AZD1775 for Advanced Solid Tumors
Condition: Solid Tumors
MeSH terms: Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      BACKGROUND:

        -  Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of
           cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest
           in response to deoxyribonucleic acid (DNA) damage to allow time for DNA repair. Recent
           preclinical data additionally implicates Wee1 in maintenance of genomic integrity during
           S phase.

        -  Adavosertib (AZD1775) is a selective inhibitor of Wee1 kinase. Recent preclinical model
           data additionally show single agent anti-tumor activity in multiple cancer cell lines
           and tumor xenografts.

        -  Preliminary data show AZD1775 is tolerable at lower doses in combination with
           chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775.

      PRIMARY OBJECTIVE:

        -  To establish the safety and tolerability of single-agent AZD1775 in patients with
           refractory solid tumors

        -  To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors

      SECONDARY OBJECTIVES:

        -  To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor
           tissue and circulating tumor cells

        -  To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors

      EXPLORATORY OBJECTIVES:

      -To identify tumor genomic alterations and gene expression patterns potentially associated
      with AZD1775 antitumor activity

      ELIGIBILITY:

        -  Patients must have histologically confirmed solid tumors for which all standard therapy
           known to prolong survival have failed, or for which standard therapies do not exist.

        -  No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever
           is shorter) prior to entering the study.

        -  Adequate organ function

      STUDY DESIGN:

        -  This study will follow a traditional 3+3 design.

        -  In Arm A starting at dose level 1, AZD1775 will be administered orally, twice a day
           (BID), for 5 doses (Day (D) 1-3) during each cycle. Starting at dose level 2 and
           onwards, AZD1775 will be administered orally, BID, for 5 doses for the first 2 weeks of
           each cycle (D1-3 and 8- 10). Each cycle is 21 days (+/- 1 day for scheduling).

        -  Once maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled
           at the MTD to further evaluate that dose for pharmacokinetics (PK) and pharmacodynamics
           (PD) endpoints.

        -  A further expansion arm of 6 additional patients with documented tumors harboring breast
           cancer type 1 or 2 (BRCA)-1 or -2 mutations will also be enrolled at the MTD to further
           explore the safety of the agent and obtain preliminary evidence of activity in this
           patient population.

        -  Based on preliminary evidence of drug activity in an alternative once-daily dosing
           schedule, patients without a documented BRCA mutation will be accrued to a once-daily
           dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated
           single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally
           once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1
           day for scheduling).

        -  During the escalation phase, tumor biopsies will be optional and will be evaluated for
           pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and
           apoptosis (gamma H2A histone family member X (yH2AX), phosphorylated Nbs1 (pNbs1),
           Rad51, Rabbit polyclonal phospho-cyclin-dependent kinases (pTyr15-Cdk) and caspase 3).
           During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be
           pursued in up to 20 additional patients enrolled at the MTD to further evaluate PD
           endpoints.
    

Detailed description: 
      BACKGROUND:

        -  Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of
           cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest
           in response to deoxyribonucleic acid (DNA) damage to allow time for DNA repair. Recent
           preclinical data additionally implicates Wee1 in maintenance of genomic integrity during
           S phase.

        -  Adavosertib (AZD1775) is a selective inhibitor of Wee1 kinase. Recent preclinical model
           data additionally show single agent anti-tumor activity in multiple cancer cell lines
           and tumor xenografts.

        -  Preliminary data show AZD1775 is tolerable at lower doses in combination with
           chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775.

      PRIMARY OBJECTIVE:

        -  To establish the safety and tolerability of single-agent AZD1775 in patients with
           refractory solid tumors

        -  To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors

      SECONDARY OBJECTIVES:

      -To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors

      EXPLORATORY OBJECTIVES:

      -To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor

      tissue and circulating tumor cells

        -  To assess whether sufficient Wee1 inhibition is maintained throughout the therapeutic
           regimen

        -  To identify tumor genomic alterations and gene expression patterns potentially
           associated withAZD1775 antitumor activity

      ELIGIBILITY:

        -  Patients must have histologically confirmed solid tumors for which all standard therapy
           known to prolong survival have failed, or for which standard therapies do not exist.

        -  No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever
           is shorter) prior to entering the study.

        -  Adequate organ function

      STUDY DESIGN:

        -  This study will follow a traditional 3+3 design.

        -  In Arm A starting at dose level 1, AZD1775 will be administered orally, twice a day
           (BID), for 5 doses (D1-3) during each cycle. Starting at dose level 2 and onwards,
           AZD1775 will be administered orally, BID, for 5 doses for the first 2 weeks of each
           cycle (D1-3 and 8- 10). Each cycle is 21 days (+/- 1 day for scheduling).

        -  Once maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled
           at the MTD to further evaluate that dose for pharmacokinetics (PK) and pharmacodynamics
           (PD) endpoints.

        -  A further expansion arm of 6 additional patients with documented tumors harboring breast
           cancer type 1 or 2 (BRCA)-1 or -2 mutations will also be enrolled at the MTD to further
           explore the safety of the agent and obtain preliminary evidence of activity in this
           patient population.

        -  Based on preliminary evidence of drug activity in an alternative once-daily dosing
           schedule, patients without a documented BRCA mutation will be accrued to a once-daily
           dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated
           single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally
           once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1
           day for scheduling).

        -  During the escalation phase, tumor biopsies will be optional and will be evaluated for
           pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and
           apoptosis (gamma H2A histone family member X (yH2AX), phosphorylated Nbs1 (pNbs1),
           Rad51, Rabbit polyclonal phospho-cyclin-dependent kinases (pTyr15-Cdk) and caspase 3).
           During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be
           pursued in up to 20 additional patients enrolled at the MTD to further evaluate PD
           endpoints.
    

Intervention name(s): MK-1775 (AZD1775)
Intervention type(s): Drug
Intervention description(s): MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.
Other intervention name(s): Adavosertib
Intervention MeSH terms: Adavosertib
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AZD1775; Adavosertib; MK-1775; Refractory; Solid Tumors; Wee1 Inhibitor; Tyrosine Kinase