| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Estrogen Receptor Positive and Androgen Receptor Positive Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.1 |
| 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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070575 |
| E.1.2 | Term | Estrogen receptor positive 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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072740 |
| E.1.2 | Term | Locally 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 | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070577 |
| E.1.2 | Term | Oestrogen receptor positive 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 24 weeks (defined as CR, PR, or SD) (by RECIST 1.1) of GTx-024 9 mg and of GTx-024 18 mg given PO daily in subjects with ER+/AR+ BC who have centrally confirmed AR+ status.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives:
- Estimate CBR at 24 weeks (by RECIST 1.1) of GTx-024 9mg and 18 mg in all subjects randomized who receive at least one dose of study
medication (the FAS) 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 objective response rate (ORR; defined as CR or PR) (by
RECIST 1.1) of GTx-024 9 mg and 18 mg at 24 weeks
- Estimate the best overall response rate of GTx-024 9mg and 18mg
- Estimate the progression free survival of subjects receiving GTx-024
9mg and 18mg
- Estimate the time to progression of subjects receiving GTx-024 9 mg
and 18mg
- Estimate duration of response (time from documentation of tumor
response to disease progression or death) of subjects receiving GTx-024 9 mg and 18 mg
- Estimate overall survival
Safety objective
Pharmacokinetic objective |
|
| 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). |
|
| E.3 | Principal inclusion criteria |
Adult postmenopausal women with metastatic or recurrent locally advanced ER+/AR+ BC.
Subject Inclusion criteria: Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Adult women (≥ 18 years of age) with metastatic orrecurrent locally advanced BC, not amenable to curative treatment by surgery or radiotherapy, with objective
evidence of disease progression.
Women must have received ≥ 1 prior hormonal treatment(s) in the metastatic or adjuvant setting.
- If the most recent hormonal treatment was in the metastatic setting, duration of response (tumor regression or stabilization of disease) to this specific course of therapy must be ≥ 6 months
- If the most recent hormonal treatment was in the adjuvant setting, duration of response (disease free) to this specific course of therapy must be ≥ 3 years
2. Histological or cytological confirmation of ER+ BC as assessed by a local laboratory using slides, paraffin blocks, or paraffin sample or by medical history: ER+ (confirmed as ER expression more than or equal to 1%
positive tumor nuclei)
3. Human epidermal growth factor receptor 2 (HER2)-negative tumor by local laboratory testing (immunohistochemistry [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)
4. 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
5. Postmenopausal women. Postmenopausal status is defined by the National Comprehensive Cancer Network as either:
- Age ≥ 55 years and one year or more of amenorrhea
- Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/mL
- Age < 55 years and surgical menopause with bilateral oophorectomy
a. Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression at the time of screening. Long term use (>6 months prior to screening) is permitted
6. Radiological or clinical evidence (bone scan, computerized tomography [CT], and magnetic resonance Imaging [MRI]) of recurrence or progression within
30 days before randomization
7. Subject must have either measurable disease or bone-only non-measurable disease, according to RECIST 1.1
8. Adequate organ function as shown by:
- Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
- Platelet count ≥ 100,000 cells/mm3
- Hemoglobin (Hgb) ≥ 9.0 g/dL
- Serum aspartate aminotransferase (AST) and alanine transaminase (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 (aPTT) < 1.5 × ULN (unless on anticoagulant treatment at screening)
9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status 4 0 or 1
10. 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 patients who are normocalcemic, therapy can be initiated at the time the patient initiates study drug
11. Subject is able to swallow capsules
12. Able and willing to give voluntary, written and signed informed consent before any screening procedure and according to local guidelines |
|
| E.4 | Principal exclusion criteria |
Subjects eligible for this study must not meet any of the following criteria:
1. Previously received > 1 course of chemotherapy (not including immunotherapies or targeted therapies) for the treatment of metastatic BC
a. Note: Subjects may have received 1 course of chemotherapy prior to surgery for the treatment of locally advanced disease and 1 course of chemotherapy for the treatment of metastatic BC; however, if surgery could not be performed, this
will count as the 1 chemotherapy course allowed prior to study
2. Known hypersensitivity to any of the GTx-024 components or subjects previously received treatment with Selective Androgen Receptor Modulator (SARM)
3. Subjects with radiographic evidence of central nervous system (CNS) metastases as assessed by CT or MRI that are not well-controlled (symptomatic or requiring control with continuous corticosteroid therapy [e.g.,dexamethasone])
a. Note: Subjects with CNS metastases are permitted to participate in the study if the CNS metastases are medically well-controlled and stable for at least 28 days after receiving local therapy (irradiation, surgery, etc.)
4. Radiotherapy within 14 days prior to randomization except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to randomization. Subjects must have recovered from radiotherapy toxicities prior to randomization
5. Currently receiving hormone replacement therapy, unless discontinued prior to screening
6. Subjects positive for Human Immunodeficiency Virus (HIV)
7. 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)
- 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.
8. Major surgery within 28 days before randomization
9. Positive hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection at screening
10. History of non-compliance to medical regimens
11. Subjects unwilling to or unable to comply with the protocol
12. Subject is currently receiving treatment with any agent listed on the prohibited medication list (See Section 6.6 Concomitant Medications/Treatments for complete list)
13. Treatment with any investigational product within < 4 half-lives for each individual investigational product OR within 28 days prior to randomization
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
Tumor response in terms of clinical benefit will be assessed by RECIST 1.1 criteria
from centrally read CT scans obtained at the 24 week assessment. Tumor response is judged relative to baseline tumor assessments. An evaluable subject will be considered to have a response of CB if the assessment indicates CR, PR, or SD. The primary assessment is among evaluable subjects in the FAS at 24 weeks in each of the 9 mg and 18 mg arms. An evaluable subject who does not have a week 24 assessment for any reason remains in the evaluable subset of the FAS and is considered a failure to achieve CB (CR, PR, or SD). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints
- CBR in the FAS and PPS at 24 weeks in each of the 9 mg and 18 mg arms.
The following secondary efficacy endpoints will be assessed among subjects in each of the 9 mg and 18 mg arms among the evaluable subjects, the FAS, and the PPS:
- ORR (CR or PR assessed by RECIST 1.1 criteria) at 24 weeks
- Best (confirmed) overall response rate (BOR). BOR is defined as the best observed response for each subject up to and including the EOT. Reponses of CR or PR should be confirmed by a repeat assessment at least 4 weeks later.
- PFS: PFS is defined as the time from randomization until objective tumor progression or death due to any cause. Subjects who have no PFS events will be censored at the date of the last adequate tumor assessment. If the subject has no
post-baseline tumor assessments, they will be censored at the time of randomization
- TTP: TTP is defined as the time from randomization until objective tumor progression or death due to disease progression. Subjects who have not progressed will be censored at the date of the last adequate tumor assessment. If
the subject has no post-baseline tumor assessments but is known to be alive, they
will be censored at the time of randomization
- Duration of response: Duration of response, in responders, is defined as the period from the date of initial CR or PR until the date of disease progression or death from any cause. Only subjects with BOR of CR or PR (i.e., responders) will be included in the analysis of duration of response. Subjects with no documented progression or death after CR or PR will be censored at the last date at which they are known to have had the CR or PR
- Overall Survival: OS is defined as the time from treatment initiation
until death or last follow up date with a maximum of 12 months post last dose. Subjects known to be alive at their last follow up will be censored at that time.
Safety endpoints
The following safety endpoints will be assessed among evaluable subjects as well as
all subjects enrolled and treated:
- AEs and concomitant medications
- Laboratory examinations (clinical chemistry, hematology, and urinalysis)
-Physical examinations
- Vital signs
- ECOG performance status
- Eye examinations
Pharmacokinetic endpoints
Plasma concentrations of GTx-024 18 mg and GTx-024 glucuronide at each assessment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
week 24 for the secondary efficacy objectives
Safety: at all times
PK: baseline(V2), V3, V5, V6 |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| future sample storage as an optional procedure |
|
| 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 | 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 | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| the two groups are independent and not compared to each other |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| another concentration of Gtx-024 |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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