Clinical Trials /

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

NCT03600467

Description:

This study's purpose is to facilitate and expedite the clinical testing of SEVI-D in a population with advanced cancer that are androgen receptor (AR) positive. Who is it for? You may be eligible for this study if you have a solid tumour with clinical/radiological progression on or following last anticancer therapy. There study has a focus on, but not exclusive to, rare or neglected cancers. Study details: All participants will be screened to confirm if their solid tumour 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 cancers that are known to be human androgen receptor positive.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Activity of Seviteronel in Patients With Androgen Receptor (AR)-Positive Solid Tumours
  • Official Title: A Single-arm, Open-label, Signal-seeking, Phase IIa Trial of the Activity of Seviteronel in Patients With Androgen Receptor (AR)-Positive Solid Tumours

Clinical Trial IDs

  • ORG STUDY ID: START
  • NCT ID: NCT03600467

Conditions

  • Solid Tumor
  • Androgen Receptor Gene Overexpression

Interventions

DrugSynonymsArms
SEVI-D (Seviteronel in combination with dexamthasone)Adrogen Postive Solid Tumours

Purpose

This study's purpose is to facilitate and expedite the clinical testing of SEVI-D in a population with advanced cancer that are androgen receptor (AR) positive. Who is it for? You may be eligible for this study if you have a solid tumour with clinical/radiological progression on or following last anticancer therapy. There study has a focus on, but not exclusive to, rare or neglected cancers. Study details: All participants will be screened to confirm if their solid tumour 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 cancers that are known to be human androgen receptor positive.

Detailed Description

      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.

      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.

      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 solid tumours

      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 solid tumors 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
    

Trial Arms

NameTypeDescriptionInterventions
Adrogen Postive Solid TumoursExperimental
  • SEVI-D (Seviteronel in combination with dexamthasone)

Eligibility Criteria

        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 and/or metastatic solid cancer of any histologic type or an earlier diagnosis
             of a poor prognosis cancer;

          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 solid tumour (ie, AR >0%) 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective tumour response or the ratio of time-to-progression over the preceding period
Time Frame:1 year
Safety Issue:
Description:Assessing radiological images at each time point using either RECIST 1..1 or RANO criteria for disease progression.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:5 years
Safety Issue:
Description:Number of Patients alive >= 5 years
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.
Time Frame:Through study completion, average 1 year
Safety Issue:
Description:The type and frequency of treatment-related adverse events as assessed by CTCAE v4.03.
Measure:Change in quality of life measurements during treatment
Time Frame:Through study completion, average 1 year
Safety Issue:
Description:Change from Baseline in EORTC QLQ-C30 v3 questionnaires
Measure:Change in pain score measurements during treatment
Time Frame:Through study completion, average 1 year
Safety Issue:
Description:Change from Baseline in BP-SF questionnaires

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:St Vincent's Hospital, Sydney

Trial Keywords

  • Androgen Receptor Positive
  • Seviteronel
  • Advanced Cancers

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