A Phase I Study of Single-agent MK-1775, a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors
- Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of
cyclindependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest
in response to DNA damage to allow time for DNA repair. Recent preclinical data
additionally implicates Wee1 in maintenance of genomic integrity during S phase.
- MK-1775 is a selective inhibitor of Wee1 kinase. Recent preclinical model data
additionally show single agent anti-tumor activity in multiple cancer cell lines and
- Preliminary data show MK-1775 is tolerable at lower doses in combination with
chemotherapeutic agents. We propose to demonstrate single-agent activity for MK-1775.
- To establish the safety and tolerability of single-agent MK-1775 in patients with
refractory solid tumors
- To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors
- To determine the effect of MK-1775 on markers of DNA damage and apoptosis in tumor
tissue and circulating tumor cells
- To evaluate the antitumor activity of MK-1775 in patients with refractory solid tumors
- 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 4 weeks prior to entering the study
- Adequate organ function
- This study will follow a traditional 3+3 design.
- For dose level 1, MK-1775 will be administered orally for 5 doses each cycle. Starting
at dose level 2 and onwards, MK-1775 will be administered orally for 5 doses for the
first 2 weeks of each cycle . Each cycle is 21 days ( 1 day for scheduling).
- Once MTD is established, 6 additional patients will be enrolled at the MTD to further
evaluate that dose for PK and PD endpoints.
- During the escalation phase, tumor biopsies will be optional and will be evaluated for
pharmacodynamic (PD) studies for evidence of DNA damage, repair, and apoptosis (H2AX,
pNbs1, ERCC1, and caspase 3). During the expansion phase, once MTD is reached,
mandatory paired tumor biopsies will be pursued in the 6 additional patients enrolled
at the MTD to further evaluate PD endpoints.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|