A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma
Study Details
Study Description
Brief Summary
This phase 2 trial is evaluating the antineoplastic activity of tivozanib (AV-951) in treating patients with recurrent or metastatic renal cell cancer. Tivozanib (AV-951) is a VEGF-receptor tyrosine kinase inhibitor, and may stop the growth of tumor cells by blocking blood flow to the tumor.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Approximately 200 patients will be enroled into the initial, 16 week, open-label period using 1.5 mg/day dosing. Patients will receive tivozanib (AV-951) continuously for 3 weeks followed by 1 week off study drug. Patients will undergo disease assessment at baseline and after Cycles 2 and 4 and response will be determined by RESIST criteria.
After the initial, 16 week open-label period, disease status will be assessed and compared to baseline using modified RECIST criteria:
-
Patients with greater than or equal to 25% tumor shrinkage will continue on their current dose of tivozanib (AV-951)
-
Patients with less than 25% tumor change (growth or shrinkage) will be randomly assigned to double-blind tivozanib (AV-951) or matching placebo for 12 weeks
-
Patients with greater than or equal to 25% tumor growth will be discontinued
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 1 Tivozanib (AV-951) administered as a solid dosage form daily for three weeks per month |
Drug: Tivozanib (AV-951)
solid oral dosage form taken daily for three weeks per one month cycle
|
| Placebo Comparator: 2 solid oral capsule containing excipients dosed daily for three weeks per month |
Drug: Placebo comparator
solid oral capsule containing excipients dosed daily for three weeks per month
|
Outcome Measures
Primary Outcome Measures
- Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) [28 weeks after study entry]
To determine the safety and tolerability of tivozanib (AV-951) with the protocol-specified dose schedule
- Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population) [16 weeks after study entry]
The ORR is defined as the rate of (CR+PR). Objective response rates following the 16-week, open-label period (investigator assessment and IRR assessment) were estimated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and was assessed by magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Overall Response (OR) = CR + PR.
- Percentage of Randomly Assigned Subjects Remaining Progression Free at 12 Weeks Following Random Assignment to Tivozanib (AV-951) or Placebo [28 weeks after study entry]
Percentages of subjects remaining progression-free at 12 weeks post-randomization were compared across the 2 treatment arms in the ITT population. A Cochran-Mantel- Haenszel (CMH) test of general association was used, stratifying by country to evaluate the null hypothesis that treatment arm is not associated with subjects remaining progression-free. Non-completers were treated as failures. Progression is defined using RECIST v1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Secondary Outcome Measures
- Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization ) [28 weeks from study entry]
PFS after randomization in the ITT population was described using the Kaplan-Meier methodology. PFS was compared across treatment arms using the log-rank test.
- Overall Progression-free Survival (From Start of Treatment) [12 months from study entry]
Number of subjects with Overall PFS (from start of treatment) was estimated using the Kaplan-Meier methodology. Subjects randomized to receive placebo were censored at randomization. Withdrawals are also censored. An alternative analysis was conducted in which PFS for subjects randomized to receive tivozanib was weighted more heavily to compensate for the information loss from randomization of other subjects to receive placebo. Additional analyses in which withdrawal was considered a PFS event were also conducted.
- Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects [Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose]
Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1.
- Maximum Observed Serum Concentration During a Dosing Interval at Steady State (Cmax) [Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose]
Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1.
- Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)] [28 weeks from study entry]
Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
≥ 18 year old males or females
-
Patients with recurrent or metastatic renal cell carcinoma (RCC) or primary RCC that is not amendable to surgical intervention
-
Histologically or cytologically confirmed renal cell carcinoma
-
Measurable disease
-
No more than one prior systemic treatment (chemotherapy or immunotherapy) for RCC.
-
No active brain metastases
-
Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months
-
No childbearing potential, or use of effective contraception during the study and for 4 weeks after the last dose of study drug
-
Archival paraffin embedded tumor tissue, if available.
-
Ability to give written informed consent
Exclusion Criteria:
-
Pregnant or lactating women
-
Primary CNS malignancies; active CNS metastases
-
Hematologic malignancies (includes: leukemia, any form; lymphoma; and multiple myeloma)
-
Any of the following hematologic abnormalities:
-
Hemoglobin ≤ 9.0 g/dL
-
ANC < 1500 per mm3
-
Platelet count < 100,000 per mm3
-
Any of the following serum chemistry abnormalities:
-
Total bilirubin > 1.5 × the ULN
-
AST or ALT ≥ 2.5 × the ULN
-
Serum albumin < 3.0 g/dL
-
Creatinine > 1.7 × ULN (or calculated CLCR <50 mL/min/1.73 m2)
-
Proteinuria > 2.5 g/24 hours or 4+ with urine dipstick
-
Significant cardiovascular disease, including:
-
Active clinically symptomatic left ventricular failure
-
Active HTN (diastolic blood pressure > 100 mmHg). Patients with a history of hypertension must have been on stable doses of anti-hypertensive drugs for ≥ 4 weeks
-
Uncontrolled hypertension: Blood pressure >140/90 mmHg on more than 2 antihypertensive medications.
-
Myocardial infarction within 3 months prior to administration of first study dose
-
Unhealed wounds (including active gastric ulcers)
-
Serious/active infection; infection requiring parenteral antibiotics
-
Inadequate recovery from prior antineoplastic therapy
-
Inadequate recovery from any prior surgical procedure; major surgical procedure within 4 weeks prior to study entry
-
Life-threatening illness or organ system dysfunction compromising safety evaluation
-
Psychiatric disorder, altered mental status precluding informed consent or necessary testing
-
Inability to comply with protocol requirements
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Vellore | Tamil Nadu | India | 632004 | |
| 2 | Kolkata | India | |||
| 3 | Mumbai | India | |||
| 4 | New Delhi | India | |||
| 5 | Pune | India | |||
| 6 | Astrakhan | Russian Federation | |||
| 7 | Ioshkar-Ola | Russian Federation | |||
| 8 | Kazan | Russian Federation | |||
| 9 | Moscow | Russian Federation | 125284 | ||
| 10 | Moscow | Russian Federation | 129128 | ||
| 11 | Moscow | Russian Federation | |||
| 12 | Novgorod | Russian Federation | |||
| 13 | Obninsk | Russian Federation | |||
| 14 | Pyatigorsk | Russian Federation | |||
| 15 | Rostove-on-Don | Russian Federation | |||
| 16 | Sochi | Russian Federation | |||
| 17 | St. Petersburg | Russian Federation | |||
| 18 | Tomsk | Russian Federation | |||
| 19 | Ufa | Russian Federation | |||
| 20 | Cherkassy | Ukraine | |||
| 21 | Dnepropetrovsk | Ukraine | |||
| 22 | Donetsk | Ukraine | |||
| 23 | Kharkov | Ukraine | |||
| 24 | Lviv | Ukraine | |||
| 25 | Uzhgorod | Ukraine | |||
| 26 | Zaporizzhya | Ukraine |
Sponsors and Collaborators
- AVEO Pharmaceuticals, Inc.
Investigators
- Principal Investigator: Dmitriy G Nosov, M.D., Russian Oncological Research Center n.a. N.N. Blokhin of the Russian Academy of Medical Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AV-951-07-201
Study Results
Participant Flow
| Recruitment Details | Participants who met all the inclusion and none of the exclusion criteria were enrolled |
|---|---|
| Pre-assignment Detail | All participants underwent inclusion and exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study related procedures. All the study assessments were performed as per the schedule of assessment. |
| Arm/Group Title | Open-label Period: Tivozanib (AV-951) | Double-blind Period: Tivozanib (AV-951) | Double-blind Period: Placebo |
|---|---|---|---|
| Arm/Group Description | Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off). | Subjects with < 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner. | Subjects with < 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner. |
| Period Title: Open Label Period (16 Weeks) | |||
| STARTED | 272 | 0 | 0 |
| COMPLETED | 196 | 0 | 0 |
| NOT COMPLETED | 76 | 0 | 0 |
| Period Title: Open Label Period (16 Weeks) | |||
| STARTED | 0 | 61 | 57 |
| COMPLETED | 0 | 35 | 48 |
| NOT COMPLETED | 0 | 26 | 9 |
| Period Title: Open Label Period (16 Weeks) | |||
| STARTED | 148 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 |
| NOT COMPLETED | 148 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Open-label Period:Tivozanib (AV-951) |
|---|---|
| Arm/Group Description | Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off). After 16 weeks (4 cycles), disease status was assessed and compared to baseline. Tivozanib was to be discontinued following disease progression or unacceptable toxicity. |
| Overall Participants | 272 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
272
100%
|
| >=65 years |
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
56.3
(9.5)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
81
29.8%
|
| Male |
191
70.2%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1
0.4%
|
| Not Hispanic or Latino |
271
99.6%
|
| Unknown or Not Reported |
0
0%
|
| Body Mass Index (kg/m^2) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [kg/m^2] |
26.5
(4.6)
|
Outcome Measures
| Title | Number of Subjects With Adverse Events (AEs)/Serious AEs (SAEs) |
|---|---|
| Description | To determine the safety and tolerability of tivozanib (AV-951) with the protocol-specified dose schedule |
| Time Frame | 28 weeks after study entry |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Open-label Period: Tivozanib (AV-951) | Double-blind Period: Tivozanib (AV-951) | Double-blind Period: Placebo |
|---|---|---|---|
| Arm/Group Description | Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off). | Subjects with < 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner. | Subjects with < 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner. |
| Measure Participants | 272 | 61 | 57 |
| Adverse events |
215
79%
|
31
NaN
|
32
NaN
|
| Serious adverse events |
16
5.9%
|
2
NaN
|
3
NaN
|
| Grade 3 or higher adverse events |
86
31.6%
|
8
NaN
|
10
NaN
|
| Treatment-related adverse events |
174
64%
|
13
NaN
|
7
NaN
|
| Discontinuations due to adverse events |
10
3.7%
|
1
NaN
|
3
NaN
|
| Deaths |
6
2.2%
|
1
NaN
|
2
NaN
|
| Title | Objective Response [Complete Response (CR) + Partial Response (PR)] Rate at 16 Week Open-Label Period (All Treated Population) |
|---|---|
| Description | The ORR is defined as the rate of (CR+PR). Objective response rates following the 16-week, open-label period (investigator assessment and IRR assessment) were estimated per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and was assessed by magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Overall Response (OR) = CR + PR. |
| Time Frame | 16 weeks after study entry |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Investigator Assessment | Independent Radiology Reviewer Assessment |
|---|---|---|
| Arm/Group Description | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. |
| Measure Participants | 272 | 272 |
| Complete response |
1
0.4%
|
0
NaN
|
| Partial response |
66
24.3%
|
49
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Open-label Period: Tivozanib (AV-951) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Exact binomial distribution |
| Estimated Value | 24.6 | |
| Confidence Interval |
(2-Sided) 95% 19.6 to 30.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Double-blind Period: Tivozanib (AV-951) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Exact binomial distribution |
| Estimated Value | 18.0 | |
| Confidence Interval |
(2-Sided) 95% 13.6 to 23.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Randomly Assigned Subjects Remaining Progression Free at 12 Weeks Following Random Assignment to Tivozanib (AV-951) or Placebo |
|---|---|
| Description | Percentages of subjects remaining progression-free at 12 weeks post-randomization were compared across the 2 treatment arms in the ITT population. A Cochran-Mantel- Haenszel (CMH) test of general association was used, stratifying by country to evaluate the null hypothesis that treatment arm is not associated with subjects remaining progression-free. Non-completers were treated as failures. Progression is defined using RECIST v1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Time Frame | 28 weeks after study entry |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Investigator Assessment (Tivozanib) | Investigator Assessment (Placebo) | Independent Radiology Reviewer (Tivozanib) | Independent Radiology Reviewer (Placebo) |
|---|---|---|---|---|
| Arm/Group Description | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. |
| Measure Participants | 61 | 57 | 61 | 57 |
| Count of Participants [Participants] |
35
12.9%
|
16
NaN
|
30
NaN
|
12
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Open-label Period: Tivozanib (AV-951), Double-blind Period: Tivozanib (AV-951) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.001 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Double-blind Period: Placebo, Independent Radiology Reviewer (Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.001 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Title | Number of Subjects With Progression Free-survival (PFS) After Random Assignment (Randomized Sub-set Only) (at 12 Weeks Post Randomization ) |
|---|---|
| Description | PFS after randomization in the ITT population was described using the Kaplan-Meier methodology. PFS was compared across treatment arms using the log-rank test. |
| Time Frame | 28 weeks from study entry |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Investigator Assessment (Tivozanib) | Investigator Assessment (Placebo) | Independent Radiology Reviewer Assessment (Tivozanib) | Independent Radiology Reviewer Assessment (Placebo) |
|---|---|---|---|---|
| Arm/Group Description | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. |
| Measure Participants | 61 | 57 | 61 | 57 |
| Number of subjects with progression |
23
8.5%
|
33
NaN
|
22
NaN
|
24
NaN
|
| Number of censored subjects |
38
14%
|
24
NaN
|
39
NaN
|
33
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Open-label Period: Tivozanib (AV-951), Double-blind Period: Tivozanib (AV-951) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.005 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Double-blind Period: Placebo, Independent Radiology Reviewer (Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.129 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Title | Overall Progression-free Survival (From Start of Treatment) |
|---|---|
| Description | Number of subjects with Overall PFS (from start of treatment) was estimated using the Kaplan-Meier methodology. Subjects randomized to receive placebo were censored at randomization. Withdrawals are also censored. An alternative analysis was conducted in which PFS for subjects randomized to receive tivozanib was weighted more heavily to compensate for the information loss from randomization of other subjects to receive placebo. Additional analyses in which withdrawal was considered a PFS event were also conducted. |
| Time Frame | 12 months from study entry |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Investigator Assessment (Tivozanib) | Investigator Assessment (Placebo) | Independent Radiology Reviewer Assessment (Tivozanib) | Independent Radiology Reviewer Assessment (Placebo) |
|---|---|---|---|---|
| Arm/Group Description | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. | All assessment were performed by the study Investigator and similarly for IRR. |
| Measure Participants | 61 | 57 | 61 | 57 |
| Number of subjects with progression |
47
17.3%
|
33
NaN
|
36
NaN
|
24
NaN
|
| Number of censored subjects |
14
5.1%
|
24
NaN
|
25
NaN
|
33
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Open-label Period: Tivozanib (AV-951), Double-blind Period: Tivozanib (AV-951) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.003 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Double-blind Period: Placebo, Independent Radiology Reviewer (Placebo) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.089 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Title | Time to Peak Plasma Concentration (Tmax) of Tivozanib in a Subset of Subjects |
|---|---|
| Description | Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. |
| Time Frame | Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK population had 21 subjects. However, there were subjects with missing data for both Cycle 1 Day 1 and Cycle 1 Day 21. Hence, the number of participants analyzed varies i.e, 20 for Cycle 1 Day 1 and 16 for Cycle 1 Day 21. |
| Arm/Group Title | Tivozanib 1.5 mg |
|---|---|
| Arm/Group Description | A total of 21 subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. |
| Measure Participants | 21 |
| Cycle 1 Day 1 |
7.122
(8.511)
|
| Cycle 1 Day 21 |
3.64
(5.61)
|
| Title | Maximum Observed Serum Concentration During a Dosing Interval at Steady State (Cmax) |
|---|---|
| Description | Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. |
| Time Frame | Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Pre-dose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK population had 21 subjects. However, there were subjects with missing data for both Cycle 1 Day 1 and Cycle 1 Day 21. Hence, the number of participants analyzed varies i.e, 20 for Cycle 1 Day 1 and 16 for Cycle 1 Day 21. |
| Arm/Group Title | Tivozanib 1.5 mg |
|---|---|
| Arm/Group Description | A total of 21 subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. |
| Measure Participants | 21 |
| Cycle 1 Day 1 |
15.51
(11.70)
|
| Cycle 1 Day 21 |
94.29
(37.80)
|
| Title | Area Under the Serum Concentration Versus Time Curve From Zero to the Last Quantifiable Sampling Point [AUC(0→24)] |
|---|---|
| Description | Tivozanib concentrations in human serum were determined. The PK population included all subjects who had taken at least 1 dose of tivozanib and whose PK profile(s) were evaluable. All subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. |
| Time Frame | 28 weeks from study entry |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK population had 21 subjects. However, there were subjects with missing data for both Cycle 1 Day 1 and Cycle 1 Day 21. Hence, the number of participants analyzed varies i.e, 20 for Cycle 1 Day 1 and 16 for Cycle 1 Day 21. |
| Arm/Group Title | Tivozanib 1.5 mg |
|---|---|
| Arm/Group Description | A total of 21 subjects received 1.5 mg tivozanib (1.3397 mg free base) in Cycle 1. |
| Measure Participants | 21 |
| Cycle 1 Day 1 |
258.2
(197.0)
|
| Cycle 1 Day 21 |
0
(0)
|
Adverse Events
| Time Frame | 1 year | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Serious treatment-emergent adverse events and treatment emergent adverse events in Safety (SAF) Population was reported. | |||||
| Arm/Group Title | Open-label Period: Tivozanib (AV-951) | Double-blind Period: Tivozanib (AV-951) | Double-blind Period: Placebo | |||
| Arm/Group Description | Subjects were enrolled into the initial, 16-week, open-label period and received tivozanib at a dose of 1.5 mg/day (oral administration). Subjects received tivozanib continuously for 3 weeks followed by 1 week off study drug (1 cycle = 3 weeks on, 1 week off). | Subjects with < 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive 1.5 mg/ day of tivozanib for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner. | Subjects with < 25% tumor change (growth or shrinkage) at the end of the 16-week open-label period were randomly assigned to receive matching placebo for 12 weeks (3 cycles; 1 cycle = 3 weeks on, 1 week off) in a double-blind manner. | |||
All Cause Mortality |
||||||
| Open-label Period: Tivozanib (AV-951) | Double-blind Period: Tivozanib (AV-951) | Double-blind Period: Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Open-label Period: Tivozanib (AV-951) | Double-blind Period: Tivozanib (AV-951) | Double-blind Period: Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 16/272 (5.9%) | 2/61 (3.3%) | 3/57 (5.3%) | |||
| Cardiac disorders | ||||||
| Myocardial infarction | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Myocardial ischemia | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Intestinal obstruction | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Infections and infestations | ||||||
| Appendicitis | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Pneumonia | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||
| Joint dislocation | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal chest pain | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Pathological fracture | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Malignant neoplasm progression | 2/272 (0.7%) | 2 | 1/61 (1.6%) | 1 | 3/57 (5.3%) | 3 |
| Metatstatic renal cell carcinoma | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Nervous system disorders | ||||||
| Paraplegia | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Reproductive system and breast disorders | ||||||
| Uterine prolapse | 0/272 (0%) | 0 | 1/61 (1.6%) | 1 | 0/57 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute respiratory failure | 2/272 (0.7%) | 2 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Epistaxis | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Pulmonary embolism | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Vascular disorders | ||||||
| Hypertensive crisis | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Hypotension | 1/272 (0.4%) | 1 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Open-label Period: Tivozanib (AV-951) | Double-blind Period: Tivozanib (AV-951) | Double-blind Period: Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 215/272 (79%) | 31/61 (50.8%) | 32/57 (56.1%) | |||
| Blood and lymphatic system disorders | ||||||
| Anemia | 6/272 (2.2%) | 6 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Diarrhea | 24/272 (8.8%) | 40 | 4/61 (6.6%) | 6 | 0/57 (0%) | 0 |
| Abdominal pain upper | 7/272 (2.6%) | 9 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Stomatitis | 6/272 (2.2%) | 13 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Vomiting | 0/272 (0%) | 0 | 2/61 (3.3%) | 2 | 1/57 (1.8%) | 1 |
| Abdominal pain | 0/272 (0%) | 0 | 1/61 (1.6%) | 1 | 3/57 (5.3%) | 3 |
| Nausea | 0/272 (0%) | 0 | 0/61 (0%) | 0 | 2/57 (3.5%) | 2 |
| General disorders | ||||||
| Asthenia | 32/272 (11.8%) | 49 | 6/61 (9.8%) | 9 | 7/57 (12.3%) | 7 |
| Fatigue | 29/272 (10.7%) | 45 | 2/61 (3.3%) | 2 | 4/57 (7%) | 6 |
| Pyrexia | 14/272 (5.1%) | 16 | 0/61 (0%) | 0 | 2/57 (3.5%) | 2 |
| Non-cardiac chest pain | 10/272 (3.7%) | 11 | 1/61 (1.6%) | 1 | 2/57 (3.5%) | 2 |
| Infections and infestations | ||||||
| Nasopharyngitis | 0/272 (0%) | 0 | 2/61 (3.3%) | 2 | 0/57 (0%) | 0 |
| Investigations | ||||||
| Gamma-glutamyl transferase increased | 15/272 (5.5%) | 27 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Anorexia | 9/272 (3.3%) | 12 | 2/61 (3.3%) | 2 | 3/57 (5.3%) | 3 |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 18/272 (6.6%) | 25 | 3/61 (4.9%) | 4 | 3/57 (5.3%) | 3 |
| Bone pain | 12/272 (4.4%) | 17 | 0/61 (0%) | 0 | 2/57 (3.5%) | 2 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Malignant neoplasm progression | 0/272 (0%) | 0 | 1/61 (1.6%) | 1 | 3/57 (5.3%) | 3 |
| Nervous system disorders | ||||||
| Headache | 11/272 (4%) | 17 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Proteinuria | 10/272 (3.7%) | 11 | 3/61 (4.9%) | 5 | 3/57 (5.3%) | 3 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Dysphonia | 54/272 (19.9%) | 76 | 3/61 (4.9%) | 7 | 0/57 (0%) | 0 |
| Dyspnea | 23/272 (8.5%) | 33 | 6/61 (9.8%) | 7 | 8/57 (14%) | 8 |
| Cough | 16/272 (5.9%) | 20 | 2/61 (3.3%) | 3 | 1/57 (1.8%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||
| Palmar-plantar erythrodysaesthesia syndrome | 6/272 (2.2%) | 16 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Rash generalized | 9/272 (3.3%) | 11 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Pruritus | 6/272 (2.2%) | 6 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
| Vascular disorders | ||||||
| Combined Hypertension | 114/272 (41.9%) | 199 | 0/61 (0%) | 0 | 0/57 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT 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.
Results Point of Contact
| Name/Title | Chief Medical Officer |
|---|---|
| Organization | AVEO Pharmaceuticals, Inc. |
| Phone | 857-400-0101 |
| Clinical@aveooncology.com |
- AV-951-07-201