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Phase I Study of MK-1775 With Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients With Recurrent Glioblastoma.


Phase 1
18 Years
N/A
Not Enrolling
Both
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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Trial Information

Phase I Study of MK-1775 With Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients With Recurrent Glioblastoma.


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) of MK-1775 (WEE1 inhibitor MK-1775) in
combination with the current standard of care (radiotherapy/temozolomide for concomitant
therapy and temozolomide for adjuvant therapy) for treating patients with newly diagnosed
glioblastoma.

II. To define the MTD of MK-1775 in combination with 6 weeks of daily (Monday-Friday [M-F])
radiotherapy (RT) and concomitant temozolomide (TMZ) administered at 75 mg/m^2/day in
patients with newly diagnosed glioblastoma. (Arm 1) III. To define the MTD of MK-1775 in
combination with adjuvant TMZ administered at 150 mg/m^2/day-200 mg/m^2/day for 5 days every
28 days in patients with glioblastoma after concurrent RT/TMZ. (Arm 2)

SECONDARY OBJECTIVES:

I. To characterize the safety profile of MK-1775 in combination with RT and concomitant TMZ
(Arm 1) and MK-1775 with adjuvant TMZ (Arm 2) in patients with newly diagnosed glioblastoma.

II. To assess the pharmacokinetic (PK) profile of MK-1775 in combination with upfront
radiation/TMZ and adjuvant TMZ in patients with newly diagnosed glioblastoma.

TERTIARY OBJECTIVES:

I. To determine the intratumoral concentration of MK-1775 achieved in patients treated with
the putative MTD.

II. To characterize the time course of MK-1775 in extracellular fluid within brain tumors
following a single oral dose of drug by microdialysis.

III. To characterize O6-methylguanine deoxyribonucleic acid (DNA)-methyltransferase (MGMT)
methylation and tumor protein p53 (P53) pathway status, also P-glycoprotein (P-gp) and wee1
expression levels in patients with newly diagnosed glioblastoma treated with standard
therapy in combination with MK-1775.

OUTLINE: This is a dose-escalation study of WEE1 inhibitor MK-1775. Patients are assigned to
1 of 2 treatment arms.

ARM I:

INITIATION COURSE: Patients receive WEE1 inhibitor MK-1775 orally (PO) on days 1, 3, and 5
or 1-5 weekly and temozolomide PO once daily (QD) for 6 weeks. Patients also undergo
concurrent radiation therapy 5 days per week for 6 weeks.

MAINTENANCE COURSES: Beginning in week 10, patients receive temozolomide PO QD on days 1-5.
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive WEE1 inhibitor MK-1775 PO QD on days 1, 3, and 5 or 1-5, and
temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 2 years and
then every 6 months thereafter.


Inclusion Criteria:



- Patients must have a tumor tissue form indicating availability of archived tissue
from initial resection at diagnosis of glioblastoma completed and signed by a
pathologist

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 × institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
ml/min/1.73m^2 for patients with creatinine levels above institutional normal

- Activated partial thromboplastin time (APTT) =< 1.5 x institutional upper limit of
normal

- Patients must be able to provide written informed consent

- Patients must have magnetic resonance imaging (MRI) within 21 days of starting
treatment

- Women of childbearing potential must have a negative serum pregnancy test prior to
study entry; women of childbearing potential and men must agree to use two birth
control methods (either two barrier methods or a barrier method plus a hormonal
method) or abstinence prior to study entry and for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
bladder; patients with prior malignancies must be disease-free for >= five years

- Patients must be maintained on a stable corticosteroid regimen (no increase for 5
days) prior to the start of treatment

- Patients must be able to swallow whole capsules

- PHASE I PATIENTS:

- Must have histologically proven glioblastoma

- Must have recovered from the immediate post-operative period

- Patients going on Arm 1 or combination dose cohort must not have received prior
radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent
(including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists,
interferons, interleukins, tumor infiltrating lymphocytes [TIL], lymphokine-activated
killer [LAK] or gene therapy), or hormonal therapy for their brain tumor;
glucocorticoid therapy is allowed

- Patients going on Arm 2 must have received planned treatment with radiation therapy
and concomitant temozolomide at least 28 days but no more than 49 days prior to
starting treatment on this study; patients must have received at least 80% of planned
temozolomide and radiation therapy with no grade 3 or grade 4 toxicity attributed to
the temozolomide; Arm 2 patients may not have received any other prior chemotherapy,
immunotherapy or therapy with biologic agent (including immunotoxins,
immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins,
TIL, LAK or gene therapy), or hormonal therapy for their brain tumor; prior Gliadel
Wafers are allowed; glucocorticoid therapy is allowed

- INTRATUMORAL DRUG DISTRIBUTION STUDY PATIENTS:

- Patients must have prior histologically proven glioblastoma that is progressive or
recurrent following radiation therapy +/- chemotherapy

- Patients must be undergoing repeat surgery that is clinically indicated as determined
by their care providers

- Patients must have measurable contrast-enhancing progressive or recurrent
glioblastoma by MRI within 21 days of starting treatment; patient must be able to
tolerate MRIs

- Patients may have an unlimited number of prior therapy regimens

- Patients must have recovered from severe toxicity of prior therapy; the following
intervals from previous treatments are required to be eligible:

- 12 weeks from the completion of radiation

- 6 weeks from a nitrosourea chemotherapy

- 3 weeks from a non-nitrosourea chemotherapy

- 4 weeks from any investigational (not Food and Drug Administration
[FDA]-approved) agents

- 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g.,
tarceva, hydroxychloroquine, bevacizumab, etc.)

Exclusion Criteria:

- Patients receiving any other investigational agents are ineligible

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to temozolomide or MK-1775 are ineligible; the
MK-1775 Investigator Brochure and the temozolomide package insert can be referenced
for more information

- Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for
treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic
drugs or not be taking any anti-epileptic drugs; patients previously treated with
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to
the first dose of MK-1775

- Patients may not be on drugs known to be moderate or potent inhibitors/inducers of
cytochrome P450 3A4 (CYP3A4), sensitive substrates of CYP3A4, or substrates of CYP3A4
with narrow therapeutic windows

- Patients may not be on anti-coagulants (warfarin, etc.) other than low-molecular
weight heparin (LMWH)

- Patients with 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, are ineligible

- Pregnant women are excluded from this study because MK-1775 has potential for
teratogenic or abortifacients effects; because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
MK-1775, breastfeeding should be discontinued if the mother is treated with MK-1775

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
MK-1775; in addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD of WEE1 inhibitor MK-1775 with 6 weeks of RT and temozolomide, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (Arm I)

Outcome Description:

Severity and frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experience grade 3 or above toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.

Outcome Time Frame:

Up to 6 weeks

Safety Issue:

Yes

Principal Investigator

Brian Alexander

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-00858

NCT ID:

NCT01849146

Start Date:

April 2013

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Gliosarcoma

Name

Location

Adult Brain Tumor ConsortiumBaltimore, Maryland  21231-1000