ASCO Update 2004: ASCO Update 2004: Focus on Prostate and Focus on Prostate and Renal Cell Cancers Renal Cell Cancers Primo N. Lara, Jr., MD Primo N. Lara, Jr., MD Associate Professor Associate Professor University of California University of California Davis Cancer Center Davis Cancer Center
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ASCO Update 2004: Focus on Prostate and Renal Cell Cancers Primo N. Lara, Jr., MD
ASCO Update 2004: Focus on Prostate and Renal Cell Cancers Primo N. Lara, Jr., MD Associate Professor University of California Davis Cancer Center. Development of Hormonal Escape. Androgen-independent cells take over. Deprive androgen. Responsive. Cell numbers. Dependent. Independent. - PowerPoint PPT Presentation
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ASCO Update 2004:ASCO Update 2004:Focus on Prostate and Focus on Prostate and
Renal Cell CancersRenal Cell CancersPrimo N. Lara, Jr., MDPrimo N. Lara, Jr., MD
Associate Professor Associate Professor
University of California University of California
Davis Cancer CenterDavis Cancer Center
Development of Hormonal EscapeDevelopment of Hormonal Escape
Prostate Cancer. London, England: Times Mirror International Publishers Ltd;1996:143.
Randomized Trials of Mitoxantrone + Randomized Trials of Mitoxantrone + Steroid vs. Steroid Alone in HRPCSteroid vs. Steroid Alone in HRPC
Kantoff, et al Kantoff, et al
(JCO 1999) N=242(JCO 1999) N=242
Mitoxantrone + Dexamethasone
Dexa alone P-value
Median survival (months) 12.3 12.6 NS
Time to treatment failure or PD (months)
3.7 2.3 0.02
QOL/Pain control Better Worse N/A
Tannock, et al Tannock, et al
(JCO 1996) N=161(JCO 1996) N=161
Mitoxantrone + Prednisone
Prednisone alone
P-value
Median survival (months) 12 12 NS
Palliative response 29% 12% 0.01
Duration of palliation 43 weeks 18 weeks <0.0001
Docetaxel 70 mg/m2 Estramustine 280 po TID D1-5, 7-11 Q 21 d Prednisone 10 mg po QD HRPC PS 0-1 Docetaxel 35 mg/m2/wk x 3wks No prev Estramustine Q 28 d chemo N=120 Prednisone AAW Mitoxantrone 12 mg/m2 iv Prednisone
Q 21 d
RANDOMIZE
Oudard, pASCO 2003 #706
Randomized Phase II Trial of Randomized Phase II Trial of Docetaxel/Estramustine/Prednisone vs. Docetaxel/Estramustine/Prednisone vs. Mitoxantrone/PrednisoneMitoxantrone/Prednisone
Randomized Phase II Trial of Randomized Phase II Trial of Docetaxel/Estramustine/Prednisone vs. Docetaxel/Estramustine/Prednisone vs. Mitoxantrone/PrednisoneMitoxantrone/Prednisone
A multicenter comparison of A multicenter comparison of docetaxel given weekly or every docetaxel given weekly or every three weeks + prednisone with three weeks + prednisone with mitoxantrone + prednisone in mitoxantrone + prednisone in
patients with hormone-refractory patients with hormone-refractory prostate cancer:prostate cancer:Study TAX-327Study TAX-327
Ronald De Wit M.D. PhDMario A.Eisenberger M.D.
Ian Tannock M.D. PhDand
TAX-327 investigators ASCO 2004 Abstract #4
TAX327Study Design
Stratification:
Pain levelPPI ≥ 2 or AS ≥ 10
vs.PPI < 2 or AS < 10
KPS≤70 vs. ≥ 80
Docetaxel 75 mg/m2 Q3 wks + Prednisone 5 mg bid
Mitoxantrone 12 mg/m2 Q3 wks +
Prednisone 5 mg bid
RANDOMIZE
Docetaxel 30 mg/m2 wkly 5 of 6 wks +
Prednisone 5 mg bid
Premedication: weekly docetaxel arm-dexamethasone 8 mg 1 hr prior to infusion; q3week docetaxel arm: dexamethasone 8 mg 12, 3, and 1 hour prior to infusion
Quality of Life ResponseQuality of Life Response> 16 points FACT-P score > 16 points FACT-P score
compared to baselinecompared to baseline
Docetaxel
3-wkly
Docetaxel
wkly
Mitoxantrone
Evaluable, n 278 270 267
Response (%)
( 95% C.I )
22
(17-27)
23
(18-28)
13
(9-18)
P-value* 0.009 0.005
*Compared to mitoxantrone
Docetaxel and Estramustine versus Docetaxel and Estramustine versus Mitoxantrone and Prednisone in Men with Mitoxantrone and Prednisone in Men with Androgen Independent Prostate Cancer:Androgen Independent Prostate Cancer: Results of Southwest Oncology Group Results of Southwest Oncology Group
Daniel P. Petrylak, M.D.1, Catherine M. Tangen, Dr.PH.2, Maha A. Hussain, M.D.3, Primo N. Lara Jr., M.D.4, Jeffrey A. Jones, M.D.5,
Mary Ellen Taplin, M.D.6, Patrick A. Burch, M.D.7, Graham F. Greene, M.D.8, Mitchell C. Benson, M.D.,1
Eric J. Small, M.D.9, Derek Raghavan, M.D., Ph.D,10 E. David Crawford, M.D.11
1Columbia University, New York, NY 2Southwest Oncology Group Statistical Center, Seattle, WA 3University of Michigan Comprehensive Cancer Center, Ann
Arbor, MI 4University of California, Davis, Sacramento, CA 5Baylor College of Medicine, Houston, TX 6University of Massachusetts Medical Center, Worcester, MA 7Mayo Clinic, Rochester, MN 8University of Arkansas for Medical Science,
Little Rock, AR 9University of California San Francisco Cancer Center, San Francisco, CA 10Cleveland Clinic Foundation, Cleveland, OH 11University of
Colorado Health Science Center, Denver, CO
ASCO 2004 Abstract #3
Schema: S9916Schema: S9916
D/E*Docetaxel 60 mg/m2 IV D2 every 21 days
Estramustine 280 mg po TID, D1-5Premedication: Dexamethasone 20 mg PO TID starting evening of D1
M/PMitoxantrone 12 mg/m2 IV every 21 daysPrednisone 5 mg po BID continuously
*Per protocol amendment January 15, 2001: Coumadin 2 mg PO daily + ASA 325 mg PO daily was added
Docetaxel and mitoxantrone doses could be increased to 70 mg/m2 and 14 mg/m2, respectively, if no grade 3 or 4 toxicities were seen in cycle 1
R Patient Stratification: Type of progression (progression of measurable or evaluable disease vs. increasing
PSA only; NCI CTC pain scale grade < 2 vs > 2; SWOG PS status 0-1 vs 2-3
Grade Grade >> 3 toxicity 3 toxicity
10
12
14
16
18
20
0
2
4
6
8
Pain Neurologic Metabolic Infection Hematologic GI Flu-like symptoms
Cardiovascular
D/E M/P
% o
f p
atie
nts
- there was no difference in toxic deaths between treatment arms
Docetaxel-based chemotherapy improves– Overall survival– Progression-free survival– Quality of life (Tax 327)
Contribution of estramustine is questionable
Reference standard for future studies in metastatic HRPC should be docetaxel
Bortezomib and Proteasome Bortezomib and Proteasome InhibitionInhibition
19SCap
20SSubunit
Chymo-tryptic
Site
Post-Glutamyl
Site
TrypticSite
1 2
3
4
5
6
7
26S Proteasome
Degrades ubiquitinated proteins Proteolysis is ATP-dependent
Bortezomib
19SCap
Chymotryptic site is rate-limiting in protein degradation
J Bio Chem. 1999; 274(32): 22123-22126; Science. 1995; 268(5210) 579-582; Bioorg Med Chem Lett. 1998; 8(4): 333-338.
Bortezomib in Combination with Bortezomib in Combination with DocetaxelDocetaxel
In vitro– Showed additive growth inhibition and apoptosis in
LNCaP and PC-3 prostate cancer cells
In vivo– In pancreatic xenograft models, bortezomib + docetaxel
demonstrated enhanced:• Reduction of tumor mass• p21 accumulation• Inhibition of tumor cell proliferation• Increased apoptosis• Reduced tumor microvessel density
Phase I/II Trial of Bortezomib Plus Phase I/II Trial of Bortezomib Plus Docetaxel in Patients With Advanced Docetaxel in Patients With Advanced Androgen-Independent Prostate CancerAndrogen-Independent Prostate Cancer
R. Dreicer,R. Dreicer,11 B. Roth, B. Roth,22 D. Petrylak, D. Petrylak,33 D. Agus, D. Agus,44 M. Meyers, M. Meyers,55 D. Esseltine,D. Esseltine,66 D. Rodriguez, D. Rodriguez,66 P. Oppedisano, P. Oppedisano,66 K. Wang, K. Wang,66 A. BoralA. Boral66
11Cleveland Clinic Foundation, Cleveland, OH; Cleveland Clinic Foundation, Cleveland, OH; 22Vanderbilt-Ingram Cancer Center, Vanderbilt-Ingram Cancer Center, Nashville, TN; Nashville, TN; 33Columbia University, New York, NY; Columbia University, New York, NY; 44Cedars-Sinai Prostate Cancer Cedars-Sinai Prostate Cancer Center, Los Angeles, CA; Center, Los Angeles, CA; 55Aventis Oncology, Bridgewater, NJ; Aventis Oncology, Bridgewater, NJ; 66Millennium Millennium Pharmaceuticals, Cambridge, MAPharmaceuticals, Cambridge, MA
ASCO 2004, Abstract #4654
Treatment ScheduleTreatment Schedule
Docetaxel 1x/wk (days 1 and 8), bortezomib 1x/wk (days 2 and 9) every 21 days
24 hours between docetaxel and bortezomib Dexamethasone 8 mg night before, morning of,
and evening after each docetaxel infusion
1 Cycle
Day 1 982
D D B B
D = docetaxelB = bortezomib
Rest
21
Dreicer et al, ASCO 2004 Abstract 4654
Results From Phase I: Results From Phase I: Dose-Escalation SummaryDose-Escalation Summary
No DLTs have been reported
MTD not reached
Cohort 4 (40 mg/m2 docetaxel + 1.3 mg/m2 bortezomib) expanded to further assess safety, tolerability, and efficacy
Data on phase II assessment of cohort 4 to be presented (N = 32)
Combination bortezomib and docetaxel at doses below MTD demonstrated promising activity
PR rate 23%
PSA decrease by ≥ 50% confirmed in 24% of patients
All measurable tumor responses and the majority of PSA responses were observed in patients who received prior chemotherapy
Measurable tumor response was observed in 1 patient who had received prior taxane therapy
Combination of docetaxel and bortezomib was well tolerated at doses assessed; adverse events were primarily low grade and manageable
Dreicer et al, ASCO 2004 Abstract 4654
A Phase II Trial of Epothilone-B Analogue BMS-247550 (NSC #710428) Administered Every 21
Days in Patients with Hormone Refractory Prostate Cancer: Southwest Oncology Group
Study S0111
M. Hussain, J. Faulkner, U. Vaishampayan, P. Lara, D. Petrylak, D. Colevas, W. Sakr, E.D.
Crawford
ASCO 2004 Abstract # 5410
SWOG- 0111SWOG- 0111 RationaleRationale
Epothilone-B Analogue BMS-247550:– New class of non-taxane tubulin polymerizing agents
resulting in mitotic arrest at G2/M transition.– High level of anti-tumor activity against in-vitro and
in-vivo tumor models that are naturally resistant or acquired resistance to paclitaxel.
– More potent than paclitaxel in tumor models.
Taxanes have demonstrated activity in patients with hormone refractory prostate cancer.
SWOG- 0111SWOG- 0111Treatment PlanTreatment Plan
Premedication: 1hr prior to BMS-247550:
Diphenhydramine 50 mg PORanitidine 150 mg PO
BMS-247550: 40 mg/m2 IV over 3hrsQ 21 days.
Registration
• PSA was monitored prior to each course.
• Objective response was assessed after every 2 courses
SWOG- 0111SWOG- 0111 PSA ResponsePSA Response
Confirmed Response 14 34%
Unconfirmed Response
2 5%
No Response 20 49%
Not Determinable 5 12%
Total 41 100%
Confirmed PSA response = 34% (95% CI: 20% to 51%)
SWOG- 0111SWOG- 0111 ConclusionsConclusions
In a cooperative group setting single agent Epothilone-B In a cooperative group setting single agent Epothilone-B analogue (BMS-247550) is active in patients with metastatic analogue (BMS-247550) is active in patients with metastatic hormone refractory prostate cancer.hormone refractory prostate cancer.
The most frequent high grade toxicities were hematologic The most frequent high grade toxicities were hematologic and neurotoxicities.and neurotoxicities.– There were no G5 toxicitiesThere were no G5 toxicities– 31% of patient were removed from study due to toxicity.31% of patient were removed from study due to toxicity.– Measures to counteract the neuropathy effects are Measures to counteract the neuropathy effects are
needed.needed.
Further studies are warranted to define this agent’s activity:Further studies are warranted to define this agent’s activity:– in first line treatment relative to standard therapy. in first line treatment relative to standard therapy. – in the second line setting. in the second line setting.
SUMMARY: HRPCSUMMARY: HRPC HRPC is a virulent, incurable disease Aggressive palliative care must be
pursued in the absence of cure Although docetaxel-based
chemotherapy can now be considered standard treatment for metastatic HRPC, the results remain suboptimal
Whenever possible, the “standard of care” for HRPC should still be clinical trial participation
~32,000 new cases; ~12,000 deaths~32,000 new cases; ~12,000 deaths Five year survival rate for Five year survival rate for
metastatic disease is 0-10%metastatic disease is 0-10% Immunotherapy with interleukin-2 Immunotherapy with interleukin-2
or interferon-alfa has generally yielded or interferon-alfa has generally yielded modest clinical benefitsmodest clinical benefits
New agents with unique mechanisms New agents with unique mechanisms of action are neededof action are needed
Image from urotext.com
ECOG 3898: Low Dose Interferon +/- ECOG 3898: Low Dose Interferon +/- Thalidomide in Advanced RCCThalidomide in Advanced RCCGordon, et al. ASCO 2004, Abstract 4516Gordon, et al. ASCO 2004, Abstract 4516
RANDOMIZE
Interferon alfa 2B 1M units SQ BID
N=353
Metastatic or locally advanced RCC
PS 0-2
(84% power to detect a 50% increase in MST from 12 to 18 months)
Interferon alfa 2B 1M units SQ BID
Thalidomide 200 mg q HS (escalated to max of 1 g)
From: Kaelin, ASCO 2004
From: Kaelin, ASCO 2004
#4502
Bevacizumab + Erlotinib in RCC
Hainsworth, et al ASCO 2004
SU11248 in Renal Cell Carcinoma: Survival Curves
Preliminary Antitumor Activity ofPreliminary Antitumor Activity ofBAY 43-9006 in Metastatic Renal Cell BAY 43-9006 in Metastatic Renal Cell
Carcinoma and Other Advanced Refractory Carcinoma and Other Advanced Refractory Solid Tumors in a Phase II Randomized Solid Tumors in a Phase II Randomized
Mark J. Ratain MD, KT Flaherty, WM Stadler, P O'Dwyer, S Kaye,H Xiong, A Patnaik, M Gore, RJ Lee, T Eisen
ASCO 40th Annual MeetingJune 5, 2004
New Orleans, Louisiana
#4501#4501
– Designed as a CRAF-targeted agent Also inhibits wild-type and mutant BRAF
– Recently demonstrated to inhibit other targets VEGFR-2, PDGFR-b, FLT-3 and c-KIT
N
CF3
Cl
NH
NH
OO
NH
O
CH3
BAY 43-9006 (sorafenib)BAY 43-9006 (sorafenib)A Novel RAF Kinase and VEGFR InhibitorA Novel RAF Kinase and VEGFR Inhibitor
BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 Trial SchemaTrial Schema
* May cross over to BAY 43-9006
12 Week Induction
> 25% Shrinkage Continue BAY 43-9006
Open Label
> 25% GrowthOff study
BAY 43-9006
Placebo*
Tumor Assessment
Baseline 12 weeks 24 weeks
>-25% to <25%Randomized
BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 Enrollment by Tumor TypeEnrollment by Tumor Type
ColorectalMelanoma
Sarcoma
Pancreas
Ovarian
Thyroid
Renal Cell
Other
Total number of patients: 484
28%
42%
8%5%
BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 RCC Bidimensional Tumor Measurements* at Week RCC Bidimensional Tumor Measurements* at Week 12:12:Change from Baseline in Target Lesions (n=89)Change from Baseline in Target Lesions (n=89)
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
% C
ha
ng
e i
n T
um
or
Me
as
ure
me
nt
Number of Patients
> 25% Growth
< 25% to >-25% Change
>-25% to -49% Shrinkage
> -50% Shrinkage
7 7
45** 24 1345** 24 13
* Investigator assessed
* * 7 of 45 patients not randomized
BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 Progression-Free Survival in RCC Patients Progression-Free Survival in RCC Patients Continuing Beyond Initial 12 WeeksContinuing Beyond Initial 12 Weeks
* Responders at 12 week assessment with >25% tumor shrinkage
12 Weeks 24 Weeks
Open Label BAY (n=37)Median = 48 weeks(88% progression free at 24 weeks)
Randomized (n=38) Median = 23 weeks(41% progression free at 24 weeks)
Epothilone B Analog (BMS 247550) in Epothilone B Analog (BMS 247550) in Metastatic RCCMetastatic RCC
Zhuang, et al. ASCO 2004, Abstract #4550Zhuang, et al. ASCO 2004, Abstract #4550
N = 54 BMS 247550 6 mg/m2/day x 5 days q 3 wks PR in 8 patients (15%) Seven additional patients had minor