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D Richards 1 , J Nemunaitis 2 , S Vukelja 1 , C Hagenstad 3 , L Campos 4 , J Letzer 5 ,

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 ,

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D Richards 1 , J Nemunaitis 2 , S Vukelja 1 , C Hagenstad 3 , L Campos 4 , J Letzer 5 ,

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  1. 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

  2. Perifosine • Oral alkylphospholipid • Inhibition of multiple signal transduction pathways • AKT inhibition • NF-kB inhibition • Activation of apoptotic pathway via JNK • Selective tumor cell accumulation and potential disruption of membrane asymmetry

  3. Potential Mechanisms of Action of Perifosine + Capecitabine • 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) • Nakanishi, C. and M. Toi, Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer, 2005. 5(4) • Leleu, X., et al., Targeting NF-kappaB in Waldenstrom macroglobulinemia. Blood, 2008. 111(10) • NF-kB Inhibition • Fluorouracil resistance associated with upregulation of NF-kB1 • Inhibition of NF-kB pathway (proteasome inhibitors, mTOR inhibitors) augments fluorouracil anti-tumor effect2 • Perifosine shown to inhibit NF-kB nuclear translocation and pathway activation3 • Anti-angiogenic effects • Downstream inhibition of VEGF receptor signaling pathway • Anti-VEGF therapy potentially augments chemotherapy

  4. Treatment Plan / Schema • 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 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

  5. Patient Demographics 38 Patients Enrolled

  6. Prior Rx by Arm 89% of patients were third line or greater

  7. Results: Safety ( n = 38 )

  8. Results: Safety ( n = 38 ) • 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

  9. Results: Response • 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 *p = 0.036 *p = 0.066

  10. Median Time to Progression (TTP) ALL EVALUABLE PATIENTS 5-FU REFRACTORY 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 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: 0.284 (0.127, 0.636) Hazard ratio: 0.186 (0.066, 0.521)

  11. Median Overall Survival (OS) ALL EVALUABLE PATIENTS 5-FU REFRACTORY 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 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) Hazard ratio: 0.410 (0.193, 0.868)

  12. 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)

  13. X-PECT Trial RANDOMIZED, DOUBLE-BLIND, PHASE III TRIAL OF PERIFOSINE + CAPECITABINE (P-CAP) VERSUS PLACEBO + CAPECITABINE (CAP) IN PATIENTS WITH REFRACTORY METASTATIC COLORECTAL CANCER Opened April 2010

  14. Patients with refractory mCRC • No prior Rx with CAP in metastatic setting Treatment / Schema Cycle = 21 Days Primary Endpoint: • Overall Survival Secondary Endpoints: • PFS, ORR, Safety • Randomized 1:1, Double-blind • N = ~430 patients • RECIST v 1.1 • CTCAE v 4.0 *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)

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