Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours
Condition: Advanced Solid Malignancies; Breast Cancer - ER+, HER2 -; Breast Cancer - ER+, HER2-, PIK3CA Gene Mutation
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      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).
    

Intervention name(s): AZD8835; AZD8835; AZD8835 in combination with fulvestrant; AZD8835 in combination with fulvestrant
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components; AZD 8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components; AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy.; AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy
Other intervention name(s): Faslodex; Faslodex
Intervention MeSH terms: Fulvestrant
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AZD8835; Fulvestrant; Breast Cancer; PIK3CA Gene Mutation