d richards 1 , j nemunaitis 2 , s vukelja 1 , c hagenstad 3 , l campos 4 , j letzer 5 ,
DESCRIPTION
Final Results of a Randomized Phase II Study of Perifosine in Combination with Capecitabine (P-CAP) vs. Placebo Plus Capecitabine (CAP) in Patients with 2 nd or 3 rd Line mCRC Abstract # 3531. D Richards 1 , J Nemunaitis 2 , S Vukelja 1 , C Hagenstad 3 , L Campos 4 , J Letzer 5 , - PowerPoint PPT PresentationTRANSCRIPT
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Final Results of a Randomized Phase II Study of Perifosine in Combination
with Capecitabine (P-CAP) vs. Placebo Plus Capecitabine (CAP) in Patients with 2nd or 3rd Line mCRC
Abstract # 3531
D Richards1, J Nemunaitis2, S Vukelja1, C Hagenstad3, L Campos4, J Letzer5,R Hermann6, P Sportelli7, L Gardner7 and J Bendell8
(1) Texas Oncology, Tyler, TX, (2) Mary Crowley Cancer Research Center, Dallas, TX,(3) Suburban Hematology/Oncology, Lawrenceville, GA, (4) Oncology Consultants, Houston, TX,
(5) Kalamazoo Hematology Oncology, Kalamazoo, MI, (6) Northwest Georgia Oncology, Marietta, GA,(7) Keryx Biopharmaceuticals, Inc., NY, NY, (8) Sarah Cannon Research Institute, Nashville, TN
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Perifosine Oral alkylphospholipid
Inhibition of multiple signal transduction pathways– AKT inhibition– NF-B inhibition– Activation of apoptotic pathway via JNK
Selective tumor cell accumulation and potential disruption of membrane asymmetry
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Potential Mechanisms of Action of Perifosine + Capecitabine
NF-B Inhibition– Fluorouracil resistance associated with upregulation of NF-B1
– Inhibition of NF-B pathway (proteasome inhibitors, mTOR inhibitors) augments fluorouracil anti-tumor effect2
– Perifosine shown to inhibit NF-B nuclear translocation and pathway activation3
Anti-angiogenic effects– Downstream inhibition of VEGF receptor signaling pathway– Anti-VEGF therapy potentially augments chemotherapy
1. Voboril, R., et al., Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J Surg Res, 2004. 120(2)
2. Nakanishi, C. and M. Toi, Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer, 2005. 5(4)
3. Leleu, X., et al., Targeting NF-kappaB in Waldenstrom macroglobulinemia. Blood, 2008. 111(10)
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Treatment Plan / Schema
Cycle = 21 Days
Primary Objective:– To compare time to progression (TTP) of P-CAP vs. CAP as 2nd or
3rd line Rx
Secondary Objective: – To compare overall response rate (CR + PR) and overall survival– To evaluate the safety of P-CAP vs. CAP
Patients with 2nd or 3rd line mCRC
No prior Rx with CAP in metastatic setting
Prior Rx with 5-FU or 5-FU based regimen
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Patient Demographics
DemographicP-CAP (n = 20)
CAP(n = 18)
All Patients(n = 38)
Median Age 65 (range 32 – 83) 65 (range 43 – 83) 65 (range 32-83)
Male / Female 14 / 6 9 / 9 23 / 15
Median Prior Rx 2 (range 1-4) 2 (range 2-5) 2 (range 1-5)
ECOG PS: 0/1 6 / 14 5 / 13 11 / 27
Refractory to prior 5 – FU Rx
14 70 %
1372%
2771%
38 Patients Enrolled
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Prior Rx by Arm
PRIOR RxP-CAP
( n = 20)CAP
(n = 18)All Patients
N=38
FOLFIRI 18 (90%) 16 (89%) 34 (89%)
FOLFOX 15 (75%) 13 (72%) 28 (74%)
FOLFIRI & FOLFOX
13 (65%) 12 (67%) 25 (66%)
Bevacizumab 15 (75%) 15 (83%) 30 (79%)
EGFR Antibody 9 (45%) 10 (56%) 19 (50%)
89% of patients were third line or greater
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Results: Safety ( n = 38 )
Most Common Grade 1 & 2 Adverse Events
Adverse EventP-CAP (20 pts)
n (%)CAP (18 pts)
n (%)
Diarrhea 15 (75%) 5 (28%)
Fatigue 10 (50%) 6 (33%)
Nausea 9 (45%) 5 (28%)
Musculoskeletal Pain 6 (30%) 3 (17%)
Hand & Foot 5 (25%) 4 (22%)
Mucositis 5 (25%) 1 (6%)
Anorexia 5 (25%) 2 (11%)
Anemia 5 (25%) 3 (17%)
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Grade 3 & 4 Adverse Events: > 10%
Adverse EventP-CAP (n=20)
CAP(n=18)
Hand and Foot 6 (30%) 0%
Anemia 3 (15%) 0%
Abdominal Pain 1 (5%) 2 (11%)
Fatigue 0% 2 (11%)
Bowel Obstruction 0% 2 (11%)
Median time to onset of Grade 3 / 4 Hand-Foot Syndrome for perifosine arm: 19 wks
Median time to onset of Hand-Foot Syndrome for CAP: 11 weeks
Results: Safety ( n = 38 )
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Results: Response
All Evaluable: n = 35
Group nCR
N (%)PR
N (%)Duration of Response
(months)SD > 12 Weeks
N (%)SD or >*
N (%)
P-CAP 20 1 (5%) 3 (15%)CR: 34
11 (55%) 15 (75%)PR: 21, 19, 11
CAP 15 0 1 (7%) PR: 7 5 (33%) 6 (40%)
*p = 0.036
5-FU Refractory: n = 25
Group nPR
N (%)Duration of Response
(months)SD > 12 Weeks
N (%)SD or >*
N (%)
P-CAP 14 1 (7%) 19 months 8 (57%) 9 (64%)
CAP 11 0 - 3 (27%) 3 (27%)
*p = 0.066
35 / 38 Patients evaluable for efficacy 3 placebo patients not evaluable: 2 off for toxicity at d 14, 46; 1 off at d 4 for other disease
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Median Time to Progression (TTP)
5-FU REFRACTORY PATIENTS
Median TTP: P-CAP:18 weeks [95% CI (12, 36)]
Median TTP: CAP: 10 weeks [95% CI (6.6, 11)]
p-value = 0.0004
Hazard ratio: 0.186(0.066, 0.521)
ALL EVALUABLE PATIENTS
Median TTP: P-CAP: 28 weeks [95% CI (12, 48)]
Median TTP: CAP: 11 weeks [95% CI (9, 15.9)]
p-value = 0.0012
Hazard ratio: 0.284(0.127, 0.636)
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Median Overall Survival (OS)
5-FU REFRACTORY PATIENTS
Median OS: P-CAP:15.1 mos [95% CI (7.3, 22.3)]
Median OS: CAP: 6.6 mos [95% CI (4.7, 11.7)]
p-value = 0.0112
Hazard ratio: 0.313(0.122, 0.802)
ALL EVALUABLE PATIENTS
Median OS: P-CAP: 17.7 mos [95% CI (8.5, 24.6)]
Median OS: CAP: 10.9 mos [95% CI (5, 16.9)]
p-value = 0.0161
Hazard ratio: 0.410(0.193, 0.868)
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Randomized Phase II Conclusions Although a small study, perifosine + capecitabine
(P-CAP) appears to improve TTP, ORR and OS compared to placebo + capecitabine (CAP)
These results are also seen in the subset of patients with 5-FU refractory disease
P-CAP was well-tolerated compared to CAP alone Increase in grade 3/4 hand-foot syndrome, anemia
A randomized ph III study comparing P-CAP to CAP in patients with refractory mCRC has been initiated (X-PECT Trial)
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X-PECT TrialRANDOMIZED, DOUBLE-BLIND, PHASE III TRIAL OF PERIFOSINE + CAPECITABINE
(P-CAP) VERSUS PLACEBO + CAPECITABINE (CAP) IN PATIENTS WITH
REFRACTORY METASTATIC COLORECTAL CANCER
Opened April 2010
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Treatment / Schema
Cycle = 21 Days
Patients with refractory mCRC
No prior Rx with CAP in metastatic setting
Randomized 1:1, Double-blind N = ~430 patients RECIST v 1.1 CTCAE v 4.0
Primary Endpoint: Overall Survival
Secondary Endpoints: PFS, ORR, Safety
*Phase I study perifosine + capecitabine with capecitabine at 1000 mg/m2 PO
BID days 1 – 14 showed safety and tolerability of combination
(ASCO 2010 Abstract # 51462)