Glioblastoma, MGMT-Unmethylated Glioblastoma
Conditions
Keywords
Glioblastoma, Brain tumor, Lisavanbulin, BAL101553
Brief summary
This Phase I study investigated the side-effects and best dose of microtubule-targeted agent BAL101553 when given together with radiation therapy in treating patients with newly-diagnosed O6-methylguanine-DNA methyltransferase (MGMT) promoter unmethylated glioblastoma (GBM). 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, stopping them from dividing, or 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 GBM.
Detailed description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of microtubule-targeted agent BAL101553 (BAL101553) in combination with standard radiation in patients with newly diagnosed MGMT promoter unmethylated 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. OUTLINE: This was a dose escalation study of the microtubule-targeted agent BAL101553. Patients received BAL101553 orally (PO) once daily (QD) for 6 weeks, concurrent with standard radiation therapy (RT) 5 days per week for 6 weeks in the absence of disease progression or unacceptable toxicity. This treatment period was followed by a 4-week no-treatment period. The duration of study treatment was defined as these 6 weeks of treatment plus the 4 weeks of rest. The safety evaluation period was the 10 weeks from start of treatment After completion of study treatment, patients were followed up at 30 days, and then every 2 months for 2 years and then every 6 months thereafter.
Interventions
DRUGMicrotubule-Targeted Agent BAL101553
Given PO
RADIATIONRadiation Therapy
Undergo radiation therapy
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Basilea Pharmaceutica
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The following inclusion criteria were applied: * Patients must have had histologically-proven GBM * Patients must have recovered from the immediate post-operative period * Patients must have had 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) were acceptable * Patients must have been 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 had 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 had 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/micro liter (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 have been able to provide written informed consent * Patients must have had baseline MRI performed within the 21 days prior to starting treatment * Women of childbearing potential must have had a negative serum pregnancy test within 72 hours prior to the first dose of BAL101553; women of childbearing potential must have agreed 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; if a woman became pregnant or suspected she was pregnant while participating in this study, she was asked to inform her treating physician immediately; male patients must have agreed not to donate sperm from the time of 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 have agreed to use condoms during the study and for at least 90 days after the end of treatment; the patient should have been 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 had no concurrent malignancies 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 have been disease-free for \>= 5 years * Patients must have been maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the start of treatment * Patients must have been able to swallow whole capsules The following
Exclusion criteria
were applied: * Patients receiving any other investigational agent * 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\]), were not eligible for the study; patients taking non-EIAEDs were permitted to take part in the study; patients previously treated with any of the prohibited concomitant medications listed above may have been enrolled if they had been off the medication for \>= 10 days prior to the first dose of BAL101553 * Patients may not have been on coumarin anti-coagulants (warfarin, etc.); heparin, low-molecular weight heparin (LMWH), or other antithrombotic medications were permitted * Patients with gastrointestinal disease, or those who had a procedure that was 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 were 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 BP combination treatment with more than two antihypertensive medications were ineligible * Significant cardiac disease or abnormality, including any 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, were ineligible * Pregnant women were excluded from this study; breastfeeding should have been discontinued if the mother was treated with BAL101553 * Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy were ineligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort | Up to 10 weeks | A DLT was defined as a clinically-significant adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications. Any DLT had to be a toxicity considered at least possibly related to BAL101553 or the combination of BAL101553 and radiation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | up to 10 weeks | Common Terminology Criteria for Adverse Events (CTCAE) displayed by increasing severity grades 3 to 5 (CTCAE grade 3/4/5 ) |
| Overall Survival (OS) Time | Day 1 to date of death - up to 1679 days (4.6 years) | OS was defined as the time from Day 1 dosing to the date of death. Patients who have not died at study closure were censored at the time of last known alive. |
| Progression Free Survival (PFS) Time | Day 1 to date of disease progression - 1092 days (3.0 years) | PFS was the interval between Day 1 dosing and the earliest date of progression. Progression was defined as: an increase in tumor size of more than 25% or the appearance of new lesions on MRI scans, significant clinical deterioration not attributable to causes other than the tumor, or death from any cause. Patients who have not progressed or died at study closure were censored at the time of their last assessment without progression. |
Countries
United States
Participant flow
Recruitment details
Treatment was administered on an outpatient basis
Participants by arm
| Arm | Count |
|---|---|
| BAL101553 4 mg Cohort BAL101553 was given as an 4 mg oral dose once daily (7 days per week) for 6 weeks, in combination with standard radiotherapy (RT) | 5 |
| BAL101553 6 mg Cohort BAL101553 was given as an 6 mg oral dose once daily (7 days per week) for 6 weeks, in combination with standard radiotherapy (RT) | 5 |
| BAL101553 8 mg Cohort BAL101553 was given as an 8 mg oral dose once daily (7 days per week) for 6 weeks, in combination with standard radiotherapy (RT) | 7 |
| BAL101553 12 mg Cohort BAL101553 was given as an 12 mg oral dose once daily (7 days per week) for 6 weeks, in combination with standard radiotherapy (RT) | 5 |
| BAL101553 15 mg Cohort BAL101553 was given as an 15 mg oral dose once daily (7 days per week) for 6 weeks, in combination with standard radiotherapy (RT) | 4 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| BAL101553 12 mg Cohort | Adverse Event | 0 | 0 | 0 | 2 | 0 |
| BAL101553 6 mg Cohort | Disease progression | 0 | 1 | 0 | 0 | 0 |
| BAL101553 8 mg Cohort | Adverse Event | 0 | 0 | 1 | 0 | 0 |
| BAL101553 8 mg Cohort | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | BAL101553 4 mg Cohort | BAL101553 6 mg Cohort | BAL101553 8 mg Cohort | BAL101553 12 mg Cohort | BAL101553 15 mg Cohort | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants | 2 Participants | 2 Participants | 14 Participants |
| Age, Continuous | 58.2 years STANDARD_DEVIATION 10.57 | 67.6 years STANDARD_DEVIATION 6.27 | 57.7 years STANDARD_DEVIATION 11.22 | 62.6 years STANDARD_DEVIATION 12.1 | 57.8 years STANDARD_DEVIATION 13.4 | 60.7 years STANDARD_DEVIATION 10.71 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 6 Participants | 5 Participants | 4 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 6 Participants | 4 Participants | 3 Participants | 23 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 7 participants | 5 participants | 4 participants | 26 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 2 Participants | 15 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 5 | 5 / 5 | 4 / 7 | 4 / 5 | 0 / 4 |
| other Total, other adverse events | 5 / 5 | 5 / 5 | 7 / 7 | 5 / 5 | 4 / 4 |
| serious Total, serious adverse events | 2 / 5 | 3 / 5 | 2 / 7 | 2 / 5 | 1 / 4 |
Outcome results
Primary
Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort
A DLT was defined as a clinically-significant adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications. Any DLT had to be a toxicity considered at least possibly related to BAL101553 or the combination of BAL101553 and radiation.
Time frame: Up to 10 weeks
Population: MTD-determining population: All patients who met any of the following criteria:~* Received at least one dose of BAL101553 and has experienced a DLT;~* Received ≥80% of their expected dose of BAL101553 and completed 6 weeks of combined treatment and 4 weeks of rest.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BAL101553 4 mg MTD-determining Cohort | Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort | 0 participants |
| BAL101553 6 mg MTD-determining Cohort | Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort | 0 participants |
| BAL101553 8 mg MTD-determining Cohort | Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort | 1 participants |
| BAL101553 12 mg MTD-determining Cohort | Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort | 1 participants |
| BAL101553 15 mg MTD-determining Cohort | Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort | 0 participants |
Secondary
Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs)
Common Terminology Criteria for Adverse Events (CTCAE) displayed by increasing severity grades 3 to 5 (CTCAE grade 3/4/5 )
Time frame: up to 10 weeks
Population: All patients who received at least one full or partial dose of BAL101553 and had at least one post-baseline safety assessment was included in the safety analysis populations.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BAL101553 4 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with only unrelated CTCAE Grade 3/4/5 AEs | 1 Participants |
| BAL101553 4 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients without CTCAE Grade 3/4/5 AEs | 3 Participants |
| BAL101553 4 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with related CTCAE Grade 3/4/5 AEs | 1 Participants |
| BAL101553 6 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with related CTCAE Grade 3/4/5 AEs | 1 Participants |
| BAL101553 6 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with only unrelated CTCAE Grade 3/4/5 AEs | 2 Participants |
| BAL101553 6 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients without CTCAE Grade 3/4/5 AEs | 2 Participants |
| BAL101553 8 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with related CTCAE Grade 3/4/5 AEs | 1 Participants |
| BAL101553 8 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with only unrelated CTCAE Grade 3/4/5 AEs | 1 Participants |
| BAL101553 8 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients without CTCAE Grade 3/4/5 AEs | 5 Participants |
| BAL101553 12 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with only unrelated CTCAE Grade 3/4/5 AEs | 2 Participants |
| BAL101553 12 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients without CTCAE Grade 3/4/5 AEs | 2 Participants |
| BAL101553 12 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with related CTCAE Grade 3/4/5 AEs | 1 Participants |
| BAL101553 15 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with related CTCAE Grade 3/4/5 AEs | 0 Participants |
| BAL101553 15 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients with only unrelated CTCAE Grade 3/4/5 AEs | 1 Participants |
| BAL101553 15 mg MTD-determining Cohort | Number of Patients With Grade 3 to Grade 5 Adverse Events (AEs) | Number of patients without CTCAE Grade 3/4/5 AEs | 3 Participants |
Secondary
Overall Survival (OS) Time
OS was defined as the time from Day 1 dosing to the date of death. Patients who have not died at study closure were censored at the time of last known alive.
Time frame: Day 1 to date of death - up to 1679 days (4.6 years)
Population: Full analysis population (FAP) included all patients who received at least one partial or complete dose of study drug, based on the intent-to-treat principle. In this study the FAP corresponded to the safety population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAL101553 4 mg MTD-determining Cohort | Overall Survival (OS) Time | 383.0 Days |
Secondary
Progression Free Survival (PFS) Time
PFS was the interval between Day 1 dosing and the earliest date of progression. Progression was defined as: an increase in tumor size of more than 25% or the appearance of new lesions on MRI scans, significant clinical deterioration not attributable to causes other than the tumor, or death from any cause. Patients who have not progressed or died at study closure were censored at the time of their last assessment without progression.
Time frame: Day 1 to date of disease progression - 1092 days (3.0 years)
Population: Full analysis population (FAP) included all patients who received at least one partial or complete dose of study drug, based on the intent-to-treat principle. In this study the FAP corresponded to the safety population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAL101553 4 mg MTD-determining Cohort | Progression Free Survival (PFS) Time | 247.0 Days |