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Part 1: Seviteronel will be administered orally beginning with 450 mg (3 x 150 mg tablets) once daily along with 0.5 mg dexamethasone, continuously in 28-day cycles with docetaxel 75mg/m2 administered intravenously 3 weekly.

Part 2: The recommended phase 2 dose for seviteronel (established in Part 1) once daily along with 0.5 mg dexamethasone, continuously in 21-day cycles with docetaxel 75mg/m2 administered intravenously 3 weekly.

Use of Seviteronel-D (Serivteronel and dexamethasone) in the treatment of androgen receptor positive solid tumours.

Seviteronel-D (Seivteronel in combination with dexamethasone)

Use of docetaxel chemotherapy for solid tumours

Rachel F Dear, PhD

Christine Chaffer, PhD

Rachel Dear, MD

To facilitate the clinical testing of seviteronel and dexamethasone (SEVI-D) in combination with docetaxel in androgen receptor (AR) positive triple-negative breast cancer.

Background:

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers and is defined by the absence of immunostaining for estrogen receptor (ER), progesterone receptor (PR), and non-amplified HER2 expression. Patients with metastatic TNBC exhibit a particularly poor clinical outcome, generally with rapid progression and a median overall survival (OS) rate of approximately 16 months. The current standard of care in the treatment of TNBC is cytotoxic chemotherapy and immunotherapy and the development of well-tolerated, effective, and targeted regimens that delay the need for cytotoxic chemotherapy and its side effects is an unmet need. Understanding breast cancer heterogeneity has enabled investigators to identify novel targets for the development of new therapeutic interventions. The androgen receptor (AR) is one such target. AR is expressed in 70-90% of all invasive breast cancers. Emerging data suggest that the AR-signalling pathway may play a critical role in breast cancer pathogenesis. Seviteronel is an orally bioavailable, selective cytochrome P450c17a (CYP17) lyase (lyase) and AR inhibitor. It is approximately 10-fold more selective for CYP17 lyase versus CYP17 17-α hydroxylase (hydroxylase) inhibition. Seviteronel inhibits the AR through competitive antagonism of both wild-type and mutated forms of the receptor. Through this unique, dual mechanism of action, it inhibits androgen production, thus reducing downstream estrogen aromatization from androgens, while also inhibiting AR binding and activation. In our own unpublished work, the investigators have shown that AR expression is often present in the cytoplasm of TNBC cells. When scoring patient samples for cytoplasmic AR, the investigators observed that \~cytoplasmic AR was present in 20% of TNBC patient tumours. This suggests that AR-targeted therapies may be beneficial for a far greater number of TNBC patients than is represented by the traditionally defined triple negative breast cancer AR subtype alone. Seviteronel has been shown to inhibit the growth in multiple breast cancer models, both in vitro and in vivo. Three early-phase prospective clinical studies investigating anti-androgen therapy have demonstrated clinical benefit of single-agent AR-targeted agents in women with metastatic AR positive TNBC. In our preliminary laboratory data (unpublished) demonstrates an increase in survival and suppression of metastatic TNBC when seviteronel is used in combination with docetaxel.

Aim:

To determine the feasibility, safety and efficacy of seviteronel and dexamethasone (SEVI-D) in combination with chemotherapy for the treatment of metastatic breast cancer. This study is conducted in two parts: part 1: dose exploration, and part 2: dose expansion.

Objectives:

To evaluate the safety and tolerability of SEVI-D and chemotherapy (docetaxel) in patients with metastatic breast cancer and determine the recommended phase II dose (RP2D) for SEVI-D/docetaxel combination therapy.

Part 1: Metastatic breast cancer

• To assess the pharmacokinetic and pharmacodynamic profiles of SEVI-D and chemotherapy (docetaxel) in metastatic breast cancer.

Part 2: Androgen receptor-positive metastatic triple-negative breast cancer

* To assess the pharmacokinetic and pharmacodynamic profiles of SEVI-D and chemotherapy (docetaxel).
* To evaluate the clinical activity SEVI-D and chemotherapy (docetaxel) in participants with cytoplasmic androgen receptor-positive metastatic triple negative breast cancer.

Design and sample size:

Part 1: Dose exploration - 6- 18 patients based on a rolling 6 design Part 2: Dose expansion - 35-45 patients in a single arm two-stage investigation

Study population:

Part 1: Patients with metastatic breast cancer. Part 2: Patients with cytoplasmic AR-positive metastatic triple-negative breast cancer confirmed by immunohistochemistry.

Study treatment:

Part 1: Seviteronel will be administered orally beginning with 450 mg (3 x 150 mg tablets) once daily along with 0.5 mg dexamethasone, continuously in 28-day cycles with docetaxel 75mg/m2 administered intravenously 3 weekly.

Part 2: The recommended phase 2 dose for seviteronel (established in Part 1) once daily along with 0.5 mg dexamethasone, continuously in 21-day cycles with docetaxel 75mg/m2 administered intravenously 3 weekly.

Screening for participation includes review of patient history, current health status, availability of a biospecimen for AR screening and patient willingness to be in a trial if eligible. Clinical and safety assessments are scheduled prior to registration and every 8 weeks until death. Imaging and other response assessments are required at baseline and every 2 cycles from cycle 1 day 1 until progression. Blood collection for translational studies will occur at: baseline (collected within 21 days prior to registration) or within 28 days of C1D1 treatment, every 2nd cycle and at the end of treatment.

Seviteronel in Combination With Chemotherapy in Androgen-receptor Positive Metastatic Triple-negative Breast Cancer

4CAST: A Phase 1b Dose Exploration and Dose Expansion, Open-label, Single-centre Study Evaluating the Safety and Efficacy of INO-464 in Combination With Chemotherapy in Patients With metASTatic Breast Cancer

Gene expression analysis (RNAseq, or single-cell RNAseq) on tumor biopsies in response to study treatments.

Expression of androgen receptor, ZEB1 and other protein markers in tumor biopsies in response to study treatment

Gene expression and/or ctDNA analysis in blood and/or tumour biopsies in response to the study treatments.

A patient will be considered evaluable for dose limiting toxicity (DLT) if they have completed two cycles of docetaxel in an 8-week period with at least 80% of the planned INO-464 dose. Toxicity will be graded using CTCAE version 5.0

Incidence, nature, and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0

The proportion of patients with a confirmed complete response or partial response as determined by the investigator according to RECIST v1.1

The time from the first occurrence of a documented confirmed complete response or partial response to the first date of recorded disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause (whichever occurs first)

The time from starting the study treatment to death from any cause

St Vincent's Hospital, Sydney

Professor Anthony Joshua

160 mg administered as four 40 mg soft gelatin capsules orally once daily

160 mg administered as four soft gelatin capsules orally once daily

Enzalutamide

Pfizer CT.gov Call Center

The purpose of this study is to determine if enzalutamide is safe and effective in the treatment of patients with advanced breast cancer that express the androgen receptor but do not express the estrogen or progesterone receptor and are not Her2 amplified.

Safety and Efficacy Study of Enzalutamide in Patients With Advanced, Androgen Receptor-Positive, Triple Negative Breast Cancer

A PHASE 2, SINGLE-ARM, OPEN-LABEL, MULTICENTER STUDY OF THE CLINICAL ACTIVITY AND SAFETY OF ENZALUTAMIDE IN PATIENTS WITH ADVANCED, ANDROGEN RECEPTOR-POSITIVE, TRIPLE-NEGATIVE BREAST CANCER

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

M2 was the metabolite of enzalutamide. The lower limit of quantitation (LLQ) was 0.0200 micrograms per milliliter (mcg/ml) for enzalutamide and M2.

An AEs was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent are events between first dose of study drug and up to 87 weeks that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of the AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. As per the NCI CTCAE, version 4.0, Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening and Grade 5= death. Only the participants with treatment-emergent AEs of Grade 3 (severe) or higher grade were reported in this outcome measure.

Criteria: Systolic blood pressure (SBP):absolute SBP\<90 millimeters of mercury (mmHg) and decrease from baseline (DFB)\>30mmHg, absolute SBP\>180mmHg and increase from baseline (IFB)\>40 mmHg, final visit or 2 consecutive visits SBP\>=20 mmHg change from baseline (CFB), most extreme post-baseline SBP\>=140mmHg, most extreme post- baseline SBP\>=180mmHg, most extreme SBP\>=140mmHg and\>=20 mmHg CFB, most extreme SBP\>=180mmHg and\>=20mmHg CFB; diastolic blood pressure (DBP): absolute DBP\>105mmHg and IFB\>30mmHg, absolute DBP\<50mmHg and DFB\>20mmHg, final visit or 2 consecutive visits DBP\>=15mmHg CFB, most extreme post-baseline DBP\>=90mmHg, most extreme post-baseline DBP\>=105mmHg, most extreme DBP\>=90mmHg and\>=15mmHg CFB, most extreme DBP\>=105mmHg and\>=15mmHg CFB; heart rate\<50beats per minute (BPM) and DFB\>20BPM or heart rate\>120BPM and IFB\>30BPM. Only those categories, in which at least 1 subject had data were reported.

Laboratory tests included hematology parameters (low lymphocytes, WBC, neutrophils, hemoglobin and platelets) and chemistry parameters (mean albumin, Blood urea nitrogen \[BUN\], calcium, Lactate dehydrogenase \[LDH\], alanine aminotransferase, Aspartate aminotransferase , bilirubin, Alkaline phosphatase, creatinine and glucose). Number of participants with change from baseline in laboratory parameters Grades by 2 or More Grades as per National Cancer Institute Common Terminology Criteria (NCI CTC) (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) were reported.

Percentage of participants with a clinical benefit at Week 16 defined as percentage of participants with a best response of complete response (CR), partial response(PR), stable disease(SD) for \>= 16 weeks on radiologic imaging based on Investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1(RECIST 1.1). An estimate of the percentage and its exact 2-sided 85% confidence interval(CI) were calculated using the Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size \<10mm short axis. PR: At least 30% decrease in sum of longest diameter (LD) of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during the study as a reference

Percentage of participants with a clinical benefit at Week 16 defined as percentage of participants with a best response of CR, PR, or SD for \>= 16 weeks on radiologic imaging based on Investigator assessment using RECIST 1.1. An estimate of the percentage and its exact 2-sided 85% CI were calculated using the Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size \<10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during the study as a reference.

Percentage of participants with a clinical benefit at Week 24 defined as percentage of participants with a best response of CR, PR, or SD for \>= 24 weeks on radiologic imaging based on investigator assessment using RECIST 1.1. An estimate of the percentage and its exact 2-sided 85% CI were calculated using the Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size \<10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during the study as a reference.

Percentage of participants with best objective response defined as percentage of participants with a best response of CR and PR based on investigator assessment of target, non-target and new lesions using RECIST 1.1. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in \<10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions.

PFS was defined as the time (in weeks) from the date of first dose of study drug to the date of documented disease progression or death due to any cause whichever occurs first as determined by the investigator using RECIST 1.1. As per RECIST 1.1, progression was defined as: \>=20 percent increase in sum of LD of target lesions taking as a reference the smallest sum of the LD recorded since the treatment started, or the appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions.

Astellas Pharma Inc

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Pfizer

Same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study. AEs and SAEs were collected for safety population.

Participants received enzalutamide 160 mg (as four 40 mg soft gelatin capsules), orally once daily until disease progression, intolerable AEs (including any seizures), non-compliance with protocol requirements, initiation of a new anti-tumor treatment, or participant or physician decision to discontinue treatment or death due to any cause (up to a maximum of 87 Weeks).

Age, Continuous

Sex: Female, Male

Intent-to-treat (ITT) population included all enrolled participants who had positive androgen receptor (AR+) breast cancer as assessed by central review and received at least 1 dose of study drug.

As per change in planned analysis, AR low population (all enrolled participants who had AR nuclear staining \> 0%, \< 10% assessed centrally) was not analyzed for efficacy and duration of response, time to response were not analyzed for any population

Pfizer ClinicalTrials.gov Call Center

Evaluable population included all enrolled participants who had centrally assessed AR + breast cancer (total nuclear AR expression in \>= 10% of tumor cells), had at least 1 dose of study drug and had at least 1 available post baseline tumor assessment evaluable as per RECIST 1.1.

Percentage of Participants With Clinical Benefit at Week 16: Evaluable Population

ITT population included all enrolled participants who had centrally assessed AR+ breast cancer and received at least 1 dose of study drug.

Percentage of Participants With Clinical Benefit at Week 16: Intent-to-Treat (ITT) Population

Percentage of Participants With Clinical Benefit at Week 24: Evaluable Population

Percentage of Participants With Clinical Benefit at Week 24: ITT Population

Analysis was performed on participants from Evaluable population who had measurable disease.

Percentage of Participants With Best Objective Response: Evaluable Population

Analysis was performed on participants from ITT population who had measurable disease.

Percentage of Participants With Best Objective Response: ITT Population

Progression-Free Survival (PFS): Evaluable Population

Progression-Free Survival: ITT Population

Enzalutamide: Day 1

M2: Day 1

Enzalutamide: Week 9

M2: Week 9

Enzalutamide: Week 17

M2: Week 17

Pharmacokinetics (PK) analysis population included all participants who received 1 dose or partial dose of study drug, and who had at least 1 enzalutamide or M2 plasma concentration assessment.

Trough Plasma Concentration of Enzalutamide and Its Metabolite,

Adverse Events

Serious Adverse Events

Safety population included all participants who receive 1 dose or partial dose of study drug.

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Number of Participants With Study Drug Discontinuation Due to Adverse Events

Number of Participants With Grade 3 or Higher Adverse Events

SBP: absolute SBP <90 mmHg and DFB>30 mmHg

SBP: FV or 2 CV SBP>=20 mmHg CFB

SBP: Most extreme post baseline SBP >=140 mmHg

SBP: Most extreme post baseline SBP >=180 mmHg

SBP:Most extreme SBP>=140 mmHg and>=20 mmHg CFB

DBP: FV or 2 CV DBP>=15 mmHg CFB

DBP: Most extreme post baseline result >=90 mmHg

DBP: Most extreme post baseline result >=105 mmHg

DBP:Most extreme DBP>=105 mmHg and>=15 mmHg CFB

DBP:Most extreme DBP>=90 mmHg and>=15 mmHg CFB

Number of Participants With Clinically Significant Change From Baseline in Vital Signs

Hemoglobin

Leukocytes

Lymphocytes

Neutrophils

Platelets

Alanine aminotransferase

Albumin

Alkaline phosphatase

Bilirubin

Calcium

Glucose

Phosphate

Number of Participants With Change From Baseline in Laboratory Parameters Grades by 2 or More Grades

Participants received enzalutamide 160 mg (as four 40 mg soft gelatin capsules), orally once daily until disease progression (DP), intolerable adverse events (AEs) (including any seizures), non-compliance with protocol requirements, initiation of a new anti-tumor treatment, or participant or physician decision to discontinue treatment or death due to any cause (up to a maximum of 87 Weeks).

Overall Study

Reproductive Control Agents

Capecitabine

Paclitaxel

Carboplatin

Albumin-Bound Paclitaxel

Mifepristone

Contraceptive Agents

Contraceptives, Oral

Contraceptive Agents, Female

Contraceptives, Postcoital

Contraceptive Agents, Hormonal

Enzalutamide 160 mg/day, continuous daily dosing in a 21-day cycle

Enzalutamide 120mg/day and mifepristone 300mg/day, continuous daily dosing in a 21-day cycle

The treating physician must select from one of the following regimens.

* Eribulin 1.4 mg/m2 IV Day 1 and Day 8 in a 21-day cycle
* Capecitabine 1000-1250 mg/m2 twice daily, orally Day 1-14 in a 21-day cycle
* Paclitaxel 80 mg/m2 IV Day 1, Day 8 in a 21-day cycle
* Carboplatin AUC 6 IV Day 1 in a 21-day cycle
* Carboplatin AUC 2 IV Day 1, Day 8 and Day 15 in a 21-day cycle

Patients randomized to TPC may be offered crossover to enzalutamide plus mifepristone treatment at the time of disease progression if they continue to meet eligibility criteria.

The treating physician must select from one of the following regimens:

* Eribulin 1.4 mg/m2 IV Day 1 and Day 8 in a 21-day cycle
* Capecitabine 1000-1250 mg/m2 twice daily, orally Day 1-14 in a 21-day cycle
* Paclitaxel 80 mg/m2 IV Day 1, Day 8 in a 21-day cycle
* Carboplatin AUC 6 IV Day 1 in a 21-day cycle
* Carboplatin AUC 2 IV Day 1, Day 8 and Day 15 in a 21-day cycle

Tiffany Traina, MD

Ayca Gucalp, MD

Katia Khoury, MD

Hope Rugo, MD

Rita Nanda, MD

Erica Mayer, MD, MPH

Lisa Carey, MD

The researchers are doing this study to find out if the study drug, enzalutamide, alone or combined with the study drug, mifepristone, is effective in treating advanced or metastatic androgen receptor-positive (AR+) triple negative breast cancer (TNBC) or estrogen receptor-low breast cancer (ER-low BC), and whether these study treatments work as well as standard chemotherapy with carboplatin, paclitaxel, capecitabine, or eribulin.

A Study of Enzalutamide, Enzalutamide in Combination With Mifepristone, or Chemotherapy in People With Metastatic Breast Cancer

A RANDOMIZED, PHASE II STUDY OF ENZALUTAMIDE, ENZALUTAMIDE WITH MIFEPRISTONE, and TREATMENT OF PHYSICIAN'S CHOICE IN PATIENTS WITH AR+ METASTATIC TRIPLE-NEGATIVE OR ER-LOW BREAST CANCER

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1).

Astellas Pharma US, Inc.

Breast Cancer Research Foundation

Corcept Therapeutics

Memorial Sloan Kettering Cancer Center

Glioblastoma

Use of SEVI-D (Serivteronel and dexamethasone) in the treatment of androgen receptor positive solid tumours.

Serivteronel will be administered orally at 450 mg (3 tables) once daily. It will be given in combination with one oral tablet of 0.5 mg tablet of Dexamethosone. SEVI-D will be continuously administered daily while on the study.

Clinical and safety assessments are scheduled every 4 weeks during the study and then every 8 weeks after the end of the safety follow up period of the study.

SEVI-D (Seviteronel in combination with dexamthasone)

This study's purpose is to facilitate and expedite the clinical testing of SEVI-D in a population with advanced GBM that are androgen receptor (AR) positive.

Who is it for? You may be eligible for this study if you have a GBM with clinical/radiological progression on or following last anticancer therapy.

Study details:

All participants will be screened to confirm if their GBM is AR positive by the study team. If eligible, participants will receive the medications of Serivteronel and Dexamethasone (also known as SEVI-D) by oral tablets continuously per cycle (4 weeks). Participants will be asked to have blood tests, scans, complete questionnaire and regularly meet with the study doctor and team.

It is hoped this research will demonstrate this treatment could be beneficial for the treatment of GBM that are known to be human androgen receptor positive.

Background:

The human androgen receptor (AR) is a steroid hormone receptor that is expressed in multiple reproductive tissues and has important effects on multiple organ systems. The AR is a major target for the treatment of prostate cancer, and, more recently, for treatment of breast cancer. However, the AR is also expressed on many other tissues and plays vital roles in other cancer types, such as head and neck cancers (eg, salivary gland and thyroid cancers), cutaneous malignancies (eg, melanoma and basal cell carcinoma), sarcomas, and genitourinary cancers (eg, renal and bladder cancers). There are very few studies investigating AR-targeted therapies for indications other than prostate or breast cancer; however the few anecdotal reports and small studies that have been performed suggest that AR-positive tumours may respond to therapy with AR-targeted agents. In this study we are concentrating on GBM Seviteronel is a dual selective P450C17,20-lyase (CYP17 lyase) and AR inhibitor currently being investigated in Phase 1/2 trials for prostate and breast cancers. Seviteronel has shown promising preclinical activity in some breast cancer models, and seviteronel in combination with dexamethasone (SEVI-D) has shown promising preliminary activity for treatment of metastatic castration-resistant prostate cancer. Therefore, SEVI-D could be beneficial for the treatment of other cancers that are known to be AR-positive such as GBM

Aim:

The overall aim is to facilitate and expedite the clinical testing of rational therapeutic hypotheses in a population with advanced cancer and unmet need, with a particular, but not exclusive, focus on rare or neglected cancers. The program will evaluate the clinical activity of SEVI-D in subjects with AR-positive GBM

Primary Objective:

To test the clinical activity of novel targeted treatments and/or indications as measured by objective tumour response or the ratio of time-to-progression on study over the preceding period

Secondary Objectives:

1. Overall survival (OS) (death from any cause);
2. Safety and tolerability of treatment (rates of adverse events)
3. Health related quality of life during treatment (EORTC QLQ-C30v.3 questionnaire or brief pain inventory, if applicable).
4. To evaluate the feasibility, efficiency and utility of an overarching framework protocol for multiple, parallel signal-seeking clinical substudies;
5. To evaluate a mechanism for screening patients for actionable biomarkers to be used to guide therapy.

Population:

Patients with AR-positive GBM as confirmed by immunohistochemistry.

Treatments:

Seviteronel, will be administered orally at 450 mg (3 x 150 mg tablets) for men with 0.5 mg dexamethasone (tablet) once daily plus a GnRH analogue (depot injection). Seviteronel, will be administered orally at 450 mg (3 x 150 mg tablets) for post menopausal women, once daily in combination with once daily 0.5 mg dexamethasone (tablet). For premenopausal women (with intact ovaries), a GnRH analogue (depot injection) will also need to be admistered. See Treatment Study Table below. Patients will take seviteronel and dexamethasone each day continuously in 28-day cycles.

Assessments:

Screening for participation in the screening platform includes the review of patient history, current health status, availability of a biospecimen for AR screening and patient willingness to be in a trial if eligible.

Clinical and safety assessments are scheduled prior to registration and then every 8 weeks until death.

Imaging and other response assessments are required at baseline and 8-weekly from cycle 1 day 1 until progression.

Blood collection for translational studies will occur at:

1. Baseline (collected within 21 days prior to registration) or within 28 days of C1D1 treatment
2. Every 2nd cycle
3. At End of treatment

START is an open-label, single-arm, multicentre Phase IIa signal-seeking trial.

Activity of Seviteronel in Patients With Androgen Receptor (AR)-Positive Glioblastoma

A Single-arm, Open-label, Signal-seeking, Phase IIa Trial of the Activity of Seviteronel in Patients With Androgen Receptor (AR)-Positive GBM

Assessing radiological images at each time point using either RECIST 1..1 or RANO criteria for disease progression.

The type and frequency of treatment-related adverse events as assessed by CTCAE v4.03.

Change from Baseline in EORTC QLQ-C30 v3 questionnaires

Change from Baseline in BP-SF questionnaires

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Seviteronel in Combination With Chemotherapy in Androgen-receptor Positive Metastatic Triple-negative Breast Cancer	NCT04947189	Triple Negative...	Seviteronel-D (... Docetaxel	18 Years -	St Vincent's Hospital, Sydney
Safety and Efficacy Study of Enzalutamide in Patients With Advanced, Androgen Receptor-Positive, Triple Negative Breast Cancer	NCT01889238	Advanced, Andro...	Enzalutamide	18 Years -	Pfizer
Seviteronel in Combination With Chemotherapy in Androgen-receptor Positive Metastatic Triple-negative Breast Cancer	NCT04947189	Triple Negative...	Seviteronel-D (... Docetaxel	18 Years -	St Vincent's Hospital, Sydney
A Study of Enzalutamide, Enzalutamide in Combination With Mifepristone, or Chemotherapy in People With Metastatic Breast Cancer	NCT06099769	Metastatic Brea...	Enzalutamide Mifepristone TPC	18 Years -	Memorial Sloan Kettering Cancer Center
Activity of Seviteronel in Patients With Androgen Receptor (AR)-Positive Glioblastoma	NCT03600467	Solid Tumor Androgen Recept...	SEVI-D (Seviter...	18 Years -	St Vincent's Hospital, Sydney
Safety and Efficacy Study of Enzalutamide in Patients With Advanced, Androgen Receptor-Positive, Triple Negative Breast Cancer	NCT01889238	Advanced, Andro...	Enzalutamide	18 Years -	Pfizer

Spots Global Cancer Trial Database for androgen receptor positive