Glioblastoma
Conditions
Brief summary
This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. Investigational means that the study drug tivozanib is still being studied. It also means that the FDA has not yet approved tivozanib for your type of cancer. Tivozanib is an anti-angiogenesis medicine that fights different types of cancer by blocking the blood supply to the tumor, so that the tumor does not receive the nutrients it requires to grow. In this research study, we are looking to see what effects, good and bad, tivozanib will have on you and your disease.
Detailed description
If you are willing to participate in this study, you will be asked to undergo some screening tests and procedures that confirm you are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out taht you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. The screening process may include the following: a medical history, mini-mental status exam, physical exam, performance status, electrocardiogram, blood tests, urine test. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria, you will not be able to participate in this research study. If you take part in this research study, you will be given a study drug-dosing calendar for each treatment cycle. Each treatment cycle lasts 28 days (4 weeks) during which time you will be taking the study drug once daily for 3 weeks and then no study drug for the last week of each cycle. The diary will also include special instructions for taking the study drug. During all cycles you will have a physical exam and you will be asked questions about your general health and specific questions about any problems that you might be having and any medications you may be taking. Standard contrast-enhanced (CE) MRI scans will be done prior to all odd-numbered study cycles. Vascular MRI scans will be done prior to start of treatment, Day 1 of treatment and prior to all even-numbered cycles. These studies will be done in the Charlestown Navy Yard. We would like to keep track of your medical condition for up to 24 months after your last dose of study treatment. We would like to do this by calling you on the telephone once a year to see how you are doing. Keeping in touch with you and checking your condition every year helps us look at the long-term effects of the research study.
Interventions
DRUGTivozanib
Sponsors
National Comprehensive Cancer Network
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed glioblastoma that has progressed based on imaging or surgery * Measurable disease * No more than 3 prior chemotherapy regimens * Must have recovered from toxicity of prior therapy. An interval of at least 3 months must have elapsed since the completion of the most recent course of radiotherapy; at least 3 weeks since last non-nitrosourea containing chemotherapy regimen or molecularly targeted agent; at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen * Life expectancy of at least 12 weeks * Able to tolerate MRIs * Willing to use adequate, highly effective contraception measures while on study and for at least 45 days after the last dose of study drug
Exclusion criteria
* Pregnant or breastfeeding * Major surgical procedure or significant traumatic injury within 28 days of starting therapy; or minor surgical procedure within 7 days * Receiving other study agents * Prior therapy with an anti-VEGF agent * History of allergic reactions attributed to compounds of similar chemical or biologic composition to tivozanib * Receiving any medications or substances that are inhibitors or inducers of CYP450 enzymes * Significant cardiovascular disease * Non-healing wound, bone fracture or skin ulcer * Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis or other gastrointestinal condition with increased risk of perforation; abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug * Uncontrolled intercurrent illness * Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug * Significant bleeding disorders within 6 months prior to administration of first dose of study drug * Currently active second primary malignancy * HIV positive and on combination antiretroviral therapy * Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of study drugs, major resection of the stomach or small bowel, or gastric bypass procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Alive and Progression Free After 6 Months | 6 months | To determine the number of patients with recurrent glioblastoma (GBM) alive and progression free 6 months (PFR6) after start of tivozanib therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival | From the start of treatment until the time of death, median duration of approximately 8 months | Overall survival is measured from the start of treatment until the time of death. |
| Median Progression-Free Survival | From the start of treatment until death or progression, median duration of approximately 2 months | Progression free survival is measured as the amount of time from the start of treatment until the time of death or disease progression. Progressive disease was assessed using MacDonald Criteria Progressive disease: Progressive neurologic abnormalities not explained by causes unrelated to tumor 40 progression (example: anti-epileptic drug or corticosteroid toxicity, electrolyte abnormalities, hyperglycemia, etc.) or a greater than 25% increase in the volume of the tumor by MRI scan. If neurologic status deteriorates on a stable or increasing dose of corticosteroids, or if new lesions appear on serial MRI scans, this will also be considered PD. |
| Best RANO Criteria Response | 2 years | Best response as assessed by Response Assessment in Neuro-Oncology (RANO) criteria. Complete response * disappearance of all enhancing disease * sustained for at least 4 weeks * stable/improved non-enhancing FLAIR/T2W lesions * no new lesions * no corticosteroids * clinically stable/improved Partial response \>50% or more decrease of all measurable enhancing lesions * sustained for at least 4 weeks * no progression of non-measurable disease * stable/improved non-enhancing FLAIR/T2W lesions * no new lesions * stable/reduced corticosteroids * clinically stable/improved Stable disease * does not qualify for complete response, partial response or progression * stable non-enhancing FLAIR/T2W lesions * stable or reduced corticosteroids * clinically stable Progression \>25% or more increase in enhancing lesions despite stable/increasing steroid dose * increase in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes * any new lesion * Clinical deterioration |
| Steroid Dosage | 2 years | The number of participants on steroids at baseline and the number of participants that increased or decreased their use of steroids during the course of treatment. Participants that required an increase and decrease in steroid use over the course of treatment were counted in both categories. |
| Number of Participants With Treatment Related Serious Adverse Events | From the start of treatment until disease progression, unacceptable toxicity, or death; median duration of approximately 2 months | The number of participants with serious adverse events deemed possibly, probably, or definitely related to treatment. Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 4). |
| Median Apparent Diffusion Coefficient (ADC) | Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks) | Change in the the median ADC value from baseline at the given timepoints. Apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion (of water molecules) within tissue. |
| Median Ktrans | Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks) | Change in the the median Ktrans value from baseline at the given time points. The volume transfer constant (Ktrans) reflects the efflux rate of gadolinium contrast from blood plasma into the tissue extravascular extracellular space (EES) |
| Relative Oxygen Saturation | Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks) | The change in relative O2 saturation from baseline to the given time points. Oxygen saturation is a relative measure of the concentration of oxygen that is dissolved or carried in a given medium as a proportion of the maximal concentration that can be dissolved in that medium. |
| Change in Tumor Volume | Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks) | Change in volume of the tumor in cubic centimeters at the given time points as compared to baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tivozanib 1.5 mg daily for 3 weeks, with 1 week off.
Tivozanib | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Tivozanib | — |
|---|---|---|
| Age, Continuous | 62 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 10 Participants | — |
| Sex: Female, Male Female | 6 Participants | — |
| Sex: Female, Male Male | 4 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 9 / 10 |
| serious Total, serious adverse events | 2 / 10 |
Outcome results
Primary
Number of Patients Alive and Progression Free After 6 Months
To determine the number of patients with recurrent glioblastoma (GBM) alive and progression free 6 months (PFR6) after start of tivozanib therapy
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tivozanib | Number of Patients Alive and Progression Free After 6 Months | 1 Participants |
Secondary
Best RANO Criteria Response
Best response as assessed by Response Assessment in Neuro-Oncology (RANO) criteria. Complete response * disappearance of all enhancing disease * sustained for at least 4 weeks * stable/improved non-enhancing FLAIR/T2W lesions * no new lesions * no corticosteroids * clinically stable/improved Partial response \>50% or more decrease of all measurable enhancing lesions * sustained for at least 4 weeks * no progression of non-measurable disease * stable/improved non-enhancing FLAIR/T2W lesions * no new lesions * stable/reduced corticosteroids * clinically stable/improved Stable disease * does not qualify for complete response, partial response or progression * stable non-enhancing FLAIR/T2W lesions * stable or reduced corticosteroids * clinically stable Progression \>25% or more increase in enhancing lesions despite stable/increasing steroid dose * increase in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes * any new lesion * Clinical deterioration
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tivozanib | Best RANO Criteria Response | Complete response | 1 Participants |
| Tivozanib | Best RANO Criteria Response | Partial response | 1 Participants |
| Tivozanib | Best RANO Criteria Response | Stable disease | 4 Participants |
| Tivozanib | Best RANO Criteria Response | Progressive disease | 4 Participants |
Secondary
Change in Tumor Volume
Change in volume of the tumor in cubic centimeters at the given time points as compared to baseline
Time frame: Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks)
Population: Measurements were not available for all participants at pre-cycle 2 and pre-cycle 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib | Change in Tumor Volume | 17.37 Cubic Centimeters |
| Tivozanib (Cycle 1 Day 2) | Change in Tumor Volume | -2.012 Cubic Centimeters |
| Tivozanib (Pre-cycle 2) | Change in Tumor Volume | -2.75 Cubic Centimeters |
| Tivozanib (Pre-cycle 3) | Change in Tumor Volume | -3.53 Cubic Centimeters |
p-value: 0.7t-test, 2 sided
Secondary
Median Apparent Diffusion Coefficient (ADC)
Change in the the median ADC value from baseline at the given timepoints. Apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion (of water molecules) within tissue.
Time frame: Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib | Median Apparent Diffusion Coefficient (ADC) | 0.0013 mm2/s |
| Tivozanib (Cycle 1 Day 2) | Median Apparent Diffusion Coefficient (ADC) | -0.00009 mm2/s |
| Tivozanib (Pre-cycle 2) | Median Apparent Diffusion Coefficient (ADC) | -0.00024 mm2/s |
| Tivozanib (Pre-cycle 3) | Median Apparent Diffusion Coefficient (ADC) | -0.00023 mm2/s |
p-value: 0.028t-test, 2 sided
Secondary
Median Ktrans
Change in the the median Ktrans value from baseline at the given time points. The volume transfer constant (Ktrans) reflects the efflux rate of gadolinium contrast from blood plasma into the tissue extravascular extracellular space (EES)
Time frame: Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib | Median Ktrans | 0.032 mL/min/100 mL |
| Tivozanib (Cycle 1 Day 2) | Median Ktrans | -0.01468 mL/min/100 mL |
| Tivozanib (Pre-cycle 2) | Median Ktrans | -0.024 mL/min/100 mL |
| Tivozanib (Pre-cycle 3) | Median Ktrans | -0.030 mL/min/100 mL |
p-value: 0.0019t-test, 2 sided
Secondary
Median Overall Survival
Overall survival is measured from the start of treatment until the time of death.
Time frame: From the start of treatment until the time of death, median duration of approximately 8 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib | Median Overall Survival | 8.1 Months |
Secondary
Median Progression-Free Survival
Progression free survival is measured as the amount of time from the start of treatment until the time of death or disease progression. Progressive disease was assessed using MacDonald Criteria Progressive disease: Progressive neurologic abnormalities not explained by causes unrelated to tumor 40 progression (example: anti-epileptic drug or corticosteroid toxicity, electrolyte abnormalities, hyperglycemia, etc.) or a greater than 25% increase in the volume of the tumor by MRI scan. If neurologic status deteriorates on a stable or increasing dose of corticosteroids, or if new lesions appear on serial MRI scans, this will also be considered PD.
Time frame: From the start of treatment until death or progression, median duration of approximately 2 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib | Median Progression-Free Survival | 2.3 Months |
Secondary
Number of Participants With Treatment Related Serious Adverse Events
The number of participants with serious adverse events deemed possibly, probably, or definitely related to treatment. Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 4).
Time frame: From the start of treatment until disease progression, unacceptable toxicity, or death; median duration of approximately 2 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tivozanib | Number of Participants With Treatment Related Serious Adverse Events | 0 Participants |
Secondary
Relative Oxygen Saturation
The change in relative O2 saturation from baseline to the given time points. Oxygen saturation is a relative measure of the concentration of oxygen that is dissolved or carried in a given medium as a proportion of the maximal concentration that can be dissolved in that medium.
Time frame: Baseline, Cycle 1 day 2, pre-cycle 2, pre-cycle 3 (1 cycle= 4 weeks)
Population: One participants was not available for assessment for the cycle 1 day 2 measurement
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivozanib | Relative Oxygen Saturation | 0.64 proportion of possible O2 concentration |
| Tivozanib (Cycle 1 Day 2) | Relative Oxygen Saturation | -0.057 proportion of possible O2 concentration |
| Tivozanib (Pre-cycle 2) | Relative Oxygen Saturation | -0.0041 proportion of possible O2 concentration |
| Tivozanib (Pre-cycle 3) | Relative Oxygen Saturation | -0.097 proportion of possible O2 concentration |
p-value: 0.033t-test, 2 sided
Secondary
Steroid Dosage
The number of participants on steroids at baseline and the number of participants that increased or decreased their use of steroids during the course of treatment. Participants that required an increase and decrease in steroid use over the course of treatment were counted in both categories.
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tivozanib | Steroid Dosage | On steroids at baseline | 4 participants |
| Tivozanib | Steroid Dosage | Decreased dosage | 3 participants |
| Tivozanib | Steroid Dosage | Increased dosage | 4 participants |
| Tivozanib | Steroid Dosage | No change | 4 participants |