This phase I trial will use the combination of irinotecan and BKM120 in patients with advanced colorectal cancer who have failed on or have become intolerant of at least one line of therapy for advanced colorectal cancer and who are candidates for irinotecan therapy.
Name: Irinotecan
Description: IV over 90 minutes on day 1 of each cycle (every 2 weeks) at the cohort assigned dose levelType: DrugIrinotecan + BKM120
Name: BKM120
Description: BKM120, oral, daily starting with cycle 1/day 2 at the cohort defined dose levelType: DrugIrinotecan + BKM120
Description: The maximum tolerated dose will be defined as the dose level prior to the dose level in which dose-escalation was stopped based on dose-limiting toxicities (DLTs). DLTs are based on specific adverse events specified in the study protocol. DLTs will be assessed during the first two cycles of treatment (28 days total).
Measure: Maximum tolerated dose Time: 28 daysDescription: Blood samples will be collected at cycle 1/day 1 and cycle 2/day 1 to determine the AUC of irinotecan in the presence and absence of BKM120.
Measure: area under the plasma concentration versus time curve (AUC) of irinotecan Time: up to 25.5 hours post dose of irinotecanDescription: Disease will be assessed at baseline and then every four cycles (8 weeks) by CT or MRI. Response will be assessed following RECIST criteria. Patients will be categorized as complete response, partial response, progressive disease, stable disease, or unknown.
Measure: Change in tumor size Time: baseline, and every 8 weeksDescription: Blood samples will be collected at cycle 1/day 1 and cycle 2/day 1 to determine the AUC of irinotecan in the presence and absence of BKM120.
Measure: Peak Plasma Concentration (Cmax) of irinotecan Time: up to 25.5 hours post-dose of irinotecanDescription: Blood samples will be collected at cycle 1/day 1 and cycle 2/day 1 to determine the AUC of irinotecan in the presence and absence of BKM120.
Measure: biological half-life of irinotecan Time: up to 25.5 hours post dose of irinotecanDescription: The Cmax of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.
Measure: Peak Plasma Concentration (Cmax) of BKM120 Time: up to 25.5 hours post-dose of irinotecanDescription: The AUC of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.
Measure: area under the plasma concentration versus time curve (AUC) of BKM120 Time: up to 25.5 hours post dose of irinotecanDescription: The biological half life of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.
Measure: Biological half life of BKM120 Time: up to 25.5 hours post dose of irinotecanSingle Group Assignment
There is one SNP
If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates - Clinical manifestation of diabetes mellitus or steroid-induced diabetes mellitus - Impairment of GI function or disease that may significantly alter the absorption of BKM120; diarrhea ≥ grade 2 - Major surgery ≤ 4 weeks prior to starting study drug - Prior treatment with a P13K inhibitor; any hematopoietic colony-stimulating growth factors ≤ 2 weeks prior to starting study drug; corticosteroids ≤ 2 weeks prior to starting study drug; chemotherapy or targeted anticancer therapy ≤4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug; small molecule therapeutics (excluding monoclonal antibodies) ≤5 effective half-lives prior to starting study drug - Currently receiving medication that has the potential to prolong the QT interval or inducing Torsades de Pointes - chronic treatment with steroids or another immunosuppressive agent. --- P13K ---