Clinical Trials /

Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours

NCT02260661

Description:

First time in patients study of AZD8835. The study has four parts. Part A AZD8835 is administered as a single agent in a multiple ascending dose escalation phase to investigate dose level for monotherapy. Part B follows the multiple ascending dose phase, additional patients with tumors with documented PIK3CA gene mutation will be enrolled to a single dose expansion phase. Part C is a second dose escalation phase in which post-menopausal patients with estrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in combination with fulvestrant. Part D follows the combination dose escalation phase of the study, additional postmenopausal patients with ER+/HER2 negative breast cancer with documented PIK3CA gene mutation will be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at maximum tolerated dose or recommended phase II dose.

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

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours
  • Official Title: A Phase I, Open-Label, Multicentre, Dose-Escalation Study to Investigate the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours

Clinical Trial IDs

  • ORG STUDY ID: D6140C00001
  • NCT ID: NCT02260661

Conditions

  • Advanced Solid Malignancies
  • Breast Cancer - ER+, HER2 -
  • Breast Cancer - ER+, HER2-, PIK3CA Gene Mutation

Interventions

DrugSynonymsArms
AZD8835Part A
AZD8835Part B
AZD8835 in combination with fulvestrantFaslodexPart C
AZD8835 in combination with fulvestrantFaslodexPart D

Purpose

First time in patients study of AZD8835. The study has four parts. Part A AZD8835 is administered as a single agent in a multiple ascending dose escalation phase to investigate dose level for monotherapy. Part B follows the multiple ascending dose phase, additional patients with tumors with documented PIK3CA gene mutation will be enrolled to a single dose expansion phase. Part C is a second dose escalation phase in which post-menopausal patients with estrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in combination with fulvestrant. Part D follows the combination dose escalation phase of the study, additional postmenopausal patients with ER+/HER2 negative breast cancer with documented PIK3CA gene mutation will be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at maximum tolerated dose or recommended phase II dose.

Detailed Description

      AZD8835 is a novel small molecule that inhibits cancer progression by blocking PI3 kinase
      pathway components p110α and p110δ.

      In this first-time-in-patient study, AZD8835 will initially be administered as a single agent
      to patients with advanced solid malignancies. Patients will be treated at a starting dose of
      20 mg twice daily (BID), administered weekly on Days 1 and 4 and will be escalated to reach a
      maximum-tolerated dose (MTD) in patients as defined by dose-limiting toxicities (DLTs). A BID
      intermittent dosing schedule administered weekly on Days 1 and 4 of an oral formulation of
      AZD8835 will be used, as deemed optimal and effective in non-clinical studies, primarily to
      determine the safety and tolerability of AZD8835. The pharmacokinetics (PK) of AZD8835 and
      potential biological activity will also be investigated. In Part A of this study, AZD8835
      will be administered as a single agent in a multiple ascending dose escalation phase to
      investigate the appropriate monotherapy dose level for clinical use. Additional dosing
      schedules may be studies, including dosing on Days 1 and 2 of each week, rather than Days 1
      and 4.

      Backfilled pharmacodynamic (PDc) cohorts in selected patients with tumours that have
      documented mutations in the phosphatidylinositol-4,5- bisphosphate 3-kinase, catalytic
      subunit alpha (PIK3CA) gene will allow further preliminary assessment of the biological
      effect of AZD8835 in these patients.

      Following the single-agent dose-escalation phase of the study, additional patients with
      tumours that have documented mutations in the PIK3CA gene will be enrolled to a single-agent
      dose-expansion phase at the MTD or recommended Phase II dose (RP2D) at the selected dose
      schedule (as appropriate) to explore further the safety, tolerability, PK, and biological
      activity at the selected dose (Part B).

      In addition, a further dose-escalation phase will be initiated following the observation of
      specific pre-determined criteria in the single-agent dose escalation, in which postmenopausal
      patients with oestrogen receptor positive (ER+), HER2 negative breast cancer will receive
      AZD8835 in combination with fulvestrant (Part C). The combination dose-escalation phase will
      investigate the appropriate combination dose level for clinical use.

      Following the combination dose-escalation phase of the study, additional postmenopausal
      patients with ER+ breast cancer and tumours with documented mutations of the PIK3CA gene will
      be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at the MTD or RP2D
      (as appropriate) to explore further the safety, tolerability, PK, and biological activity at
      the selected dose (Part D).
    

Trial Arms

NameTypeDescriptionInterventions
Part AExperimentalAZD8835 single agent dose escalation
  • AZD8835
Part BExperimentalFollowing the single agent dose escalation (Part A), additional patients with mutations in the PIK3CA gene will be enrolled to a single agent dose expansion phase at the MTD or recommended phase II dose (RP2D) at the selected dose schedule (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part B). Part B will include patients with ER+/HER2 negative breast cancer whose tumours have a mutation of the PIK3CA gene and patients with any solid tumours which have a mutation of the PIK3CA gene.
  • AZD8835
Part CExperimentalAZD8835 in combination with fulvestrant dose escalation
  • AZD8835 in combination with fulvestrant
Part DExperimentalFollowing the combination dose escalation segment of the study (Part C), additional postmenopausal patients with ER+/HER negative breast cancer and mutations of the PIK3CA gene will be enrolled to a AZD8835 and fulvestrant combination dose expansion phase at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part D).
  • AZD8835 in combination with fulvestrant

Eligibility Criteria

        Inclusion Criteria:

          1. Part A: Histological or cytological confirmation of a solid tumor and disease
             progression. Part B: Histological or cytological confirmation of ER positive, HER2
             negative breast cancer and disease progression or any other solid tumor with a PIK3CA
             gene mutation. Part C: Histological or cytological confirmation of ER positive, HER2
             negative postmenopausal breast cancer with locally advanced or metastatic disease that
             is eligible for fulvestrant treatment. Part D: Histological or cytological
             confirmation of ER positive, HER2 negative postmenopausal breast cancer with locally
             advanced or metastatic disease that is eligible for fulvestrant treatment. Patients
             must also present with a tumor related mutation of the PIK3CA gene.

          2. Availability of archival tumour tissue sample. If archival sample is not available, a
             fresh tumour biopsy must be provided.

          3. At least one measurable lesion per RECIST v1.1. However, breast cancer patients with
             only bone disease are also eligible.

          4. ECOG Performance Status 0-1.

          5. Adequate organ function at baseline:

               1. Serum total bilirubin ≤ 1.5 x ULN and AST/SGOT and ALT/SGPT ≤ 2.5 x ULN or ≤ 5 x
                  ULN if liver metastases are present.

               2. Creatinine ≤ 1.5 x ULN, or calculated or measured creatinine clearance ≥ 50
                  mL/min, or 24-hour measured urine creatinine clearance ≥ 50 mL/min.

               3. Platelets ≥ 100 x 10^9, Hb ≥ 90 g/L, ANC ≥ 1.5 x 10^9/L.

               4. aPTT ≤ 1.5 x ULN

               5. Fasting glucose < 140 mg/dL (7.8 mmol/L).

               6. Glycated haemoglobin (HbA1c) < 8%

          6. Female patients and male patients with female partners of child bearing potential must
             be using adequate contraception.

        Exclusion Criteria:

          1. Recent chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational
             drugs within 21 days or 5 half-days from enrolment.

          2. Received palliative/focal radiotherapy within 2 weeks of first dose of study
             treatment.

          3. Major surgery ≤ 21 days from beginning of study drug

          4. Any of the following cardiac criteria: CHF > Class II, cardiac ventricular arrhythmia
             requiring therapy, unstable angina or new-onset angina, QTcF interval >470ms, abnormal
             ECHO or MUGA at baseline (LVEF <50%).

          5. Leptomeningeal disease

          6. Part A: Intolerable AEs due to other PI3K inhibitors, dual PI3K and mTOR inhibitors or
             AKT inhibitors. Parts B, C, and D: Prior exposure to any of the following:
             pharmacological inhibitors of AKT, PI3K, or dual PI3K and mTOR kinase activity

          7. Strong inhibitors and potent inducers of CYP3A4

          8. Peripheral neuropathy CTCAE v4.03 Grade ≥ 3

          9. Diarrhoea CTCAE v4.03 Grade ≥ 2

         10. Acute or chronic pancreatitis

         11. Clinically manifest diabetes mellitus, history of gestational diabetes mellitus and/or
             known glucose intolerance.

         12. Patients currently receiving any medication that has the potential to prolong the QT
             interval or induce Torsades de Pointes

         13. Spinal cord compression or brain metastases unless asymptomatic and not requiring
             steroids for at least 4 weeks

         14. Patients in the combination arms - known hypersensitivity to fulvestrant

         15. Therapeutic treatment with Coumadin or any other coumarin-derivative anticoagulant

         16. Impaired GI function or GI disease that may interfere with absorption of AZD8835 or
             patients unable to take oral medication

         17. As judged by the investigator any evidence of severe or uncontrolled systemic disease

         18. Patients treated with hematopoietic colony-stimulating growth factors e.g., G-CSF,
             GM-CSF, M-CSF) ≤ 2 weeks prior to start. Erythropoietin or darbepoetin is allowed if
             it was initiated at least 2 weeks prior to entry
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the maximum tolerated dose (MTD) or recommended Phase II dose of oral AZD8835 as a single agent and in combination with fulvestrant
Time Frame:At the end of one cycle of treatment
Safety Issue:
Description:MTD - A dose will be considered non-tolerated and dose escalation will stop if 2 or more of up to 6 evaluable patients experience a dose limiting toxicity at a dose level. Once the non-tolerated dose is defined, the MTD will be confirmed at the previous dose level below the non-tolerated dose or a dose between the non-tolerated dose and the last tolerated dose my be investigated. A minimum of 6 evaluable patients are required to determine the MTD. Recommended Phase II dose - A minimum of 6 evaluable patients is necessary to determine the recommended dose. A dose will be considered non-tolerated and dose escalation will stop if 2 or more patients experience a dose dose limiting toxicity at a dose level.

Secondary Outcome Measures

Measure:To establish the pharmacokinetic profile of oral AZD8835 as a single agent and in combination with fulvestrant
Time Frame:Venous blood samples will be collected pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 96 hours post dose - exact schedule varies according to Part A, B, C, or D
Safety Issue:
Description:Venous blood samples (2 mL) for determination of concentrations of AZD8835 and the investigation of AZ8835 metabolites in plasma will be taken during Parts A, B, C, D
Measure:To evaluate the preliminary efficacy and anti-tumor activity of oral AZD8835 as a single agent or in combination with fulvestrant
Time Frame:Tumour response will be assessed at the completion of Cycle 2 (Week 8) and patients will be restaged after every 8 weeks for up to 1 year and every 12 weeks thereafter; assessments should be performed until disease progression.
Safety Issue:
Description:Categorization of objective tumor response will be based on RECIST v1.1 guidelines for complete response, partial response, stable disease, or progression of disease
Measure:To evaluate the pharmacodynamic (PDc) effect of oral AZD8835 as a single agent and in combination with fulvestrant
Time Frame:Tumour biopsies will be collected: (1) at pretreatment, (2) at one on-treatment time point (preferably Cycle 2 Day 1), and (3) at end of study treatment (preferably at disease progression)
Safety Issue:
Description:Tumor samples will be analyzed to assess PRAS40 phosphorylation, AKT phosphorylation, S6 phosphorylation, FOXO3a localisation

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:AstraZeneca

Trial Keywords

  • AZD8835
  • Fulvestrant
  • Breast Cancer
  • PIK3CA Gene Mutation

Last Updated

October 7, 2016