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

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

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)

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

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

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

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%)

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 )

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

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)

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)

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)

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

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)