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Cabazitaxel (Jevtana)
A new chemotherapy for use
following taxotere (docetaxel) failure and thus can be considered a ≥
2nd line chemotherapy for HRPC patients.
Author:
Howard Hansen
Date:
24 June 2010
Introduction
Cabazitaxel (Jevtana)
(Sanofi-aventis). This new taxane chemotherapy drug was approved by the FDA on
17 June 2010. The approval was for use in combination with prednisone
for treatment of patients with metastatic hormone-refractory prostate
cancer (mHRPC) previously treated with a taxotere (docetaxel) containing
regimen. The original designation for cabazitaxel was XRP-6258.
Patients eventually become resistant to docetaxel
because of a mechanism in prostate cancer cells called
the multidrug resistant (MDR) pump, which pumps the
anticancer drug out of the cancer cell before it can
exert its effects. The MDR pump appears to be unable to
recognize cabazitaxel, enabling the drug to enter and
effectively kill the prostate cancer cells.
It works by disrupting the microtubular
network that is essential for mitotic and interphase
cellular functions and causes inhibition of cell
division and cell death. (3)
The phase III trial that resulted in FDA approval is
covered below.
Note the following abbreviations:
D for docetaxel (taxotere)
Cabazitaxel/Prednisone - CbzP
PD - Progressive Disease
OS - Overall Survival
RESIST criteria - used for measurable tumors.
Dose and Schedule
Cabazitaxel: 25mg/m2 every 3 weeks plus Prednisone
10mg/day. Some have suggested a starting dose of 20mg/m2
every 3 weeks should have been used. A starting
dose of 15mg/m2 might also be effective with less
toxicity in some patients.
Cabazitaxel was compared to Mitoxantrone 12mg/m2 every 3
weeks in combination with prednisone 10mg/day.
Patients - phase III (TROPIC) (1,2)
755 patients with mHRPC who were previously treated with
taxotere containing regiments. The patients were
randomized to either cabazitaxel 25mg/m2 IV every 3
weeks or mitoxantrone 12 mg/m2 every 3 weeks - both arms
included prednisone 10mg/day
More specifically, the patients had ECOG PS 0-2, and
adequate organ function and who had prior hormone
therapy, chemotherapy, and radiotherapy, but had
progressive disease (PD) during or after Docetaxel
(cumulative dose ≥225 mg/m2
-- or at least 3 75mg/m2 taxotere doses.).
The final report on this trial indicates median doses
much higher than 225mg/m2 --
Median prior Docetaxel dose was 576 mg/m2for
CbzP and 529 mg/m2
for MP. Median follow-up
was 12.8 mos. Median number of cycles was 6 for CbzP and
4 for MP. The table below summarize the results. The
hazard ratio results are not included here - see the
original abstract (1).
| |
|
Population |
Mitoxantrone
Prednisone |
Cabazitaxel
Prednisone
|
| |
N (%) |
Median
OS (mos) |
N (%) |
Median
OS (mos) |
| ITT |
377
(100) |
12.7 |
378
(100) |
15.1 |
| PD
while on D |
103
(27) |
12.0 |
113
(30) |
14.2 |
| PD
after last D dose |
|
|
|
|
|
<3 mos |
180
(48) |
10.3 |
158
(42) |
13.9 |
|
≥3 mos |
91
(24) |
17.7 |
103
(27) |
17.5 |
|
ITT = Intent to Treat; PD = Progressive Disease; OS =
Overall survival; D = docetaxel (or taxotere).
Investigator-assessed response rates using RECIST
criteria was 14.4% and 4.4% for cabazitaxel-treated and
mitoxantrone-treated patients, respectively, p=0.0005
(25% of the patients had measurable disease.)
No complete responses were observed on either arm.
(14.4% seems to be a pretty low response rate - no
details are given).
Adverse Reactions
The most common (≥10%) grade 1-4 adverse reactions
included neutropenia, anemia, leukopenia,
thrombocytopenia, diarrhea, fatigue, nausea, vomiting,
constipation, asthenia, abdominal pain, hematuria, back
pain, anorexia, peripheral neuropathy, pyrexia, dyspnea,
dysgeusia, cough, arthralgia and alopecia. The most
common (≥5%) grade 3-4 adverse reactions were
neutropenia, leukopenia, anemia, febrile neutropenia,
diarrhea, fatigue and asthenia.
Deaths due to causes other than disease progression
within 30 days of the last dose were reported in 18 (5%)
cabazitaxel-treated patients and 3 (<1%)
mitoxantrone-treated patients. The most common fatal
adverse reactions in cabazitaxel-treated patients were
infections (n=5), and renal failure (n=4).). One death
was due to diarrhea-induced dehydration and electrolyte
imbalance. There was a geographic variance in the number
of deaths where <1% of patients died on the therapy,
while in Europe, the rate was 4.9% of patients receiving
cabazitaxel and 3.0% for patients receiving
mitoxantrone. The difference might be attributed to
better management of toxicities, including neutropenia
in North America.
G-CSF may be administered to reduce the risks of
neutropenic complications associated with cabazitaxel
use. Primary prophylaxis with G-CSF should be
considered in patients with high-risk clinical features
including age > 65 years, poor performance status,
previous episodes of febrile neutropenia, extensive
prior radiation ports, poor nutritional status, or other
serious comorbidities. Therapeutic use of G-CSF and
secondary prophylaxis should be considered in patients
at an increased risk for neutropenia complications.
Other Information
Because of the risk of severe hypersensitivity,
patients should be premedicated with an antihistamine, a
corticosteroid and an H2 antagonist. In addition,
antiemetic prophylaxis is recommended. This is
more like a taxol chemotherapy than taxotere.
Full prescribing information, including clinical
trial information, safety, dosing, drug-drug
interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/201023lbl.pdf
Cabazitaxel can cross the blood-brain-barrier and
therefore has the potential to be useful against
metastatic brain lesions as well as systemic disease,
but this has not been demonstrated yet.(3). At reference
#3 they have the following information:
"A semi-synthetic derivative of the
natural taxoid 10-deacetylbaccatin III with potential antineoplastic
activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the
inhibition of microtubule depolymerization and cell division, cell cycle
arrest in the G2/M phase, and the inhibition of tumor cell
proliferation. Unlike other taxane compounds, this agent is a poor
substrate for the membrane-associated, multidrug resistance (MDR),
P-glycoprotein (P-gp) efflux pump and may be useful for treating
multidrug-resistant tumors. In addition, cabazitaxel penetrates the
blood-brain barrier (BBB). Check for
active clinical trials or
closed clinical trials using this agent. (NCI
Thesaurus)"
References
1.
J. S. De Bono, S. Oudard, M. Ozguroglu, S. Hansen, J. H.
Machiels, L. Shen, P. Matthews, A. O. Sartor, for the
TROPIC Investigators, Cabazitaxel or
mitoxantrone with prednisone in patients with metastatic
castration-resistant prostate cancer (mCRPC) previously
treated with docetaxel: Final results of a multinational
phase III trial (TROPIC), 2010 ASCO annual meeting,
abstract number 4508, J Clin Oncol 28:15s, 2010 (suppl; abstr 4508)
2. A. O. Sartor,
S. Oudard, M. Ozguroglu, S. Hansen, J. H.
Machiels, L. Shen, S. Gupta, J. S. De Bono, for
the TROPIC Investigators; Cabazitaxel or
mitoxantrone with prednisone in patients with
metastatic castration-resistant prostate cancer
(mCRPC) previously treated with docetaxel: Final
results of a multinational phase III trial
(TROPIC). 2010 Genitourinary Cancers Symposium,
abstract no. 9.
3. The NCI drug dictionary has
some information on cabazitaxel.
http://www.cancer.gov/drugdictionary/?CdrID=534131
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