This phase I trial studies the side effects and best dose of microtubule-targeted agent
BAL101553 when given together with radiation therapy in treating patients with newly
diagnosed glioblastoma. Drugs used in chemotherapy, such as microtubule-targeted agent
BAL101553, work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy
uses high-energy x-rays to kill tumor cells and shrink tumors. Giving microtubule-targeted
agent BAL101553 and radiation therapy may work better in treating patients with glioblastoma.
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose of microtubule-targeted agent BAL101553
(BAL101553) in combination with standard radiation in patients with newly diagnosed MGMT
promoter unmethylated glioblastoma (GBM).
SECONDARY OBJECTIVES:
I. To estimate safety and tolerability of the combination of BAL101553 in combination with
standard radiation in patients with newly diagnosed MGMT promoter unmethylated GBM.
II. To determine overall and progression-free survival. III. To assess the pharmacokinetics
of BAL101553 and BAL27862. IV. To explore expression of biomarkers, including BubR1, stathmin
and EB1 at baseline (exploratory biomarkers).
OUTLINE: This is a dose escalation study of the microtubule-targeted agent BAL101553.
Patients receive microtubule-targeted agent BAL101553 orally (PO) once daily (QD) on days
1-42 and undergo concomitant standard radiation therapy 5 days per week for 6 weeks in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and then every 2
months for 2 years and then every 6 months thereafter.
Inclusion Criteria:
- Patients must have histologically-proven GBM
- Patients must have recovered from the immediate post-operative period
- Patients must have tumor MGMT methylation status of unmethylated as determined by
local pathologist using a Clinical Laboratory Improvement Act (CLIA)-approved
diagnostic test; results of routinely-used methods for MGMT methylation testing (e.g.
methylation-specific [MS]- polymerase chain reaction [PCR] or quantitative PCR) are
acceptable
- Patients must be able to undergo magnetic resonance imaging (MRI) of the brain with
gadolinium
- Patients must not have received prior radiation therapy (RT), chemotherapy,
immunotherapy or therapy with a biologic agent (including immunotoxins,
immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins,
tumor-infiltrating lymphocytes, lymphokine-activated killer cells, or gene therapy),
or hormonal therapy for their brain tumor; glucocorticoid therapy is allowed
- Patients must have a tumor tissue form indicating availability of archived tissue from
initial resection at diagnosis of GBM, 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 =< 1.5 x institutional upper limit of normal (ULN), unless the patient
has known Gilbert's syndrome
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x ULN
- Creatinine =< 1.5 x ULN
- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > ULN
- Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5
x ULN
- Sodium >= 130 mmol/L
- Patients must be able to provide written informed consent
- Patients must have baseline MRI performed within the 21 days prior to starting
treatment
- Women of childbearing potential must have a negative serum pregnancy test within 72
hours prior to the first dose of BAL101553; women of childbearing potential must agree
to use highly-effective contraceptive methods for the duration of study participation
and for an additional 90 days after the last dose of study drug; highly-effective
contraceptive methods include male or female sterilization (bilateral tubal occlusion
or vasectomy); intrauterine device (IUD); combined (estrogen- and
progesterone-containing) hormonal contraception (oral, vaginal ring or transdermal
patch) with an ethinylestradiol dose of at least 30 ug, plus use of male condoms
(preferably with spermicides), female condoms, a female diaphragm or a cervical cap;
or total sexual abstinence; should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately; male patients must agree not to donate sperm from the first dose of study
drug until 90 days after the end of treatment; male patients, without a vasectomy and
with a partner of childbearing potential, must agree to use condoms during the study
and for at least 90 days after the end of treatment; the patient should be instructed
that their female partner should use another form of contraception for the duration of
the study and continue this use for at least 90 days after the last dose of study drug
- 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 >= 5 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
Exclusion Criteria:
- Patients receiving any other investigational agents
- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to BAL101553
- Patients on drugs that are strong inhibitors and/or inducers of CYP2C9, CYP2C19 or
CYP3A4 (including enzyme-inducing anti-epileptic drugs [EIAEDs]), are not eligible for
treatment under this protocol; patients taking non-EIAEDs are permitted to take part
in the study; patients previously treated with any of the prohibited concomitant
medications listed above may be enrolled if they have been off of the medication for
>= 10 days prior to the first dose of BAL101553
- Patients may not be on coumarin anti-coagulants (warfarin, etc.); heparin,
low-molecular weight heparin (LMWH), or other antithrombotic medications are permitted
- Patients with gastrointestinal disease, or those who have had a procedure that is
expected to interfere with the oral absorption or tolerance of BAL101553 (e.g.,
functionally-relevant gastrointestinal obstruction, or frequent vomiting unresolved
upon anti-emetic supportive care)
- Patients with peripheral neuropathy >= Common Terminology Criteria for Adverse Events
(CTCAE) grade 2
- Patients with ataxia >= CTCAE grade 2
- Patients with known acute or chronic hepatitis B or hepatitis C infection \
- Patients with systolic blood pressure (SBP) >= 140 mmHg or diastolic blood pressure
(DBP) >= 90 mmHg at the screening visit are ineligible; patients with an initial
clinic blood pressure (BP) >= 140/90 mmHg may be included if SBP < 140 mmHg and DBP <
90 mmHg is confirmed in two subsequent BP measurements on the same day
- Patients with blood pressure (BP) combination treatment with more than two
antihypertensive medications are ineligible
- Significant cardiac disease or abnormality, including any one of the following:
- Left ventricular ejection fraction < 50% at screening (assessed by
echocardiography, cardiac MRI or multigated acquisition [MUGA])
- Corrected QT Fridericia's correction formula (QTcF) > 470 ms on screening
electrocardiogram (ECG), or a clinically-relevant ECG abnormality
- Congenital long QT syndrome
- History of sustained ventricular tachycardia, ventricular fibrillation, or
torsades de pointes
- Presence of atrial fibrillation with tachyarrhythmia (ventricular response rate >
100 beats per minute [bpm])
- Bradycardia (heart rate < 50 bpm)
- Complete left bundle branch block.
- Bifascicular block (complete right bundle branch block and anterior or posterior
left hemiblock)
- Myocardial infarction, acute coronary syndrome (including unstable angina),
coronary revascularization procedures, or coronary arterial bypass grafting
within the 6 months prior to starting study drug
- Cardiac troponin (either troponin T or troponin I) > ULN
- Congestive heart failure of New York Heart Association class III or IV
- Unstable angina pectoris
- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection or psychiatric illness/social situations that would limit
compliance with study requirements, are ineligible
- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with BAL101553
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible
