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 SECOND OR THIRD LINE METASTATIC COLORECTAL CANCER (mCRC) Donald Richards 1, John Nemunaitis 2, Sasha Vukelja 1, Christopher Hagenstad 3, Luis Campos 4, Jeffrey Letzer 5, Robert Hermann 6, Peter Sportelli 7, Lesa Gardner 7 and Johanna Bendell 8 1 Texas Oncology, Tyler, TX; 2 Mary Crowley Cancer Research Center, Dallas, TX; 3 Suburban Hem/Onc, Lawrenceville, GA; 4 Oncology Consultants, Houston, TX; 5 Kalamazoo Hem/Onc, Kalamazoo, MI; 6 Northwest GA Oncology, Marietta, GA; 7 Keryx Biopharmaceuticals, NY, NY; 8 Sarah Cannon Research Institute, Nashville, TN PRIMARY OBJECTIVE To compare the time to progression (TTP) of patients treated with P-CAP vs. CAP as 2 nd or 3 rd line treatment for mCRC SECONDARY OBJECTIVES To further evaluate the safety of P-CAP vs. CAP To compare the overall response rate (ORR = CR + PR) and overall survival (OS) of patients treated with P-CAP vs. CAP Nearly 40% of colorectal tumors have alterations in the PI3 kinase/Akt pathway, including activating mutations in p110  or loss of PTEN 1,2,3 Perifosine is a novel oral signal transduction modulator with multiple effects including Akt and NF-  B inhibition A potential mechanism of resistance to 5-FU is upregulation of NF-  B 4 Capecitabine (Xeloda ® ) has demonstrated activity in the treatment of metastatic colorectal cancer (mCRC), though single agent efficacy is limited in patients who previously progressed on 5-fluorouracil (5-FU) therapy 5 A phase I trial has shown perifosine 50 mg QD safely combines with capecitabine 825 mg/m 2 BID d 1 – 14 every 21 days, and has demonstrated preliminary efficacy signals in patients with mCRC Based on the phase I results, an exploratory ph II randomized double-blind, placebo controlled study was initiated in patients with 2 nd or 3 rd line mCRC evaluating perifosine + capecitabine (P-CAP) vs. placebo + capecitabine (CAP) Efficacy results presented at ASCO GI 2010 showed an improvement in ORR (20% vs. 7%) and with a statistically significant improvement in time-to-progression (TTP) and in overall survival (OS) for all evaluable and 5-FU refractory patients treated with P-CAP vs. CAP 6 We now report the final results of this trial, as well as final results for the subset of patients with 5-FU refractory mCRC PATIENT POPULATION Patients with 2 nd or 3 rd line mCRC No previous treatment with capecitabine in the metastatic setting Previous treatment with 5-FU or a 5-FU based regimen Plts > 100K ANC > 1.5 HCT > 28% Creatinine < 2.5 mg/dl ECOG PS: 0 - 2 35 patients evaluable for response (3 patients on CAP not evaluable; 2 due to toxicity (days 14, 46), 1 due to new malignancy on day 6) In this randomized phase II trial, perifosine + capecitabine (P-CAP) demonstrates an improvement in TTP and OS compared to placebo + capecitabine (CAP) in patients with 2 nd or 3 rd line mCRC. ORR was also improved for P-CAP over CAP. The improvements in TTP and OS with P-CAP compared to CAP are also seen in patients with 5-FU refractory disease. One patient with 5-FU refractory disease had a PR on P-CAP. P-CAP was well tolerated compared to CAP alone. A phase I study to evaluate the combination of perifosine + capecitabine using a higher dose of capecitabine at 1000 mg/m 2 PO BID days 1 – 14 is complete. No DLT’s were observed and the combination was well tolerated (ASCO 2010 Abstract 51462). PK of perifosine and capecitabine are being examined. Given the improvement in efficacy seen in this randomized phase II trial of P-CAP compared to CAP in 5- FU refractory patients, a randomized phase III study comparing P-CAP to CAP in patients with refractory mCRC is now open (X-PECT Trial). ASSESSMENT RECIST 1.0 criteria for response rate and NCI CTCAE v3.0 for toxicity assessment ADVERSE EVENTS (n = 38) ALL EVALUABLE (n = 35) CONCLUSIONS The Investigators wish to thank the Research Nurses, Staff, and especially the Patients and Families for their participation in this Study Kaplan-Meier method was used to calculate TTP and OS Groupn CR n (%) PR n (%) Duration of Response SD > 12 wks n (%) CR + PR + SD > 12 wks* n (%) PD < 12 wks n (%) P-CAP201 (5%)3 (15%) CR: 36 months 11 (55%)15 (75%)5 (25%) PR: 21, 19, 11 months CAP1501 (7%) PR: 7 months 5 (33%)6 (40%)9 (60%) Grade 3 & 4 Adverse Events: > 10% Adverse EventP-CAP (n=20)CAP (n=18) Hand and Foot6 (30%)0% Anemia3 (15%)0% Abdominal Pain1 (5%)2 (11%) Fatigue0%2 (11%) Bowel Obstruction0%2 (11%) *Survival calculated from date of randomization until date of death from any cause, whether or not additional therapies were received after removal from treatment Most Common Grade 1 & 2 Adverse Events Adverse Event P-CAP (20 pts) n (%) CAP (18 pts) n (%) Diarrhea15 (75%)5 (28%) Fatigue10 (50%)6 (33%) Nausea9 (45%)5 (28%) Musculoskeletal Pain6 (30%)3 (17%) Hand and Foot5 (25%)4 (22%) Mucositis5 (25%)1 (6%) Anorexia5 (25%)2 (11%) Anemia5 (25%)3 (17%) Prior Rx P-CAP (n=20) CAP (n=18) All Patients (n=38) FOLFIRI18 (90%)16 (89%)34 (89%) FOLFOX15 (75%)13 (72%)28 (74%) FOLFIRI & FOLFOX 13 (65%)12 (67%)25 (66%) Bevacizumab15 (75%)15 (83%)30 (79%) EGFR Antibody 9 (45%)10 (56%)19 (50%) Demographic P-CAP (n=20) CAP (n=18) All Patients (n=38) Median Age65 (32 - 83)66 (43 - 83)65 (32 – 83) Male / Female14 / 69 / 923 / 15 Median Prior Rx2 (1 – 4)2 (2 – 5)2 (1 – 5) ECOG PS 0 / 16 / 145 / 1311 / 27 Refractory to Prior 5-FU 14 (70%)13 (72%)27 (71%) Groupn PR n (%) Duration of Response SD > 12 wks n (%) CR + PR + SD > 12 wks n (%) PD < 12 wks n (%) P-CAP141 (7%)19 months8 (57%)9 (64%) p=0.066 5 (36%) CAP110-3 (27%) 8 (73%) 5-FU REFRACTORY (n = 25) RESULTS: OVERALL SURVIVAL* (OS) ALL EVALUABLE PATIENTS 5-FU REFRACTORY PATIENTS 1.Brugge, J., M.C. Hung, and G.B. Mills, A new mutational AKTivation in the PI3K pathway. Cancer Cell, 2007. 12(2): p. 104-7 2.Rychahou, P.G., et al., Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. PNAS, 2008. 105(51): p. 20315-20. 3.Sawai, H., et al., Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival. BMC Gastroenterol, 2008. 8: p. 56 4.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): p. 178-88 5.Lee, J.J., et al., Single-agent capecitabine in patients with metastatic colorectal cancer refractory to 5-fluorouracil/leucovorin chemotherapy. Jpn J Clin Oncol, 2004. 34(7): p. 400-4. 6.Bendell, J., et al., Randomized Phase II Study of Perifosine in Combination with Capecitabine (P-CAP) vs. Placebo Plus Capecitabine (CAP) in Patients with Second or Third Line Metastatic Colon Cancer. Abstract 447, ASCO 2010 Gastrointestinal Cancers Symposium Median time to Grade 3/4 Hand & Foot Syndrome for P-CAP: 19 weeks (range 3 – 49 weeks) RESULTS: TIME TO PROGRESSION (TTP) REFERENCES RESULTS: OVERALL RESPONSE RATE (ORR) RESULTS: SAFETY PATIENT CHARACTERISTICSINTRODUCTION OBJECTIVES TREATMENT REGIMEN 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 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) *p=0.036 ALL EVALUABLE PATIENTS 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) 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)