TAPS01

Targeted drug intervention to inhibit cancer progression in men on active surveillance for prostate cancer. Therapeutics in Active Prostate cancer Surveillance.

Research summary

The numbers of men diagnosed with prostate cancer in the United Kingdom (UK) and worldwide is increasing. In the UK 46,690 men were diagnosed in 2014 alone and it is estimated this figure will be closer to 70,000 by 2030. A significant proportion of these men will present with organ-confined and low or intermediate-risk disease. There is increasing recognition that many men with low and intermediate-risk prostate cancer do not need immediate radical therapy. The concept of Active Surveillance (AS) rather than immediate radical therapy has therefore gained popularity as a first management option for these men. AS seeks to monitor men closely and initiate treatment if and when this becomes necessary. Monitoring is performed by a combination of regular Prostatic specific antigen (PSA) blood tests, imaging by multi-parametric MRI (mpMRI), and scheduled repeat prostate biopsies

There is sufficient evidence that pharmacological intervention used as short-term therapy in men with low to intermediate-risk disease can inhibit the growth of prostate tumours and delay or remove the need for radical therapy in men managed by active surveillance. Given the irrefutable role of the androgen receptor in prostate cancer pathogenesis it is logical to target this pathway as a method of inhibiting or delaying disease progression.

This window study will be built on the known anti-androgen effects of apalutamide and investigate the efficacy of using it as a short intervention strategy to cause a physiological change in the tumour by reducing its volume. Tumour volume can be measured using the well-established place of mpMRI defined tumour volumes as a surrogate of disease presence and change. The rationale for a short duration treatment is that it will not have the long term debilitating effects of androgen deprivation on general health and prevent the onset of androgen resistance. It is anticipated that if successful, this approach could be a new therapeutic strategy for these men who otherwise are living and waiting for their disease to progress or not.

This is a single arm open labelled window study of the use of short term apalutamide in men on active surveillance for prostate cancer. This is a single site study undertaken at Cambridge University Hospitals NHS Foundation Trust. It is planned to recruit 10 evaluable participants. The trial duration for individuals will be approximately 5 months, consisting of a 45 day screening period, 90-day treatment and assessment period and then a final treatment safety follow-up visit at 4-6 weeks after completion of treatment.

clinicaltrials.gov

Main inclusion criteria

To be included in the trial the participant must:

  • Have given written Informed Consent (IC) to participate

  • Be aged 18 years or over

  • ECOG status 0-2

  • Diagnosed with prostate cancer

  • Patient selection of active surveillance as a management option

  • Prostate mpMRI demonstrates a visible tumour and congruent with diagnostic biopsy result from the mpMRI defined lesion

  • At least 6 months since initiation of active surveillance and last rebiopsy event

  • Willing to use two highly effective forms of contraception throughout their participation in the trial and for three months after their last dose of apalutamide.

  • Low or intermediate risk prostate cancer according to NICE classification

  • MRI score of ≥ 3 for lesion probability using PIRADS version 2 reporting criteria

  • Adequate organ function (measured within 14 days prior to planned first apalutamide administration) as demonstrated by the following values:

Normal full blood and white cell count

  • Absolute neutrophil count (ANC) ≥1500/μL

  • Platelets ≥100,000/μL

  • Haemoglobin ≥9.0 g/dL

Adequate liver function:

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal (ULN)

AND

  • Total bilirubin ≤ 1.5 times the ULN unless in the presence of Gilbert’s syndrome with an elevated indirect fraction

Adequate renal function:

  • Glomerular filtration rate (GFR) >30ml/min AND Serum creatinine ≤ 2 times the ULN concurrent with creatinine clearance ≥ 50mL/min (both calculated by the output of the Cockcroft and Gault equation)

Main exclusion criteria

The presence of any of the following will preclude participant inclusion:

  • Contraindication to apalutamide

  • Hypersensitivity to any of the trial drugs or excipients

  • Clinically significant change in tumour volume as assessed by mpMRI at the baseline in comparison to previous standard of care mpMRI prior to enrolment into the trial

  • Concurrent medication that can lower seizure threshold and in particular aminophylline/theophylline, atypical antipsychotics (eg, clozapine, olanzapine, risperidone, ziprasidone), bupropion, lithium, meperidine, pethidine, phenothiazine antipsychotics (eg, chlorpromazine, mesoridazine, thioridazine), tricyclic and tetracyclic antidepressants (eg, amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine)

  • Any patients with uncontrolled thyroid disease

  • Prior localised therapy for prostate cancer

  • Any prior use of androgen deprivation therapy or androgen receptor targeting agents

  • Any prior systemic therapy for prostate cancer

  • Clinical contraindication to MRI including presence of pacemaker or cochlear implants

  • Presence of any other implanted devices that are conditional at 1.5T but not 3T

  • Presence of pelvic metalwork

  • Claustrophobia precluding MRI examination

  • Other medical contra-indications to use of gadolinium-based contrast agents

  • Current refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of apalutamide

  • As judged by the Investigator, any patient considered a poor medical risk due to a serious uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection

  • Judgement by the Investigator that the patient is unsuitable to participate in the trial and the patient is unlikely to comply with trial procedures, restrictions and requirements

  • Patients with previous non-related malignancy that have undergone treatment with curative intent or who are under ongoing treatment

  • Participation in any other clinical trials involving an IMP or interventional delivery

Chief investigator

Mr Vincent Gnanapragasam

Contact details

Cancer Theme Email: [email protected]