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

NCT02525068 | Unknown Phase 2 DMC

• 5 other identifiers: ICR-CTSU/2012/100372013-004091-34CRUKE/12/050ISRCTN17168679ISS53630011
• Study Type: interventional
• Target: 136
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Adenocarcinoma of the Prostate

Keywords

enzalutamide; AZD5363; Prostate

Outcome Measures

Primary Outcomes (4)

• 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

  35 days

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

  35 days

• 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

  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

• 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

  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)

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

  35 days

• Phase I - Antitumour activity of the combination

  35 days

• Randomised phase II and phase II expansion - Overall survival and radiographic progression free survival

  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

• Maximum PSA decline and circulating tumour cell (CTC) fall

  12 weeks

• Pain Palliation - Randomised phase II only

  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

Study Arms (3)

Phase ISafety Run-In

EXPERIMENTAL

18 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.

Drug: AZD5363; Drug: Enzalutamide

Randomised phase II

PLACEBO COMPARATOR

100 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.

Drug: AZD5363; Drug: Enzalutamide

Single stage phase II expansion cohort

EXPERIMENTAL

Following 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

Drug: AZD5363; Drug: Enzalutamide

Interventions

AZD5363 DRUG

Until confirmed disease progression.

Phase ISafety Run-In; Randomised phase II; Single stage phase II expansion cohort

Enzalutamide DRUG

Until confirmed disease progression.

Also known as: MDV3100, Xtandi

Phase ISafety Run-In; Randomised phase II; Single stage phase II expansion cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: lead
• Royal Marsden NHS Foundation Trust: collaborator

Study Sites (1)

Royal Marsden Hospital

Sutton, Surrey, SM2 5PT, United Kingdom

RECRUITING

Related Publications (1)

• 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.

  PMID: 32205016 DERIVED

MeSH Terms

Interventions

capivasertib; enzalutamide

Study Officials

• Johann De Bono, Professor

  Institute of Cancer Research, United Kingdom

  PRINCIPAL INVESTIGATOR

Central Study Contacts

RE-AKT Trial Manager

CONTACT

RE-AKT-icrctsu@icr.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2015
• First Posted: August 17, 2015
• Study Start: December 1, 2014
• Primary Completion: December 31, 2019
• Study Completion: March 1, 2020
• Last Updated: August 8, 2018

Record last verified: 2015-08

Locations

GB (1)