A Trial of Irinotecan and BKM120 in Previously Treated Advanced Colorectal Cancer

Inclusion Criteria * Histologically or cytologically confirmed metastatic or unresectable adenocarcinoma of the colon or rectum with measurable disease (patients who have become resistant or intolerant of at least one-line of chemotherapy regimen are eligible) * Patients who had had previous treatment with Irinotecan and who have definite progression on Irinotecan are eligible provided they are not a candidate for other therapeutic treatment options. Definitive progression is defined as progression of disease while on Irinotecan or within 4 weeks of discontinuing Irinotecan. * ≥ 18 years old * ECOG performance status ≤ 2 (Karnofsky \> 60%) * ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb \>9 g/dL * Serum bilirubin within normal range (or \< 1.5 x IULN if liver metastases present; or total bilirubin ≤ 3.0 x IULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) * AST (SGOT) or ALT (SGPT) within normal range (or ≤ 3.0 x upper limit of normal if liver metastases present) * adequate renal function as evidenced by creatinine ≤ 1.5 x IULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal. * serum calcium (corrected for serum albumin) within normal limits. Biphosphonate use for malignant hypercalcemia control is not allowed. * Serum magnesium ≥ the institutional lower limit of normal (ILLN) and potassium within institutional normal limits. * serum lipase ≤ IULN; serum amylase ≤ IULN; fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) * females of child-bearing potential must have negative serum pregnancy test within 72 hours prior to treatment. Cannot be pregnant or nursing. * Males and females must agree to use effective contraceptive method. * INR ≤ 2 Exclusion Criteria * Previous treatment with chemotherapy, biologic therapy, or wide field radiotherapy \< 4 weeks or limited field radiation for palliation \< 2 weeks prior to starting study drug; must have recovered from side effects of such therapy * Known hypersensitivity to BKM120 or to its excipients or to irinotecan * Untreated brain metastases. Patients with metastatic CNS tumors may participate in this trial, if the patient is \> 4 weeks from therapy completion, is clinically stable and is not receiving corticosteroid therapy * Known polymorphism in UGTAIA or Gilbert's syndrome * Acute or chronic liver, renal disease or pancreatitis * Medically documented history or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, history of suicidal attempt or ideation, or homicidal ideation; ≥ CTCAE grade 3 anxiety; meets cutoff score of ≥ 10 in the PHQ-9 or cut-off of ≥ 15 in GAD-7 mood scale, respectively, or selects positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9) * Clinically significant heart disease including: Left ventricular ejection fraction (LVEF) \<50% as determined by echocardiogram; ventricular arrhythmias except for benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker; valvular disease with documented compromised cardiac function; symptomatic pericarditis; QTc \> 480 msec on screening ECG (using QTcF formula; angina pectoris that requires use of anti-anginal medication * History of cardiac dysfunction including: acute myocardial infarction ≤ 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function; history of documented congestive heart failure (NYHA Class III or IV; document cardiomyopathy * Other concurrent severe and/or uncontrolled concomitant medical conditions * Significant symptomatic deterioration of lung function. 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. Note: Topical applications (eg rash), inhaled sprays (eg obstructive airways diseases), eye drops or local injections (eg intra-articular) are allowed. Patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (eg dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible. * therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant. * any medications or substances that are inhibitors or inducers of specific CYP450 enzyme(s). * any other study agents * Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug. Herbal medications include, but are not limited to St. John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits. * Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy * Women who are pregnant or breast feeding; adults of reproductive potential not using an effective method of birth control. * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL and estradiol \< 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during treatment for 8 days after stopping treatment and for additional 12 weeks after study drug discontinuation. Highly effective contraception is defined as: true abstinence: Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner should be the sole partner for that patient. * Use of a combination of any two of the following (a+b): Placement of an intrauterine device (IUD) or intrauterine system (IUS); Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository; Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 potentially decreases the effectiveness of hormonal contraceptives. * Fertile males must use condom during treatment, for 8 days after stopping treatment and for additional 12 weeks after study drug discontinuation and should not father a child in this period. * Known diagnosis of human immunodeficiency virus (HIV) infection * History of another malignancy within 3 years, except cured basal cell skin carcinoma or excised cervical carcinoma in situ * Previous treatment with Irinotecan who have definite progression on Irinotecan.