Presentation on theme: "Results of the X-PECT Study: A phase III randomized double-blind placebo-controlled study of perifosine plus capecitabine (P-CAP) vs. placebo plus capecitabine."— Presentation transcript:
Results of the X-PECT Study: A phase III randomized double-blind placebo-controlled study of perifosine plus capecitabine (P-CAP) vs. placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC) Bendell JC, Ervin T, Senzer N, Richards D, Firdaus I, Lockhart C, Cohn A, Saleh M, Sportelli P, Gardner L, Eng C.
Disclosures No conflicts to disclose PRESENTED BY: Johanna C. Bendell, M.D.
Metastatic Colorectal Cancer (mCRC) 3 rd most common cancer in US 5 year survival approximately 11% in the metastatic setting Current treatment options for mCRC 5-FU, oxaliplatin, irinotecan, bevacizumab, and, if Kras wild- type, cetuximab or panitumumab Capecitabine is approved for first line mCRC, however is often used in the refractory setting Refractory mCRC Median PFS 2 months, median OS 4-6 months Additional treatment options for patients refractory mCRC are needed.
Src Ras Raf1 MEK 1/2 ERK 1/2 PIP3 PI3K AKT/PKB Pathway PLC- 1 mTOR PTEN GSK3β MDM2 p53 NF-κB Apoptosis Growth, Translation ERK Pathway Cell cycle, Glucose metabolism 20-40% of CRC have PI3K mutation 15-20% have PTEN loss/mutation MAPK pathway is also dysregulated in ~60% of CRC PI3K/ AKT Pathway and Its Downstream Targets MEKK1 MEK4 MAPK Pathways: JNK p21 Cell cycle arrest Perifosine
Potential Mechanisms of Action of Perifosine + Capecitabine NF- Inhibition –Fluorouracil resistance associated with upregulation of NF- –Inhibition of NF- pathway (proteasome inhibitors, mTOR inhibitors) augments fluorouracil anti-tumor effect –Perifosine shown to inhibit NF- nuclear translocation and pathway activation Synergy studies – perifosine plus fluorouracil Perifosine inhibition of NF- B ELISA SW-620 cell line
Patients with 2 nd or 3 rd line mCRC No prior Rx with CAP in metastatic setting Prior Rx with 5-FU or 5- FU based regimen Randomized Phase II R Perifosine 50 mg PO QD Capecitabine 825 mg/m 2 BID d 1 – 14 N = 20 Placebo PO QD Capecitabine 825 mg/m 2 BID d 1 – 14 N = 18 Cycle = 21 Days Primary Objective: To compare time to progression (TTP) of P-CAP vs. CAP as 2 nd or 3 rd line Rx Secondary Objective: To compare overall response rate (CR + PR) and overall survival (OS) To evaluate the safety of P-CAP vs. CAP Bendell JCO 2011
X-PECT Treatment / Schema R Perifosine 50 mg PO QD Capecitabine 1000 mg/m 2 BID d 1 - 14 Placebo PO QD Capecitabine 1000 mg/m 2 BID d 1 - 14 Cycle = 21 Days Randomized 1:1, Double-blind, placebo-controlled phase III N = ~430 patients Primary endpoint: OS Log-rank test with two-sided Type 1 error rate of 0.05. 90% power to detect a treatment difference at the two-sided 0.05 significance level mOS for P-CAP group assumed 7.75 mo and 5.5 mo for CAP group Stratification factors: K-ras mutation status, oxaliplatin discontinuation secondary to toxicity vs. progression Secondary endpoints – RR, PFS, toxicity, biomarkers US trial – 66 sites, enrollment 3/30/2010-8/10/2011, 468 randomized Patients with refractory mCRC No prior Rx with CAP in metastatic setting unless rad- sensitizing
Key eligibility criteria Histologically (or cytologically) confirmed adenocarcinoma of the colon or rectum that is recurrent or metastatic Patients must have failed available therapy for the treatment of advanced colorectal cancer. –Progressive disease during or within 6 months after fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab, and for K-ras wild-type (WT) patients, anti-EGFR antibody (cetuximab/panitumumab) containing therapies, with most recent progression by RECIST criteria. –For oxaliplatin-based therapy, failure of therapy will also include patients who progressed within 12 months of adjuvant therapy and patients who had oxaliplatin stopped secondary to toxicity No previous capecitabine in the metastatic setting (except radiosensitizing) ECOG 0-1, age > 18 years, adequate bone marrow, renal, and hepatic function
Patient Demographics Placebo (N=234)Perifosine (N=234) n%n% Age < 65 yrs15265.013758.5 ≥ 65 yrs8235.09741.5 Sex Female9942.311047.0 Male13557.712453.0 ECOG Performance Status 09339.79339.7 113658.113557.9
OS Analysis in ITT Population Placebo (N=234)Perifosine (N=234) Overall No. of Patients234 No. of Events178 (76.07%)187 (79.91%) Median OS (95% CI) (mos)6.9 (5.9, 7.4)6.4 (5.1, 6.9) HR (95% CI) (Relative to Placebo)1.111 (0.905, 1.365) P-value (Log-rank)0.315 K-Ras Wild Type No. of Patients116114 Median OS (95% CI) (mos)6.8 (5.1, 7.7)6.6 (5.1, 7.9) HR (95% CI) (Relative to Placebo)1.020 (0.763, 1.365) P-value (Log-rank)0.894 K-Ras Mutant No. of Patients118120 Median OS (95% CI) (mos)6.9 (5.6, 8.0)5.4 (4.7, 6.8) HR (95% CI) (Relative to Placebo)1.192 (0.890, 1.596) P-value (Log-rank)0.238
Subgroup – PFS – Kras WT and oxaliplatin discontinuation secondary to toxicity PRESENTED BY:
Subgroup – OS – Kras WT and oxaliplatin discontinuation secondary to toxicity PRESENTED BY:
Subgroup – Kras WT and oxaliplatin discontinuation secondary to toxicity PRESENTED BY: PlaceboPerifosine Progression Free Survival No. of Patients4046 Median PFS Time (95% CI) (wks)6.6 (6.1, 12.4)18.1 (11.6, 22.1) HR (95% CI) (Relative to Placebo)0.514 (0.329, 0.801) P-value (Log-rank)0.003 Overall Survival No. of Patients4046 Median OS Time (95% CI) (mos)6.2 (4.1, 7.9)8 (6.4, 10.6) HR (95% CI) (Relative to Placebo)0.769 (0.477, 1.239) P-value (Log-rank)0.280
Biomarker studies Baseline paraffin samples were requested from all patients –75% obtained A subset of patients participated in a biomarker cohort Pre- and on-treatment pBMC’s and plasma Whole blood for genomics Pre- and on-treatment core biopsy and FNA Biomarker evaluation is pending –Interest in subset of Kras WT and oxaliplatin discontinuation secondary to toxicity –Oxaliplatin associated with upregulation of pathways including Src (via ROS), FAK, and others –When oxaliplatin is stopped secondary to toxicity rather than resistance, are these cells different? How does this interact with Kras?
Conclusions Despite promising data from a small randomized phase II study, the addition of perifosine to capecitabine for patients with refractory colorectal cancer did not show a benefit –Differences between the treatment groups between the phase II and III - ? less pretreatment –There was no significant difference in toxicity profiles between the two arms Biomarker studies are pending to evaluate if any subgroups may have received benefit –Is there a real signal in the patients who stopped oxaliplatin secondary to toxicity and who are also Kras WT? –Refractory colorectal cancer cells are different As we continue to search for new agents in the treatment of colorectal cancer, biomarker analyses are a necessity to help us understand what we are doing
Thank you We wish to thank the patients and their families for their participation in this trial We also thank the investigators and staff from the participating sites