AZD1775 for Advanced Solid Tumors

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 DNA damage to allow time for DNA repair. Recent preclinical data
additionally implicates Wee1 in maintenance of genomic integrity during S phase.

- 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, 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 MTD is established, 6 additional patients will be enrolled at the MTD to further
evaluate that dose for PK and PD endpoints.

- A further expansion arm of 6 additional patients with documented tumors harboring 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 (yH2AX, pNbs1, Rad51, 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.

- ELIGIBILITY CRITERIA:

- 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.

- Patients must have measurable disease or evaluable disease for the escalation phase;
for the 6 additional patients enrolled at MTD for further evaluation of PK and PD
endpoints (Expansion Cohort A). For the 6-patient BRCA-mutation expansion cohort,
patients must have measurable disease; however, tumor biopsies are optional. For
Expansion Cohort B, patients must have tumor amenable to biopsy (excisional or
incision biopsies of skin or H & N lesions under visualization) and willingness to
undergo a tumor biopsy or patient will be undergoing a procedure due to medical
necessity during which the tissue may be collected, or tumor biopsy tissue from a
previous research study or medical care is available for submission at registration.
Criteria for the submission of tissue are:

- Tissue must have been collected within 3 months prior to registration

- Patient has not received any intervening therapy for their cancer since the
collection of the tumor sample

- Tumor tissue must meet the minimum requirements

- Patients must have completed any chemotherapy, radiation therapy, surgery, or biologic
therapy greater than or equal to 3 weeks (or > 5 half-lives, whichever is shorter)
prior to entering the study. Patients must be greater than or equal to 2 weeks since
any prior administration of a study drug in an exploratory IND/Phase 0 study or more
than or equal to 1 week from palliative radiation therapy. Patients must have
recovered to eligibility levels from prior toxicity or adverse events.

- Age greater than or equal to 18 years of age.

- ECOG performance status less than or equal to 1 (Karnofsky >60%)

- Life expectancy of greater than 3 months.

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- hemoglobin >9 g/dL

- total bilirubin less than or equal to 1.5 times institutional upper limit of
normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of
normal

- creatinine less than or equal to 1.5 times institutional upper limit of normal OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients
with creatinine levels above institutional normal.

- The effects of AZD1775 on the developing human fetus are unknown. For this reason and
because molecular inhibitors of Wee1 kinase are known to be teratogenic, women of
child-bearing potential (WoCBP) may be included only if acceptable contraception is in
place for two weeks before study entry, for the duration of the treatment with the
study drug, and for 2 months after the last dose of AZD1775. Male patients who are
involved in the study must agree to avoid procreative and unprotected sex (i.e., by
using acceptable forms of contraception) and must not donate sperm during the study
and for 3 months after the last dose of AZD1775. Where the female partner is pregnant
or not using effective birth control, men should be advised to abstain while in the
study and for 3 months after the last dose of AZD1775. Female partners, who are of
child-bearing potential, of men participating in clinical studies of AZD1775 will also
be required to use effective contraceptive measures while their partner is on study
drug and for 3 months thereafter. Male patients will be advised to arrange for the
freezing of sperm samples prior to the start of the study should they wish to father
children while on AZD1775 or during the 3 months after stopping AZD1775.

- Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with the study drugs, breastfeeding should be
discontinued prior to the first of study drug and women should refrain from nursing
throughout the treatment period and for 14 days following the last dose of study drug.

- Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube
administration is not allowed. Any gastrointestinal disease which would impair ability
to swallow, retain, or absorb drug is not allowed.

- Ability to understand and the willingness to sign a written informed consent document.

- Patients with prostate cancer can continue to receive treatment with GnRH agonists
while on study, as long as there is evidence of disease progression on therapy.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- Patients with known active brain metastases or carcinomatous meningitis are excluded
from this clinical trial. Patients whose brain metastatic disease status has remained
stable for greater than or equal to 4 weeks following treatment of brain metastases
are eligible to participate at the discretion of the principal investigator.

- Eligibility of subjects receiving any medications or substances with the potential to
affect the activity or pharmacokinetics of AZD1775 will be determined following review
by the principal investigator.

- Patients receiving any medications or substances that are inhibitors or inducers of
CYP3A4, or CYP3A4 substrates need to be reviewed by the principal investigator.
Continuation of such medications will be at the discretion of the principal
investigator. Concomitant use of aprepitant or fosaprepitant is prohibited. As
grapefruit and Seville oranges are known to contain moderate inhibitors of CYP3A4,
these fruits or their products (including marmalade, juice, etc.) should be avoided
while taking AZD1775. The use of sensitive substrates of CYP3A4, such as atorvastatin,
simvastatin and lovastatin, is also prohibited in this study. Herbal preparations are
not allowed throughout the study. These herbal medications include but are not limited
to: St. John's wort, kava, ephedra (mahung), gingko biloba, dehydroepiandrosterone
(DHEA), yohimbe, saw palmetto and ginseng.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because the effects of the study drugs on
the developing fetus are unknown.

- HIV positive patients on antiretroviral therapy are ineligible because of the
potential for PK interactions.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women of all races and ethnic groups are eligible for this trial.