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.