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Adenocarcinoma of the ProstatePhase 2RE-AKTNCT02525068

A Study of Enzalutamide in Combination With AZD5363 in Patients With mCRPC

A Phase 2 study testing AZD5363 and Enzalutamide in people with Adenocarcinoma of the Prostate, run by Institute of Cancer Research, United Kingdom at 1 site in United Kingdom.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

A multicentre prospective, randomised, phase II interventional study in mCRPC patients previously treated with 1-2 lines of chemotherapy and at least 12 weeks of abiraterone with a safety run-in and single stage phase II expansion cohort. Read more about this study

Who is it for?
Ages 18 years and older, men only
Conditions the study is for
Adenocarcinoma of the Prostate
What is being tested?
AZD5363 and Enzalutamide
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
136 participants
Where
1 siteUnited Kingdom
Study dates
Dec 2014to Mar 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Written informed consent.
  • Histological diagnosis of adenocarcinoma of the prostate and with tumour tissue accessible for research analyses for this trial (e.g. Phosphatase and Tensin Homologue (PTEN) testing). Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma.
  • Metastatic Castration-Resistant Prostate Cancer (mCRPC).
  • Progressed after 1 or 2 lines of taxane based chemotherapy.
  • Progressed after abiraterone (pre or post chemotherapy). Patients must have received at least 12 weeks of treatment with abiraterone.
  • Age ≥18 years.
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  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
  • PSA ≥ 10ng/ml.
  • Documented willingness to use an effective means of contraception while participating in the study and for 12 months post last dose of treatment
  • Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM).
  • Received prior castration by orchiectomy and/or ongoing Luteinizing Hormone-Releasing Hormone (LH-RH) agonist treatment.
  • Progression of disease by PSA utilizing PCWG2 criteria and at least another of the following criteria;
  • Bone scan: disease progression as defined by at least 2 new lesions on bone scan.
  • Soft tissue disease progression defined by modified RECIST 1.1.
  • Clinical progression with worsening pain and the need for palliative radiotherapy for bone metastases.
  • PHASE I SAFETY RUN IN and EXPANSION COHORT - inclusion criteria:
  • Willing to have a biopsy to obtain tumour tissue for biomarker analyses prior to and after treatment.
  • SINGLE STAGE PHASE II EXPANSION COHORT ONLY - inclusion criteria:
  • Prior exposure to enzalutamide of at least 12 weeks is required with documented disease progression biochemically and/or radiologically by PCWG2 or RECIST 1.1 criteria. Patients should have received at least 12 weeks of enzalutamide outside of the trial with evidence of disease progression (by PSA with 3 rising values as per PCWG2 criteria or soft tissue progression as per RECIST v1.1).
  • Archival tumour tissue available for the analysis of PTEN loss by the central laboratory

Who cannot join

  • Prior treatment with enzalutamide (MDV3100) (not applicable for the phase I safety run in or for the single stage phase II expansion cohort, see inclusion criteria 14).
  • Prior treatment with Phosphatidylinositide 3-kinases (PI3K), AKT, TOR kinase or Mammalian target of rapamycin (mTOR) inhibitors (see Appendix C).
  • Surgery, chemotherapy, or other anti-cancer therapy within 4 weeks prior to trial entry/randomisation into the study (6 weeks for bicalutamide). Any other therapies for prostate cancer, other than Gonadotropin-releasing hormone (GnRH) analogue therapy, such as progesterone, medroxyprogesterone, progestins (megestrol), or 5-alpha reductase inhibitors (e.g., finasteride or dutasteride), must be discontinued at least 2 weeks before the first dose of study drug.
  • Participation in another clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry / randomisation.
  • Prior limited field radiotherapy within 2 weeks or wide field radiotherapy within 4 weeks of trial entry / randomisation.
  • History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism.
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  • History of loss of consciousness or transient ischemic attack within the previous 12 months of trial entry / randomisation.
  • Known brain or leptomeningeal involvement.
  • Use of potent inhibitors or inducers of Cytochrome P450 isoenzymes (CYP3A4, CYP2C9, CYP2C19 and CYP2D6) (see Appendix B) within 2 weeks before trial entry / randomisation (3 weeks for St John's Wort) must be avoided.
  • Clinically significant abnormalities of glucose metabolism as defined by any of the following:
  • Diagnosis of diabetes mellitus type I
  • Fasting plasma glucose ≥ 7.0 mmol/L for those patients without a pre-existing diagnosis of Type 2 diabetes mellitus
  • ≥ 9.3 mmol/L for those patients with a pre-existing diagnosis of Type 2 diabetes mellitus
  • Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (63.9 mmol/mol) (conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) - 2.15] x 10.929)
  • Requirement for insulin for routine diabetic management and control
  • Requirement for more than two oral hypoglycaemic medications for routine diabetic management and control
  • Inadequate organ and bone marrow function as evidenced by:
  • Haemoglobin <85 g/L
  • Absolute neutrophil count <1.0 x 109/L
  • Platelet count < 75 x 109/L
  • Albumin ≤25 g/dL
  • Aspartate Transaminase (AST) / Serum Glutamic-Oxaloacetic Transaminase (SGOT) and/or Alanine Transaminase (ALT) / Serum Glutamic Pyruvate Transaminase (SGPT) ≥ 2.5 x Upper Limit of Normal (ULN) (≥ 5 x ULN if liver metastases present)
  • Total bilirubin ≥ 1.5 x ULN (except for patient with documented Gilbert's disease)
  • Serum Creatinine > 1.5 x ULN
  • Inability or unwillingness to swallow oral medication.
  • Malabsorption syndrome or other condition that would interfere with enteral absorption.
  • Any of the following cardiac criteria;
  • Mean resting corrected QT interval (QTcF) >470msec obtained from 3 consecutive ECGs taken within 5 minutes
  • Any clinically important abnormalities in rhythm, conduction, or morphology of a resting ECG (e.g., complete left bundle branch block, third degree heart block)
  • Any 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, or any concomitant medication known to prolong the QT interval or with a potential for Torsades de Pointes
  • Experience of any of the following procedures or conditions in the preceding six months:coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) ≥ Grade2
  • Uncontrolled hypotension defined as - systolic blood pressure (BP) <90 mmHg and/or diastolic BP <50 mmHg
  • Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
  • Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications.
  • Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5mg of dexamethasone per day or an equivalent dose of other anti-inflammatory corticosteroid, for the use of concomitant steroids on this trial please refer to section 12.1. Patients in which corticosteroids cannot be stopped prior to entering the trial are allowed a maximum of 10mg of prednisolone per day or equivalent. In the case of corticosteroid discontinuation, a 2-week (14 days) washout is required with a mandatory PSA check prior to starting the trial. If the PSA has declined compared to the value obtained prior to stopping corticosteroids, patients will not be eligible for study. Patients can only enter the study with a confirmed PSA increase.
  • Malignancies other than prostate cancer within 5 years prior to trial entry / randomisation, except for adequately treated basal or squamous cell skin cancer.
  • Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy.
  • Inability to comply with study and follow-up procedures.
  • Patients with predominately small cell or neuroendocrine differentiated prostate cancer are not eligible.

Trial locations and contacts

1 site in 1 country.

RE-AKT Trial Manager contact

RE-AKT-icrctsu@icr.ac.uk

United Kingdom1 site, 1 recruiting

  • Royal Marsden Hospital

    Sutton, Surrey, SM2 5PT

    Johann De Bono, Professor

    Recruiting

Other trials in United Kingdom

About this study

Official title: A Randomised Phase II Study of Enzalutamide (MDV3100) in Combination With AZD5363 in Patients With Metastatic Castration-Resistant Prostate Cancer (RE-AKT)

A multicentre prospective, randomised, phase II interventional study in mCRPC patients previously treated with 1-2 lines of chemotherapy and at least 12 weeks of abiraterone with a safety run-in and single stage phase II expansion cohort.

Read the detailed description

Patients with mCRPC will receive enzalutamide and AZD5363 (or enzalutamide and placebo in the randomised phase II) until confirmed disease progression.

The trial aims to identify the safety and tolerability of enzalutamide and AZD5363 and identify recommended phase II dose of AZD5363 (phase I safety run-in). The randomised phase II will estimate and compare the anti-tumour activity of AZD5363 and enzalutamide, and placebo and enzalutamide as measured by response. The single stage phase II expansion cohort will estimate the anti-tumour activity of AZD5363 and enzalutamide in patients who have previously progressed on enzalutamide alone.

Being tested
AZD5363, Enzalutamide
Keywords
enzalutamide, AZD5363, Prostate

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD5363Drug

    Until confirmed disease progression.

  • EnzalutamideDrug

    Also called MDV3100, Xtandi

    Until confirmed disease progression.

Study groups in NCT02525068
Study groupRoleWhat they receive
Phase ISafety Run-InExperimental18 patients will receive the combination of enzalutamide and AZD5363 (on an intermittent schedule 4 days on 3 days off) to determine the AZD5363 dose to be used for the randomised phase II and single stage phase II expansion cohort. Approximately three dose-levels of AZD5363 in combination with enzalutamide are planned although other dose levels may be required.
Receives: Drug: AZD5363; Drug: Enzalutamide
Randomised phase IIPlacebo comparator100 patients will be randomised in a 1:1 ratio to receive 160mg enzalutamide od + AZD5363 bid 4 days on 3 days off (recommended dose from Phase I) vs 160mg enzalutamide od + matching placebo bid 4 days on 3 days off.
Receives: Drug: AZD5363; Drug: Enzalutamide
Single stage phase II expansion cohortExperimentalFollowing progression on enzalutamide alone, 18 patients will receive enzalutamide 160mg od and AZD5363 bid (recommended dose from phase I) 4 days on 3 days off
Receives: Drug: AZD5363; Drug: Enzalutamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase I: Type, frequency, severity, seriousness and relatedness of adverse events

    Type according to Medical Dictionary for Regulatory Activities (MedDRA), frequency according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4, seriousness, and relatedness of study treatment-emergent adverse events will be assessed

    Measured: 35 days

  2. Phase I: Laboratory abnormalities will be assessed according to NCI CTCAE v4

    Measured: 35 days

  3. Randomised phase II: Best overall tumour response

    Best overall tumour response as defined by Prostate Specific Antigen (PSA) decline of ≥50% (according to PCWG2), confirmed objective response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or ONLY for patients with detectable circulating tumour cell count of ≥5/7.5ml blood at baseline, conversion of CTC <5/7.5ml blood nadir

    Measured: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to an estimated 22-24 months

  4. Phase II expansion: Best overall tumour response

    Best overall tumour response as defined by PSA decline of ≥50% (according to PCWG2), confirmed objective response by RECIST 1.1 or ONLY for patients with detectable circulating tumour cell count of ≥5/7.5ml blood at baseline, conversion of CTC <5/7.5ml blood nadir

    Measured: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to an estimated 22-24 months

Secondary outcomes (6)

  1. Phase I and phase II expansion only - Pharmacokinetic (PK) assay analyses

    PK assay analysis including endpoints of Peak Plasma Concentration (Cmax) and Area under the plasma concentration versus time curve (AUC)

    Measured: 35 days

  2. Phase I - Antitumour activity of the combination

    Measured: 35 days

  3. Randomised phase II and phase II expansion - Overall survival and radiographic progression free survival

    Measured: From date of randomization/trial entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to (estimated) 12 months

  4. Maximum PSA decline and circulating tumour cell (CTC) fall

    Maximum PSA decline and CTC fall by 30% at any time during the trial and at 12 weeks.

    Measured: 12 weeks

  5. Pain Palliation - Randomised phase II only

    Pain palliation will be assessed using the Brief Pain Inventory (Short Form) (BPI-SF) worst pain intensity score

    Measured: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to (estimated) 12 months

  6. Number of Adverse events will be graded according to NCI-CTCAE v4

    Measured: From trial entry until 30 days post date of last dose or death from any cause

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Aug 2015 (estimated)
  2. Study startDec 2014
  3. Primary completion31 Dec 2019 (estimated)
  4. Study completionMar 2020 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
136 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02525068
Sponsor's protocol ID
ICR-CTSU/2012/10037
Other IDs
2013-004091-34, CRUKE/12/050, ISRCTN17168679, ISS53630011
Acronym
RE-AKT
Status last verified
Aug 2015
First submitted
17 Jul 2015
Last updated
8 Aug 2018
Results posted
No
Data monitoring committee
Yes

Publications

  • Kolinsky MP, Rescigno P, Bianchini D, Zafeiriou Z, Mehra N, Mateo J, Michalarea V, Riisnaes R, Crespo M, Figueiredo I, Miranda S, Nava Rodrigues D, Flohr P, Tunariu N, Banerji U, Ruddle R, Sharp A, Welti J, Lambros M, Carreira S, Raynaud FI, Swales KE, Plymate S, Luo J, Tovey H, Porta N, Slade R, Leonard L, Hall E, de Bono JS. A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2020 May;31(5):619-625. doi: 10.1016/j.annonc.2020.01.074. Epub 2020 Feb 21.

    PubMed 32205016

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing AZD5363 and Enzalutamide in people with Adenocarcinoma of the Prostate, run by Institute of Cancer Research, United Kingdom at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 8 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact RE-AKT Trial Manager (RE-AKT-icrctsu@icr.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I: Type, frequency, severity, seriousness and relatedness of adverse events (time frame: 35 days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02525068, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Aug 2018.

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