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Avastin®(Bevacizumab) for
Hormone-Refractory Prostate Cancer
Avastin Combined with Docetaxel (Taxotere)
Might Serve as a ≥ 2nd Line Chemotherapy.
Avastin Combined with Thalidomide and Taxotere
also is promising, but has
only been tested in chemotherapy-naive men.
Introduction
Avastin (bevacizumab) is a recombinant, humanized antivascular endothelial growth factor
antibody that specifically inhibits VEGF (anti-VEGF). In pre-clinical
models it has
synergistic or additive tumor inhibition effects with several chemo agents (1)
including doxorubicin,
topotecan, paclitaxel, docetaxel, and also with radiotherapy.
Changes
observed include decreased vascular vessel diameter, density and
permeability in response to Avastin treatment. These changes in the
vascular structure resulted in an increase in intratumoral uptake of
chemotherapy implying a combination treatment would be better than Avastin
alone. Also, combination treatment with radiation increased tumor
oxygenation and tumor growth inhibition.
Definitions
CR - Complete Response.
PR - Partial Response
PSA RR - PSA Response Rate (≥50 Decline in PSA).
SD - Stable Disease.
VEGF - Vascular Endothelial Growth Factor.
MAb - monoclonal antibody.
rhuMAb - recombinant humanized monoclonal antibody
Studies in
Hormone-Refractory Prostate Cancer
Avastin with Docetaxel,
Prior Chemotherapy Allowed, HRPC, metastatic
Di Lorenzo et
al (4) have described their phase II trial of Avastin and Taxotere in men
who had previously been treated with Taxotere and other cytotoxic drugs. In their table of patient
characteristics, they list the various chemotherapies that trial
participants had received. All had prior bisphosphonates. Prior chemotherapies
included (listed with chemotherapy, no of patients.)
-
Docetaxel,
20
-
Mitoxantrone, 20
-
Vinorelbine,
13
-
Cyclophosphamide, 5
-
Thalidomide
3,
-
Platinum
Compounds 7
No. of
Patients: 20, 20 with bone mets and 8 with bone and measurable lesions.
Dose/Schedule: Avastin, 10mg/kg and taxotere 60mg/m2 every 3 weeks. Oral
dexamethasone 8mg 12h before, immediately before and 12 h after taxotere. g-csf
was allowed if needed.
Results (No.
of Patients/ Percent):
-
Measurable
Disease: CR 0, PR 3 (37.5%), SD 2 (25%).
-
PSA ≥ 50% Decrease:
11 (55%).
-
PSA
≥ 25% to
49% Decrease: 2 (10%).
PSA SD <25% decrease to < 25% increase: 2 (10%).
Median
Overall Survival: 9 mos. (4-12.5 mos.)
Progression Free Survival: 4 mos. (2-6 mos.)
Toxicity
(grade 3 and 4 have been highlighted). Based on table 4 from (4).
|
Toxicity data experienced per
patient (n = 20) |
Tax327 Phase III (n=332) |
|
Toxicity
|
Grade 1–2 |
Grade 3 |
Grade 4 |
Grade
(any or as indicated) |
|
Neutropenia
|
8 (40%) |
3 (15%) |
1 (5%) |
32 (gr 3/4) |
|
Anemia
|
4 (20%) |
1 (5%) |
0% |
5 (gr 3/4) |
|
Thrombocytopenia
|
8 (57%) |
2 (10%) |
1 (5%) |
1 (gr 3/4) |
|
Edema
|
3 (15%) |
0% |
0% |
19 |
|
Hypertension
|
7 (35%) |
0% |
0% |
- |
|
Nausea/vomiting
|
7 (35%) |
2 (10%) |
0% |
42 |
|
Peripheral neuropathy
|
5 (25%) |
1 (5%) |
0% |
30 |
|
Lacrimation
|
5 (25%) |
0% |
0% |
10 |
|
Myalgia
|
5 (25%) |
0% |
0% |
14 |
|
Dyspnea
|
3 (15%) |
0% |
0% |
15 |
|
Fatigue |
- |
- |
- |
5 (gr 3/4); 53 overall. |
A Case Study
A related study by Ning YM et al
(8) found that adding avastin and thalidomide to a patient who had
previously failed docetaxel chemotherapy reversed the resistance to
docetaxel thereby extending docetaxel activity. The patient had metastatic
CRPC disease with biochemical progression. The patient responded an
additional 7 months.
Phase III Trial With Taxotere and Avastin (CALGB 90401)
The latest news on this trials results as of 3/12/2010 indicate Avastin
and Taxotere is unlikely to be approved for HRPC disease. The following news
item gives very little information but until ASCO 2010 abstracts come out
(June) we probably won't know more. Adding avastin to taxotere/prednisone
likely just adds more toxicity, not longer survival.
"Roche's Avastin Fails to Meet Goal of Prostate
Study (Update2) By Angela Cullen
March 12
(Bloomberg) -- Roche Holding AG said its Avastin cancer medicine failed to
extend the life of men with late-stage prostate cancer in a study, limiting
the Swiss drugmaker's efforts to expand the use of its biggest medicine.
A
combination of the biologic drug, chemotherapy and the prednisone pill
didn't extend overall survival compared with treatment with the latter two
medicines alone, Basel, Switzerland-based Roche said in an e-mailed
statement today. The final-stage trial was sponsored by the U.S. Cancer and
Leukemia Group B and the National Cancer Institute."
CALGB 90401: Randomized Double Blinded Placebo controlled Phase III Trial Comparing
Docetaxel + Prednisone with or without Bevacizumab in men with HRPC.
Patients could not have had prior thalidomide, bevacizumab
or any other antiagiogenesis agents. They also couldn't use concurrent
G-CSF, GM-CSF or pegfilgrastim.
Furthermore, they were not allowed to have had prior emcyt, suramin or any other cytotoxic chemotherapy (prior or
concurrent). There were two arms in this trial.
Both arms used:
Dexamethasone 8 mg po x 3 doses (changed
to may use IV)
Docetaxel 75 mg/m2 on day 1 q 21 days
Prednisone 10 mg po daily (allowed
to modify due to tox)
Arm A had the
Placebo: Placebo IV on day 1 q 21 days
Arm B had the study drug: Bevacizumab 15 mg/kg IV on day 1 q 21 days
Status: CALGB issued the
following information on this phase III clinical trial:
A Randomized Double-Blinded Placebo Controlled Phase
III Trial Comparing Docetaxel And Prednisone With And Without Bevacizumab (IND
#7921, NSC #704865) In Men With Hormone Refractory Prostate Cancer. The
CALGB Data and Safety Monitoring Board (DSMB) has recommended that the
results of CALGB 90401 be released to the study team. The study did not
meet its primary objective of an overall survival benefit. It is planned
that the details of these findings will be presented at the ASCO Annual
Meeting in June, 2010.
CALGB 90401 has been closed to accrual since
December 21, 2007 and all patients have completed protocol treatment. The
DSMB recommendations are not based on safety issues and there is no plan to
unblind treatment assignments. Patient notification is not required.
Institutions should continue to submit follow-up data as specified in the
protocol.
Comment: Di Lorenzo et al, using a different dose
(and smaller sample size) had great success with taxotere plus avastin as a
≥
2nd line chemotherapy (4). As part of a sequential chemotherapy
protocol, this could be a better option than that followed by CALGB 90401.
What Other Combinations Using Avastin Might be of Use in HRPC?
YM Ning (5) et al have studied the taxotere, avastin and thalidomide
combination. Their phase II trial is based on the hypothesis that combining
the mechanistically different anti-angiogenic agents, Thalidomide (T) and
Bevacizumab (Bv), with Taxotere would block multiple angiogenic pathways and
lead to potent anti-tumor activity. Thalidomide does not affect the target of Bevacizumab (VEGF) in
xenograft models of AIPC, but appears to alter circulating endothelial cells
and inhibits TNF expression.
Patients: All were chemotherapy naive. All had progressive metastatic castration resisitant prostate cancer (mCRPC). Total
patients enrolled: 60.
Treatment: Taxotere 75mg/m2 & Bv 15mg/kg day 1 every 21
days + 200mg thalidomide every day at bedtime and 10mg every day of
prednisone. Also they used enoxaparin for thrombosis prevention and
pegfilgrastim if grade >3 neutropenia.
Results:
PSA RR: 51 of 60 (88%); 5 had PSA declines of < 50% &
41 of 60 (71%) had a decline of > 80%.
Measurable disease: 63% overall response rate consisting of 2 complete, 18
partial, 11 stable and 1 progressive.
Progression Free Survivial: estimated median 18.2
months.
Significant toxicities: febrile neutropenia (5/60), syncope (5/60), GI
perforation or fistula (3/60), thrombosis (3/60), grade 3 bleeding (2/60).
Side Effects
The side effects seen by Di Lorenzo et al(4) are listed above.
Recently a meta-analysis (6) of 7956 patients with a variety of solid tumors
were included. 12% developed blood clots of which 6% were serious enough to
require treatment. Both high and low dose avastin patients had blood
clots, but the incidence rate varied by cancer type -- most notably it was
19% in corectal cancer versus 7% in breast cancer patients. Two other
antiangiogenic drugs (lenalidomide
and Thalidomide) also cause blood clots and are often used with
anticoagulation. Whether or not this meta-analysis results in a warning
label remains to be seen.
The safety of avastin (bevacizumab) in patients with central nervous system
(CNS) metastases was retrospectively reviewed by UP Rohr et al (7) from 3
datasets where they found that the rate of cerebral hemorrhages in patients
with CNS metastases treated with avastin is low -- similar to historical
rates. Hemorrhage rates were 3.29%, 0.93% and 0.8% among Avastin treated
patients. Patients have been excluded from clinical trials using
Avastin if they had CNS metastases. The present study questions the need for
this exclusion.
For the full prescribing information which includes information on side
effects visit the Genentech Avastin web
pages.
Conclusion
Based on the
results to date, the combination of taxotere and avastin looks very
promising. By adding thalidomide to this mix, there appears to be an
even greater reason to continue this direction of treatment.
Unfortunately, for HRPC, Avastin has yet to be approved by the U.S. FDA.
Di Lorenzo et
al (4) used a reduced dose of taxotere (60mg/m2) and Avastin (10mg/kg) in
chemotherapy pre-treated men and got a PSA RR of 55% and a Measurable
disease overall RR of 62.5% (PR 3 (37.5%), SD 2 (25%)). Ning et al (5) got a
PSA RR of 88% and Measurable disease overall RR of 63% in chemo-naive
patients, but had two complete responses while Di Lorenzo had none.
The PFS numbers are very improved with the triple combination vs the double
(4 mos for double vs 18.2 for triple).
Until the
avastin, thalidomide, taxotere combination is tested on chemotherapy
pre-treated patients, it is not possible to tell whether or not adding
thalidomide makes any significant difference. We can look forward to a
trial of this option as well as the results of the phase III trial.
Author: Howard Hansen, 13 August 2008,
updated 9 April 2009
Note: The author is not a medical doctor and cannot render medical
advice. As a prostate cancer patient, this was written in an attempt to
understand these treatments and how it affects me. I make no claims that
this review is definitive, complete or authoritative and I request any
contributions to, or clarification of the subject which might contribute to
the issue or inquiry. In conjunction with a medical team, every cancer
patient must make their own decisions regarding treatment options. Your own
medical team's directions should be carefully followed.
(1)
Gerber HP, Ferrara N,
Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in
combination with cytotoxic therapy in preclinical studies,
Cancer Res. 2005 Feb 1;65(3):671-80.
(2) David M. Reese, PhD,Paige Fratesi, BS,
Michelle Corry, RN, William Novotny, MD,
Eric Holmgren, PhD,and Eric J. Small, MD, A Phase II Trial of Humanized Anti-Vascular Endothelial Growth
Factor Antibody for the Treatment of Androgen-Independent Prostate Cancer, The Prostate Journal Volume
3 Issue 2 Page 65 - April/May/June 2001
doi:10.1046/j.1525-1411.2001.32007.x
(3) J. Picus, S. Halabi, B. Rini, N. Vogelzang, Y. Whang, E.
Kaplan, W. Kelly, E. Small; The use of bevacizumab (B) with docetaxel (D)
and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial
results of CALGB 90006; ASCO 2003, Abstract No: 1578.
(4) Di Lorenzo G, Figg WD, Fossa SD, Mirone V, Autorino R, Longo N, Imbimbo C,
Perdonà S, Giordano A, Giuliano M, Labianca R, De Placido S, Combination of
Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory
Prostate Cancer: A Phase 2 Study, Eur Urol. 2008 Feb 5. [Epub ahead of
print] Eur Urol (2008), doi:10.1016/j.eururo.2008.01.082. (5)
Ning YM, Gulley JL, Arlen PM, Woo S,
Steinberg SM, Wright JJ, Parnes HL, Trepel JB, Lee MJ, Kim YS, Sun H, Madan
RA, Latham L, Jones E, Chen CC, Figg WD, Dahut WL, Phase II Trial of
Bevacizumab, Thalidomide, Docetaxel, and Prednisone in Patients With
Metastatic Castration-Resistant Prostate Cancer, J Clin Oncol. 2010 Mar 22.
[Epub ahead of print]
PMID: 20308663.
(6) Nalluri SR, Chu D, Keresztes R, Zhu
X, Wu S, Risk of venous thromboembolism with the angiogenesis inhibitor
bevacizumab in cancer patients: a meta-analysis, JAMA, 2008 Nov
19;300(19):2277-85.
(7) U. P. Rohr, S. Augustus, S. F.
Lasserre, P. Compton, J. Huang;
Safety of bevacizumab in patients with metastases to the central nervous
system, J Clin Oncol 27:15s, 2009 (suppl; abstract 2007), 2009 ASCO Annual
Meeting.
(8) Ning YM, Figg WD, Dahut WL.,
Reversal of docetaxel resistance with bevacizumab and thalidomide,
Clin Genitourin Cancer. 2009 Aug;7(2):E37-8; DDOP/OODP/CDER, Food and Drug
Administration, Silver Spring, MD, USA.
Access to AvastinAvastin is very expensive. Many insurance plans do
not cover it. Here's what one member of the email list researched about
this:
"I've done some research and found that
Genentech (maker of Avastin) has an Access Solutions department that works
with patients (and doctors) and insurance companies to see what will be
covered. If they cannot work out a solution with the insurance company,
they will work with the patient to have Genentech reimburse for the Avastin.
I called and spoke with a delightful woman who assured me that they will
help with securing the drug. The Access Solutions number for patients is 1
(888)249-4918 and a real person answers! If any of you are thinking of
Avastin as a possibility, please call that number or go to
https://www.genentechaccesssolutions.com/index_avastin.jsp ."
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