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A Phase I Study of Single-agent MK-1775, a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Neoplasms, Lymphoma

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Trial Information

A Phase I Study of Single-agent MK-1775, a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors


BACKGROUND:

- 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
tumor xenografts.

- 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.

PRIMARY OBJECTIVE:

- 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

SECONDARY OBJECTIVES:

- 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

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 4 weeks prior to entering the study

- Adequate organ function

Study Design:

- 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.

Inclusion Criteria


- 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.

- Patients must have completed any chemotherapy, radiation therapy, surgery, or
biologic therapy greater than or equal to 4 weeks 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. Patients must have recovered to
eligibility levels from prior toxicity or adverse events.

- Age greater than or equal to18 years of age.

- ECOG performance status less than or equal to 2 (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

- 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 MK-1775 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 and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of
study participation, and 2 months after completion of MK-1775 administration.

- 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.

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 MK-1775 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 is prohibited.

- 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors

Outcome Time Frame:

January, 2014

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

130032

NCT ID:

NCT01748825

Start Date:

November 2012

Completion Date:

September 2015

Related Keywords:

  • Neoplasms
  • Lymphoma
  • MK-1775
  • Refractory
  • Solid Tumors
  • Wee1 Inhibitor
  • Tyrosine Kinase
  • Neoplasms
  • Lymphoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892