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
Inclusion Criteria:
1. To be eligible for treatment in the study, patients must continue to meet all of the
inclusion criteria and none of the exclusion criteria at the time of registration.
Male or female patients, aged 18 years and older, with pathologically confirmed
advanced GBM;
2. Sufficient and accessible tissue for molecular screening;
3. Patients receiving their last line of standard treatment or who have received and
failed all standard anticancer therapy (where standard therapy exists) or have
documented unsuitability for any further standard anticancer therapy Poor prognosis
cancers or cancers with low expected response rate to standard treatment (in the
opinion of the investigator and based on available evidence) may be screened on an
earlier line of treatment.
1. Failure is defined as either progression of disease (clinical or radiological) or
intolerance to standard therapy resulting in the discontinuation of the therapy.
2. Documented unsuitability for further standard therapy includes known
hypersensitivity, organ dysfunction or other patient factors that would make
therapy unsuitable in the judgement of the responsible investigator;
4. ECOG performance status 0, 1 or 2;
5. Willing and potentially able to comply with study requirements, including treatment,
timing and/or nature of required assessments; It is the intention to screen patients
who are in principle wishing to take part in the START study if they are found to have
an appropriate tumour biomarker and are still eligible for enrolment at the time of
the treatment phase;
6. Signed, written informed consent to participation in the molecular screening and
treatment study.
7. Received and failed all standard anticancer therapy or have documented unsuitability
for any further standard therapy, if standard therapy exists;
8. Clinical or radiological progression on or following last anticancer therapy;
9. Adequate organ system function as assessed by the following minimal laboratory
requirements (within 7 days prior to first administration of study drug):
1. bone marrow function; platelets ≥ 100 x 109/L, ANC ≥ 1.5 x 109/L, and haemoglobin
≥9g/dL (5.6mmol/L); white blood cell count ≥3,000 cells/μL
2. liver function; ALT/AST ≤ 3 x ULN (in the absence of liver metastases, ≤ 5 x ULN
for patients with liver involvement) and total bilirubin ≤1.5xULN;
3. renal function; serum creatinine ≤1.5xULN;
10. Meet any additional inclusion criteria specified in the relevant study addendum;
11. Signed, written informed consent to participation in the specific treatment study.
12. AR-positive GBM confirmed by immunohistochemistry
13. Able to comply with study requirements
Exclusion Criteria:
Exclusion criteria will include those relevant for screening but also include:
1. Suitable for standard therapy or accepted standard care, if the patient has not been
previously treated;
2. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications
which may contraindicate participation and/or interact with seviteronel, dexamethasone
or the GnRH analogue;
3. Other co-morbidities or conditions that may compromise assessment of key outcomes or
in the opinion of the clinician, limit the ability of the patient to comply with the
protocol;
4. For non central nervous system (CNS) cancers, patients with symptomatic CNS
involvement of his/her cancer. Subjects with stable neurological function, on stable
doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS
progression within 12 weeks prior to study entry are eligible;
5. History of another malignancy within 2 years prior to registration unless adequately
treated and determined free of progressive and metastatic disease for at least 6
months. Patients with a past history of adequately treated carcinoma-in-situ, basal
cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial
transitional cell carcinoma of the bladder are eligible;
6. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal,
infertile, or use a reliable means of contraception. Women of childbearing potential
must have a negative pregnancy test done within 7 days prior to registration. Men must
have been surgically sterilised or use a barrier method of contraception (double
barrier, if required).
7. Known history of hypersensitivity to active or inactive components of seviteronel,
dexamethasone, and/or GnRH analoge;
8. Previous treatment with seviteronel or same class of agent;
9. Treatment with any of the following anti-cancer therapies prior to the first dose of
study treatment:
- Radiation therapy, surgery or tumour embolization within 14 days prior to the
first dose of study treatment. Palliative radiotherapy (for analgesia) is
acceptable only if the irradiated field does not include target lesions;
- Immunotherapy within 28 days prior to the first dose of study treatment;
- Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5
half-lives of a drug prior to the first dose of study treatment or until recovery
from previous therapy (whichever is longer);
10. Administration of any investigational treatment within 30 days or 5 half-lives
(whichever is longer) prior to receiving the first dose of study treatment;
11. Active prostate cancer requiring treatment.
12. Active breast cancer requiring treatment.
13. Symptomatic central nervous system cancer. Subjects with stable neurological function,
on stable doses of steroids/anti-epileptics over 4 weeks prior to screening are
eligible.
14. Corrected QT interval by the Fridericia correction formula (QTcF) on the screening
electrocardiogram (ECG) >470 msec. If the screening ECG QTcF interval is >470 msec, it
may be repeated once, and if the repeat ECG is <470 msec, the patient may be enrolled.
15. Clinically significant cardiac arrhythmias (eg, ventricular tachycardia, ventricular
fibrillation, torsades de pointes, second degree or third degree atrioventricular
heart block without a permanent pacemaker in place).
16. Any medical condition that could preclude patient participation in the study, pose an
undue medical hazard, or which could interfere with study results.
17. Class III or IV Congestive Heart Failure as defined by the New York Heart Association
functional classification system within the previous 6 months.
18. Known active Human Immunodeficiency Virus, Hepatitis B, or Hepatitis C infections.
