Tivozanib for Recurrent Glioblastoma

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01846871
• Collaborator: National Comprehensive Cancer Network (Other)
• Enrollment: 10
• Location: 1
• Arm: 1
• Duration (Months): 35
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Drug: Tivozanib	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Tivozanib in Recurrent Glioblastoma
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tivozanib 1.5 mg daily for 3 weeks, with 1 week off.	Drug: Tivozanib; Other Names: AV-951

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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.

3. 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.

4. 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

5. 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.

6. 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

7. 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.

8. 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)

9. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Comprehensive Cancer Network

Investigators

• Principal Investigator: Elizabeth Gerstner, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Elizabeth R. Gerstner, MD, Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01846871
• Other Study ID Numbers: 13-069
• First Posted: May 3, 2013
• Last Update Posted: Jan 8, 2019
• Last Verified: Dec 1, 2018

• Additional relevant MeSH terms: Glioblastoma

Study Results

Participant Flow

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Period Title: Overall Study
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Overall Participants	10
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	6 60%
Male	4 40%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Alive and Progression Free After 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Measure Participants	10
Count of Participants [Participants]	1 10%

2. Secondary Outcome

Title	Number of Participants With Treatment Related Serious Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Measure Participants	10
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Median Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Measure Participants	10
Median (95% Confidence Interval) [Months]	8.1

4. Secondary Outcome

Title	Median Progression-Free Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Measure Participants	10
Median (95% Confidence Interval) [Months]	2.3

5. Secondary Outcome

Title	Best RANO Criteria Response
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Measure Participants	10
Complete response	1 10%
Partial response	1 10%
Stable disease	4 40%
Progressive disease	4 40%

6. Secondary Outcome

Title	Steroid Dosage
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
Measure Participants	10
On steroids at baseline	4 40%
Decreased dosage	3 30%
Increased dosage	4 40%
No change	4 40%

7. Secondary Outcome

Title	Change in Tumor Volume
Description	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)

Outcome Measure Data

Analysis Population Description

Measurements were not available for all participants at pre-cycle 2 and pre-cycle 3

Arm/Group Title	Tivozanib (Baseline)	Tivozanib (Cycle 1 Day 2)	Tivozanib (Pre-cycle 2)	Tivozanib (Pre-cycle 3)
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.
Measure Participants	10	10	9	8
Median (Inter-Quartile Range) [Cubic Centimeters]	17.37	-2.012	-2.75	-3.53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib (Pre-cycle 3)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Median Apparent Diffusion Coefficient (ADC)
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib (Baseline)	Tivozanib (Cycle 1 Day 2)	Tivozanib (Pre-cycle 2)	Tivozanib (Pre-cycle 3)
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.
Measure Participants	10	10	10	10
Median (Inter-Quartile Range) [mm2/s]	0.0013	-0.00009	-0.00024	-0.00023

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib, Tivozanib (Pre-cycle 3)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Median Ktrans
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tivozanib (Baseline)	Tivozanib (Cycle 1 Day 2)	Tivozanib (Pre-cycle 2)	Tivozanib (Pre-cycle 3)
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.
Measure Participants	10	10	10	10
Median (Inter-Quartile Range) [mL/min/100 mL]	0.032	-0.01468	-0.024	-0.030

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib, Tivozanib (Pre-cycle 3)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Relative Oxygen Saturation
Description	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)

Outcome Measure Data

Analysis Population Description

One participants was not available for assessment for the cycle 1 day 2 measurement

Arm/Group Title	Tivozanib (Baseline)	Tivozanib (Cycle 1 Day 2)	Tivozanib (Pre-cycle 2)	Tivozanib (Pre-cycle 3)
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.	1.5 mg daily for 3 weeks, with 1 week off.
Measure Participants	10	9	10	10
Median (Inter-Quartile Range) [proportion of possible O2 concentration]	0.64	-0.057	-0.0041	-0.097

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tivozanib, Tivozanib (Pre-cycle 3)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	From the start of treatment until disease progression, unacceptable toxicity, or death; median duration of approximately 2 months.
Arm/Group Title	Tivozanib
Arm/Group Description	1.5 mg daily for 3 weeks, with 1 week off. Tivozanib
All Cause Mortality
	Tivozanib
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Tivozanib
	Affected / at Risk (%)	# Events
Total	2/10 (20%)
Gastrointestinal disorders
Colonic perforation	1/10 (10%)	1
Nervous system disorders
Seizure	2/10 (20%)	2
Edema cerebral	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Tivozanib
	Affected / at Risk (%)	# Events
Total	9/10 (90%)
Blood and lymphatic system disorders
Anemia	2/10 (20%)	3
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, cerumen in right ear	1/10 (10%)	1
Ear and labyrinth disorders - Other, hearing loss in right ear	1/10 (10%)	1
Ear and labyrinth disorders - Other, Intermittent hearing loss	1/10 (10%)	1
Vertigo	1/10 (10%)	1
Eye disorders
Eye disorders - Other, Hemanopsia	1/10 (10%)	1
Eye disorders - Other, Retro Orbital pressure	1/10 (10%)	1
Gastrointestinal disorders
Diarrhea	1/10 (10%)	2
Mucositis oral	2/10 (20%)	3
Nausea	2/10 (20%)	2
General disorders
Fatigue	7/10 (70%)	7
Gait disturbance	1/10 (10%)	1
Non-cardiac chest pain	1/10 (10%)	1
Infections and infestations
Paronychia	1/10 (10%)	1
Skin infection	1/10 (10%)	1
Investigations
Alanine aminotransferase increased	1/10 (10%)	1
Alkaline phosphatase increased	2/10 (20%)	3
Aspartate aminotransferase increased	1/10 (10%)	1
Investigations - Other, SGOT elevated	1/10 (10%)	1
Investigations - Other, SGPT elevated	1/10 (10%)	1
Lymphocyte count decreased	3/10 (30%)	4
Platelet count decreased	2/10 (20%)	2
White blood cell decreased	4/10 (40%)	5
Metabolism and nutrition disorders
Anorexia	1/10 (10%)	1
Hyperglycemia	1/10 (10%)	1
Hypokalemia	2/10 (20%)	4
Hypophosphatemia	2/10 (20%)	2
Musculoskeletal and connective tissue disorders
Muscle weakness left-sided	1/10 (10%)	1
Muscle weakness lower limb	1/10 (10%)	1
Muscle weakness right-sided	1/10 (10%)	1
Nervous system disorders
Abducens nerve disorder	1/10 (10%)	1
Ataxia	1/10 (10%)	1
Cognitive disturbance	2/10 (20%)	2
Dizziness	1/10 (10%)	1
Headache	4/10 (40%)	4
Nervous system disorders - Other, Altered Coordination (right)	1/10 (10%)	1
Nervous system disorders - Other, Cognitive Dysfunction	1/10 (10%)	1
Nervous system disorders - Other, numbness right limbs	1/10 (10%)	1
Nervous system disorders - Other, Speech impairment	1/10 (10%)	1
Nystagmus	1/10 (10%)	1
Pyramidal tract syndrome	1/10 (10%)	1
Seizure	4/10 (40%)	4
Psychiatric disorders
Anxiety	2/10 (20%)	2
Confusion	3/10 (30%)	3
Depression	2/10 (20%)	2
Renal and urinary disorders
Proteinuria	1/10 (10%)	1
Urinary urgency	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Hiccups	1/10 (10%)	1
Hoarseness	1/10 (10%)	1
Voice alteration	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/10 (10%)	1
Palmar-plantar erythrodysesthesia syndrome	1/10 (10%)	1
Skin ulceration	1/10 (10%)	1
Vascular disorders
Hypertension	4/10 (40%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.