Clinical Trials /

AZD5363 in Patients With Advanced Solid Tumors Harboring AKT Mutations

NCT03310541

Description:

This study will test the recommended dose of AZD5363 (recommended from a previous phase 1 study of the drug) in patients with specific AKT mutations. In patients who have ER positive breast cancer with an AKT mutation, they will also be receiving a standard breast cancer drug called fulvestrant that is given as an injection. In patients who have prostate cancer with an AKT mutation, they will also be receiving a standard prostate cancer drug called enzalutamide that is taken orally.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AZD5363 in Patients With Advanced Solid Tumors Harboring AKT Mutations
  • Official Title: A Pilot Study of AZD5363 for Patients With Advanced Solid Tumors Harboring Mutations in AKT1, AKT2, or AKT3

Clinical Trial IDs

  • ORG STUDY ID: 17-322
  • NCT ID: NCT03310541

Conditions

  • Breast Cancer
  • Prostate Cancer
  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
AZD5363Prostate, Previously treated with Enzalutamide
EnzalutamideProstate, Previously treated with Enzalutamide
FulvestrantER+ Breast, Previously treated with Fulvestrant

Purpose

This study will test the recommended dose of AZD5363 (recommended from a previous phase 1 study of the drug) in patients with specific AKT mutations. In patients who have ER positive breast cancer with an AKT mutation, they will also be receiving a standard breast cancer drug called fulvestrant that is given as an injection. In patients who have prostate cancer with an AKT mutation, they will also be receiving a standard prostate cancer drug called enzalutamide that is taken orally.

Trial Arms

NameTypeDescriptionInterventions
Prostate, Previously treated with EnzalutamideExperimental28-DAY CYCLE AZD5363 400mg PO twice daily for 4 days on, 3 days off, every week + Enzalutamide 160 mg PO once daily
  • AZD5363
  • Enzalutamide
ER+ Breast, Previously treated with FulvestrantExperimental28-DAY CYCLE AZD5363 400mg PO twice daily for 4 days on, 3 days off, every week + Fulvestrant 500mg IM days 1, 15, 29 (cycle 2 day 1) and then every 4 weeks
  • AZD5363
  • Fulvestrant
Advanced Solid TumorsExperimental28-DAY CYCLE AZD5363 480mg PO twice daily for 4 days on, 3 days off, every week
  • AZD5363

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed recurrent or metastatic advanced solid tumor, for which there
             is no curative-intent treatment option and confirmation of the presence of AKT1, AKT2,
             or AKT3 mutations detected by the MSK-IMPACT assay platform or other CLIA-approved
             test

          -  ER+ breast cancer patients must have received and progressed on Fulvestrant and be
             post-menopausal

          -  Prostate cancer patients must have received and progressed on enzalutamide

          -  Age ≥ 18 years

          -  ECOG performance status ≤ 1

          -  Life expectancy of ≥ 12 weeks

          -  Measurable disease as defined by the tumor specific relevant response criteria for the
             breast and other solid tumor cohorts (measurable disease is not required for
             enrollment in the prostate cancer cohort):

               -  RECIST version 1.1 criteria

               -  Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria.

               -  RANO criteria

          -  Females should be using adequate contraceptive measures (see Section 0), should not be
             breast feeding and must have a negative pregnancy test prior to start of dosing if of
             child-bearing potential or must have evidence of non-child-bearing potential by
             fulfilling one of the following criteria at screening:

               -  Post-menopausal defined as:

               -  Aged more than 50 years and amenorrhoeic for at least 12 months following
                  cessation of all exogenous hormonal treatments

               -  Estradiol, FSH and LH levels in post-menopausal range while receiving LHRH
                  analogues for medical castration in patients with breast cancer.

               -  Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
                  oophorectomy or bilateral salpingectomy but not tubal ligation.

          -  Male patients should be willing to use barrier contraception (i.e. condoms)

        Exclusion Criteria:

          -  ER+ breast cancer patients harboring the AKT1 E17K mutation (patient population tested
             in MSK IRB# 14-214, study D3610C00001 part E, ClinicalTrials.gov NCT01226316).

          -  No known activating mutations in KRAS, NRAS, HRAS and BRAF

          -  Diabetes mellitus type 1

          -  Fasting plasma glucose [fasting is defined as no calorific intake for at least 8
             hours]:

               -  ≥ 126 mg/dL for those patients without a pre-existing diagnosis of Type 2
                  diabetes mellitus

               -  ≥ 167mg/dL for those patients with a pre-existing diagnosis of Type 2 diabetes
                  mellitus

          -  Glycosylated haemoglobin (HbA1C) ≥8.0%

          -  Requirement for insulin for routine diabetic management and control

          -  Requirement for >2 oral hypoglycaemic medications for routine diabetic management and
             control

          -  Treatment with any of the following:

               -  Any investigational agents or study drugs from a previous clinical study within
                  30 days of the first dose of study treatment

               -  Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks or 5
                  half lives, whichever is shorter, of the first dose of study treatment, except
                  fulvestrant, enzalutamide or hormonal therapy with LHRH analogues for medical
                  castration in patients with breast or prostate cancer, which are permitted

               -  Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6
                  within 2 weeks before the first dose of study treatment (3 weeks for St John‟s
                  Wort).

               -  Major surgery (excluding placement of vascular access) within 4 weeks of the
                  first dose of study treatment

               -  Radiotherapy with a wide field of radiation within 4 weeks of the first dose of
                  study treatment

               -  AKT inhibitors

          -  With the exception of alopecia, any unresolved toxicities from prior therapy greater
             than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of
             starting study treatment

          -  Spinal cord compression or brain metastases unless asymptomatic, treated and stable
             and not requiring steroids for at least 4 weeks prior to start of study treatment

          -  As judged by the investigator, any evidence of severe or uncontrolled systemic
             diseases, including active bleeding diatheses, or active infection including hepatitis
             B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is
             not required.

          -  Any of the following cardiac criteria:

               -  Resting corrected QT interval (QTc) > 480 msec obtained from electrocardiogram
                  (ECG)

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting electrocardiogram (ECG) eg, 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

               -  Experience of any of the following procedures or conditions in the preceding 6
                  months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
                  infarction, angina pectoris, congestive heart failure New York Heart Association
                  (NYHA) Grade ≥2

               -  Uncontrolled hypotension - Systolic blood pressure (BP) <90mmHg and/or diastolic
                  BP <50mmHg

               -  Left ventricular ejection fraction (LVEF) below lower limit of normal for site.

          -  Inadequate bone marrow reserve or organ function as demonstrated by any of the
             following laboratory values:

               -  Absolute neutrophil count < 1 x 10^9/L

               -  Platelet count < 100 x 10^9/L

               -  Haemoglobin < 9.0 g/dL

               -  ALT > 2.5 times the upper limit of normal (ULN) if no demonstrable liver
                  metastases, or >5 times ULN in presence of liver metastases

               -  AST > 2.5 times ULN if no demonstrable liver metastases, or >5 times ULN in
                  presence of liver metastases.

               -  Total bilirubin > 1.5 times ULN (patients with confirmed Gilbert‟s syndrome may
                  be included in the study)

               -  Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min;
                  confirmation of creatinine clearance is only required when creatinine is > 1.5
                  times ULN

               -  Proteinuria 3+ on dipstick analysis or >500 mg/24 hours

               -  Sodium or potassium outside normal reference range for site

          -  Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
             swallow the formulated product or previous significant bowel resection that would
             preclude adequate absorption of AZD5363

          -  History of hypersensitivity to active or inactive excipients of AZD5363, fulvestrant
             and enzalutamide or drugs with a similar chemical structure or class to these agents.

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:number of patients with an objective response rate (ORR) of AZD5363
Time Frame:1 year
Safety Issue:
Description:A response is defined as any of the following: a response according to RECIST v 1.1, PCWG3 (for patients with measurable visceral and/or nodal disease at baseline) or RANO as applicable or a reduction in the PSA level of 50% or more (for prostate cancer patients without visceral and/or nodal disease at baseline), with a confirmatory assessment at least 4 weeks later.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • AZD5363
  • AKT Mutations
  • 17-322

Last Updated

October 11, 2017