Clinical Trials /

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

NCT03250299

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Microtubule-Targeted Agent BAL101553 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: ABTC 1601
  • NCT ID: NCT03250299

Conditions

  • Glioblastoma
  • MGMT-Unmethylated Glioblastoma

Interventions

DrugSynonymsArms
Microtubule-Targeted Agent BAL101553BAL101553, Microtubule-targeted Agent BAL101553Dose Level 1 8mg - BAL101553

Purpose

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

      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 microtubule-targeted agent BAL101553.

      Patients receive microtubule-targeted agent BAL101553 orally (PO) once daily (QD) on days
      1-42 and undergo 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, every 2 months for
      2 years and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level 1 8mg - BAL101553Experimental8mg BAL101553 PO (7 days per week), combined with RT days 1-5 for 6 weeks followed by 4 week rest. Off treatment after 4 week rest. Microtubule-targeted Agent BAL101553 Radiation Therapy Laboratory Biomarker Analysis Pharmacological Study
  • Microtubule-Targeted Agent BAL101553
Dose Level 2 15mg - BAL10553Experimental15mg BAL101553 PO(7 days per week), combined with RT days 1-5 for 6 weeks followed by 4 week rest. Off treatment after 4 week rest. Microtubule-targeted Agent BAL101553 Radiation Therapy Laboratory Biomarker Analysis Pharmacological Study
  • Microtubule-Targeted Agent BAL101553
Dose Level 3 20mg - BAL10553Experimental20mg BAL101553 PO(7 days per week), combined with RT days 1-5 for 6 weeks followed by 4 week rest. Off treatment after 4 week rest. Microtubule-targeted Agent BAL101553 Radiation Therapy Laboratory Biomarker Analysis Pharmacological Study
  • Microtubule-Targeted Agent BAL101553
Dose Level 4 25mg - BAL10553Experimental25mg BAL101553 (7 days per week), combined with RT days 1-5 for 6 weeks followed by 4 week rest. Off treatment after 4 week rest. Microtubule-targeted Agent BAL101553 Radiation Therapy Laboratory Biomarker Analysis Pharmacological Study
  • Microtubule-Targeted Agent BAL101553

Eligibility Criteria

        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 14
             days prior to treatment start and are required to agree to have the test repeated
             within 72 hours prior to the first dose of BAL101553; women of childbearing potential
             and men 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 are ineligible

          -  Patients with a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to BAL101553 are ineligible

          -  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), are ineligible

          -  Patients with peripheral neuropathy >= Common Terminology Criteria for Adverse Events
             (CTCAE) grade 2 are ineligible

          -  Patients with ataxia >= CTCAE grade 2 are ineligible

          -  Patients with known acute or chronic hepatitis B or hepatitis C infection are
             ineligible

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:up to 10 weeks
Safety Issue:
Description:Number of Dose limited Toxicities per dose level. ANC < 500mm3; 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

Secondary Outcome Measures

Measure:Proportion of subjects with Grade 3 and Grade 4 AEs
Time Frame:1.5 years
Safety Issue:
Description:CTC AE 4.0
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:Median time of survival along with 95% confidence interval
Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:Median time of progression-free survival along with 95% confidence interval
Measure:Maximum Plasma Concentration
Time Frame:Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post dose on days 1 and 22
Safety Issue:
Description:PK of microtubule-targeted agent BAL101553 and BAL27862
Measure:Time of Maximum Plasma Concentraion
Time Frame:Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post dose on days 1 and 22
Safety Issue:
Description:PK of microtubule-targeted agent BAL101553 and BAL27862
Measure:Area Under the Concentration-time Curve (AUC)
Time Frame:Pre-dose, 0.5, 1, 2, 4, 6, and 24 hours post dose on days 1 and 22
Safety Issue:
Description:PK of microtubule-targeted agent BAL101553 and BAL27862

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center

Last Updated

August 28, 2017