Microtubule-Targeted Agent BAL101553 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase I Study to Determine the Safety and Tolerability of the Oral Microtubule Destabilizer BAL101553 in Combination With Standard Radiation in Patients With MGMT Promoter Unmethylated Newly Diagnosed Glioblastoma

Conditions
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Glioblastoma, MGMT-Unmethylated Glioblastoma

Intervention / Treatment
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* Drug: Microtubule-Targeted Agent BAL101553
* Radiation: Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Finding<br>Fixed 3+3 dose escalation of BAL101553 (7 days per week), combined with RT days 1-5 for 6 weeks followed by 4 week rest. | Drug: Microtubule-Targeted Agent BAL101553<br>* Given PO<br>* Other names: BAL101553, Microtubule-targeted Agent BAL101553;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Cancer Radiotherapy, Irradiate, irradiated, irradiation, RADIATION, Radiation, radiation therapy, Radiation Therapy, Radiotherapeutics, radiotherapy, Radiotherapy, RT, Therapy, Radiation;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Number of Dose limited Toxicities per dose level. ANC < 500/mm3; Platelets < 25K; Febrile neutropenia; any event which prevents 80% administration of planned BAL101553 dose; >/= gr 2 CNS ischemia; >/= gr 2 neurological toxicities interfering with AODL not resolved within 2wks; gr 3/4 non-hematological, non-CNS toxicities with expections | up to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with Grade 3 and Grade 4 AEs | CTC AE 4.0 / 5.0 | up to 10 weeks | 
| Overall Survival | Median time of survival along with 95% confidence interval | initial diagnosis to date of death - up to 2 years | 
| Progression Free Survival | Median time of progression-free survival along with 95% confidence interval | initial diagnosis to date of progression - up to 2 years | 
| Maximum Plasma Concentration | PK of microtubule-targeted agent BAL101553 and BAL27862 | Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post dose on days 1 and 22 | 
| Time of Maximum Plasma Concentraion | PK of microtubule-targeted agent BAL101553 and BAL27862 | Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post dose on days 1 and 22 | 
| Area Under the Concentration-time Curve (AUC) | PK of microtubule-targeted agent BAL101553 and BAL27862 | Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post dose on days 1 and 22 |