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Phase II Trial of Tivozanib (AV-951) versus a Placebo
Following are details of the study.
Trial Study Methods
The study was conducted in Russia, the Ukraine, and India. A total of 272 patients entered the study and were given 1.5 mg/day of tivozanib for 16 weeks at which point they were evaluated for tumor growth and divided into three groups:
- a) If ≥ 25% shrinkage, patients were kept on tivozanib for an additional 12 weeks
- b) If < 25% shrinkage or growth, patients were randomized into two groups:
i) kept on tivozanib for an additional 12 weeks
ii) put on a placebo for 12 weeks - c) If ≥ 25% growth, discontinued treatment
Taken from Aveo's poster, the trial design looks like this:
Tivozanib Phase II Study Design
Note that those patients who were in the middle category, that is, they had less than 25% tumor shrinkage but also less than 25% tumor growth, were then randomized to either stay on tivozanib or to be put on a placebo. The purpose of the placebo arm was to see whether patients saw stability due to the drug itself or would have been stable with or without the drug.
Primary endpoints for evaluation were:
- Objective response rate (ORR) at 16 weeks
- Comparison of progression-free survival rates at 12 weeks after having been randomized to either tivozanib or placebo in group b) above
- Safety of the therapy
Dose reductions were required in 23 patients (8.5%) and dose interruptions in 8 patients (2.9%). 73% of patients had a prior nephrectomy. 83% of the patients had clear cell histology and 17% other. The number of prior treatments and the risk category, which predicts a priori overall survival for the study population, and is measured by the Memorial Sloan-Kettering (MSKCC) Prognostic Score, are as follows.
|
No. Prior Treatments |
Patients (%) |
|
0 |
146 (53.7%) |
|
1 |
75 (27.6%) |
|
≥ 2 |
51 (18.8%) |
|
MSKCC Prognostic Score |
Patients (%) |
|
Favorable |
81 (29.8%) |
|
Intermediate |
156 (57.4%) |
|
Poor |
22 (8.1%) |
|
Unknown |
13 (4.8%) |
Safety
Approximately 55% of patients suffered from hypertension with 8.4% of those having grade 3/4 symptoms. 21% had dysphonia (hoarseness) and another 10% or so exhibited asthenia (muscle weakness), diarrhea, or fatigue. Significant for their absence were the low incidence rates (<5%) for hand-foot syndrome, stomatitis (sores in the mouth), and proteinuria (high protein level in the urine). Laboratory abnormalities included elevated liver enzyme levels.
Response
The progression-free survival (pfs) by independent radiological review for the entire study population was 11.8 months. The investigators stratified the results by clear cell patients (pfs=364 days) and non-clear cell patients (pfs=220 days). The tumor response rates were as follows.
|
Response |
All Patients n = 272 |
Clear Cell Pts n = 226 |
Non-Clear Cell Pts n = 46 |
|
CR |
1 (0.4%) |
1 (0.4%) |
0 (0.0%) |
|
PR |
681 (25%) |
60 (26.6%) |
8 (17.3%) |
|
SD |
160 (58.8%) |
131 (58%) |
29 (63%) |
|
PD |
21 (7.7%) |
18 (8%) |
3 ( 6.5%) |
|
NE |
22 (8.1%) |
16 (7.1%) |
6 (13%) |
|
ORR |
69 (25.4%) |
61 (27.0%) |
8 (17.4%) |
|
1 unconfirmed in 19 patients; CR=complete response, PR=partial response, SD=stable disease, PD = progressive disease, NE=not evaluable, ORR=overall response rate=CR+PR |
|||
Patients with < 25% Shrinkage/Growth
For those patients in group b) above, 58 patients were randomized to continue receiving tivozanib for another 12 weeks, while 53 patients received a placebo for 12 weeks. The patients who remained progression-free after 12 weeks are shown in the following table, verifying that tivozanib was indeed active in patients with stable disease.
|
Tivozanib (n = 58 patients) |
Placebo (n = 53 patients) |
|
34 (58.6%) |
20 (37.7%) |
Comments
Tivozanib shows promise as a VEGF inhibitor both for its efficacy (11.8 months progression-free survival and 83% of patients had at least some tumor shrinkage although only 25% had enough shrinkage to qualify for a ‘partial response') and its safety. Given favorable results in a Phase III trial, which is planned to commence in December 2009, it will probably win FDA approval as an anti-kidney cancer drug, joining the other tyrosine kinase inhibitors such as Sutent and Nexavar. In terms of safety, hypertension is a prevalent side effect, which is common with other TKIs. The Phase III trial should be announced within the next month or two and will include sites in the U.S. If tivozanib continues to show a low level of toxicity in a Phase III trial, it could be a candidate for a combination with other targeted therapies or even a cytotoxic agent, if one is found. Currently, Aveo is conducting a Phase I trial using the combination of tivozanib and temsirolimus (Torisel) testing for safety and maximum tolerated dose. The results of this trial will be reported on by Aveo at the AACR-EORTC Conference in Boston this November.
For a reality check, these TKIs have not proven to have durable responses and have not been curative either. Tivozanib seems to be no exception with only one complete response in 272 patients. Possibly, it will yield longer stability in combination with other agents. Finally, tivozanib seems to have an effect on non-clear cell patients with over 7 months progression-free survival solidifying the view that anti-angiogenic therapy is effective against non-clear cell renal carcinoma. Unfortunately, Aveo did not stratify the patients in the other histology category by papillary, chromophobe, etc. so we don't know the individual response rates by pathology type.
IC50 Value of Tivozanib
IC50 is the concentration of a drug that is necessary to inhibit a biological process. So, for example, the IC50 (50% inhibitory concentration) value for tivozanib vis-à-vis VEGFR-1 is .21 nanoMolars (nM). This means that .21 nM of tivozanib inhibits the biologic functioning of VEGFR-1 by 50% in vitro. By comparison, axintinib, also an inhibitor of VEGFR-1, has an IC50 value of 1.2 nM. Nexavar is not an inhibitor of VEGFR-1. The following chart, extracted from Aveo's poster, compares the IC50 values for a few TKIs. Note the fact that tivozanib is a potent drug, as shown by its low IC50 values, does not necessarily mean that it is an effective drug, but it may reduce side effects enabling it to be a candidate for combination trials.
VEGF, or vascular endothelial growth factor, is a protein that promotes angiogenesis or the growth in blood vessels, which in the case of kidney cancer, support tumor growth. VEGFR is the class of receptors to VEGF, which if bound to by a tyrosine kinase inhibitor like tivozanib will inhibit new blood vessel growth that supports tumor spread.
|
Agent |
VEGEFR1 |
VEGEFR2 |
VEGEFR3 |
|
tivozanib |
0.21 |
0.16 |
0.24 |
|
axitinib |
1.2 |
0.25 |
0.29 |
|
pazopanib |
10 |
30 |
47 |
|
Sutent (sunitinib) |
2 |
10 |
17 |
|
Nexavar (sorafenib) |
N/A |
90 |
20 |