A study into the pharmacodynamic biomarker effects of AZD2014 (an mTOR1/2 inhibitor) given prior to radical prostatectomy

Research summary

In the UK prostate cancer is the 4th most common cause of cancer death (accounting for 7% of total cancer deaths). Furthermore, in men, it is the 2nd most common cause of cancer death after lung cancer and accounts for 13% of cancer deaths. As with other solid tumours early-stage disease can be treated with curative intent, e.g. by radical prostatectomy (RP) or external beam radiotherapy (EBRT). Following diagnosis, patients undergo risk stratification (guided by a specialist multi-disciplinary team (MDT), which is central to advising patients regarding their treatment options. For patients with localised prostate cancer treatment options typically include radical prostatectomy, radical radiotherapy or active surveillance. For men presenting with high-risk prostate cancer, i.e. those with the highest incidence of treatment failure from radical therapy, disease progression and mortality ultimately will occur in a significant proportion of such patients. A widely accepted definition of high-risk disease is based on D’Amico’s risk classifications and is used in a number of national guidelines, including those published by the National Institute for Clinical Excellence (NICE). These include a Gleason sum score of 8 or more, or at least T2c clinical stage or a presenting PSA ≥ 20 ng/mL. Better identification of patients at high risk of relapse and improvements in therapy are high priority areas for research.

Altered PI3k/AKT/mTOR signalling is strongly implicated in prostate cancer and development of agents targeting this signalling pathway might be utilised in early hormone-sensitive disease as opposed to CRPC. Before implementing a study in early, high-risk disease the proposed study will build confidence and more fully characterise the molecular pharmacology of AZD2014 in patients with prostate cancer. The chosen dose and duration of AZD2014 are predicted to be: tolerable given the toxicity data currently available, effective on pharmacodynamic biomarkers and unlikely to interfere with the planned treatment pathway including radical prostatectomy. 

The study will use the window of opportunity prior to radical prostatectomy in order to investigate the pharmacodynamic biomarker changes that occur in prostate tumour tissue following the administration of the mTOR 1/2 inhibitor (AZD2014). This is a phase I single-arm, open-label, prospective study. This will be a single centre study. If during the course of the study recruitment falls significantly behind the targeted level, the addition of further centres may be considered. A maximum of 20 men, evaluable for the purpose of this study, with prostate cancer will be recruited. It is intended that each subject on study will take AZD2014 for two weeks (14 days +/− two days) prior to radical prostatectomy and will be followed up six weeks after the completion of surgery. The minimum duration of the study for a patient is 9 weeks. The maximum duration of the study for a patient is 16 weeks providing surgery is not significantly delayed. In the unlikely event that radical prostatectomy surgery is delayed, participants may receive AZD2014 treatment for a maximum duration of 21 consecutive days. If surgery is significantly delayed, participants will stop AZD2014 treatment and will be given the option to recommence treatment for a two week period prior to the revised surgery date, providing they still satisfy the eligibility criteria.

Main inclusion criteria

To be included in the trial the patient must:

  1. Have given written informed consent to participate

  2. Men aged 18 years or over

  3. ECOG performance status 0 or 1

  4. Patient suitable for radical prostatectomy

  5. Access to archived diagnostic tissue or consent to undergo repeat biopsy, if necessary.

  6. Diagnosis of:

    1. High risk disease: either one or more of stage T2c – T3a, or PSA level >20 ng/mL, or Gleason score ≥ 8

    2. Intermediate risk disease with two or more of: stage T2 (any), PSA>10, Gleason 7

  7. Adequate bone marrow reserve and organ function as demonstrated by any of the following laboratory values:

    1. Absolute neutrophil count ≥ 1.9 x 109/L

    2. Platelet count ≥ 140 x 109/L

    3. Haemoglobin ≥ 125 g/L

    4. Adequate hepatic function:

      1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal (ULN) and

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

    5. Adequate renal function:

      1. Serum creatinine ≤1.5 times ULN concurrent with creatinine clearance ≥ 50 mL/min (calculated by Cockcroft and Gault equation)

  8. Willing to abstain from sex (where true abstinence is in line with the preferred and usual lifestyle of the participant) or use a barrier contraceptive method, e.g. condom and spermicide, for the duration of the trial and for up to 6 months afterwards. Patients refrain from donating sperm from the start of dosing until 16 weeks after discontinuing study treatment.

  9. Normal chest radiograph and oxygen saturations. If abnormal a chest CT scan may be performed, as clinically indicated, patients may be eligible for the study providing the chest CT scan does not reveal conditions listed under the specific exclusion criteria (Section 10.2).

  10. Patients who are currently/have recently been involved in non-drug-based research are eligible to participate.

Main exclusion criteria

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

  1. Contraindication to AZD2014

    1. Unable to swallow or retain oral medication

    2. 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 AZD2014

    3. History of hypersensitivity to active or inactive excipients of AZD2014 or drugs with a similar chemical structure or class to AZD2014, e.g. rapamycin and its analogues or other mTOR inhibitors.

  2. Patients who have undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 12 months:

    1. coronary artery bypass graft

    2. angioplasty

    3. vascular stent

    4. myocardial infarction

    5. angina pectoris

    6. congestive heart failure New York Heart Association Grade ≥ 2

    7. ventricular arrhythmias requiring continuous therapy

    8. supraventricular arrhythmias including atrial fibrillation, which are uncontrolled

    9. haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding

  3. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, e.g.

    1. severe hepatic impairment

    2. interstitial lung disease [bilateral, diffuse, parenchymal lung disease]

    3. uncontrolled chronic renal diseases (glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis)

    4. current unstable or uncompensated respiratory or cardiac conditions,

    5. uncontrolled hypertension

    6. active bleeding diatheses

    7. active infection including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required.

    8. Hyperlipidaemia

    9. Diabetes Type I or uncontrolled Type II (HbA1c > 7mmol/L assessed locally)

  4. Previous malignancy treated with systemic therapy (surgery and radiotherapy are permitted) within 5 years prior to commencing AZD2014 treatment. With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.03) Grade 1 at the time of starting study treatment.

  5. Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study

  6. Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age). History of Torsades de Pointes.

  7. Exposure to potent or moderate inhibitors and inducers of CYP3A4/5, Pgp (MDR1) and BCRP if taken within the stated washout periods before the first dose of study treatment.

  8. Exposure to sensitive or narrow therapeutic range substrates of the drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K within the appropriate wash-out period (a minimum of 5 x reported elimination half-life) before the first dose of study treatment.

  9. Use of any haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 4 weeks prior to receiving study drug

  10. Abnormal echocardiogram (ECHO) defined as left ventricular ejection fraction [LVEF] <50%

  11. Mean resting QTc (Fridericia) ≥ 470 msec as per local reading

  12. Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements

  13. Patients who are currently/have previously been involved in interventional research using systemic anti-cancer treatment (within the last 5 years) will not be eligible to participate.

  14. Patients with a desire to have children following the study will not be recruited.

Chief investigator

Dr Simon Pacey

Contact details

Cancer Theme Email: [email protected]