedures as assessed by the Investigator;
17. Concurrent participation in another therapeutic clinical trial.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the study will be to assess the proportion of subjects with CB Response at 16 weeks (CR+PR+SD) in subjects with TNBC and centrally confirmed AR+ who receive at least one dose of study drug (evaluable subjects).
CB in a subject is defined as a CR, a PR, or SD as measured by RECIST 1.1 and confirmed by central review. These measurements will be confirmed by a central image-reading facility.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• To estimate the proportion of women with TNBC regardless of central confirmation of AR status (FAS) who achieve CB at 16 weeks in response to treatment with 18 mg doses of GTx-024
The following secondary efficacy outcome measures apply to both the evaluable subset of the FAS as well as to the FAS:
• To estimate the proportion of women with TNBC who achieve CB at 24 weeks in response to treatment with 18 mg doses of GTx-024
• To assess ORR in subjects treated with GTx-024 18 mg. ORR is defined as the proportion of subjects with a CR or PR at 16 and 24 weeks as measured by RECIST 1.1. For subjects with non-measurable (non-target) disease only at baseline, ORR is defined as the proportion of subjects with a CR at 16 and 24 weeks as measured by RECIST 1.1
• To assess BOR in subjects treated with GTx-024 18 mg as measured by RECIST 1.1 and defined as: The best overall response is the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. For subjects with non-measurable (non-target) disease only at baseline, SD will be defined as those with non-CR/non-PD combined response
• To assess PFS in subjects treated with GTx-024 18 mg. PFS is defined as the time elapsed between treatment initiation and tumor progression as measured by RECIST 1.1 or death
• To assess TTP in subjects treated with GTx-024 18 mg. TTP is defined as the time elapsed between treatment initiation and tumor progression as measured by RECIST 1.1 or death due to disease progression
• To assess duration of response (time from documentation of tumor response to disease progression or death) in subjects treated with GTx-024 18 mg
• To assess overall Survival: Median OS and 95% confidence intervals will be estimated by the Kaplan-Meier method and the survival function and associated 95% confidence intervals will be constructed at key time points. Follow up will be up to 24 months post treatment initiation for each subject and subjects alive at that time will be censored. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
week 16
week 24
during treatment period after week 24
up to 24 months post treatment |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | 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 | No |
| 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) | No |
| 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 | 24 |
| 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 |
| Australia |
| Bulgaria |
| Czech Republic |
| Hungary |
| Lithuania |
| Romania |
| Ukraine |
| United Kingdom |
| United States |
|
| 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 | 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 |
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