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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Irinotecan; Drug: BKM120

Detailed Description

Although survival of patients with advanced colorectal cancer has improved in the last two decades, the overwhelming majority of these patients will still succumb from this disease. It is the third most commonly diagnosed malignancy in the United States. We have witnessed significant leaps in understanding colorectal cancer carcinogenesis as well as in identification of a number of prognostic and predictive factors associated with this malignancy. With the use of combination chemotherapy and the addition of targeted agents, the median survival of patients with advanced colorectal cancer has improved from 4-6 months with supportive care to over 2 years.

Molecularly directed therapy for cancer holds promise to a more personalized approach to treating cancer. Increase understanding of tumorigenesis has resulted in the identification of promising targets of therapy for more strategic approach to treatment of this malignancy. However, even with the development of molecularly directed treatment, the therapy for advanced colorectal cancer remains to be primarily palliative in nature to majority of patients. There is definite need for a more effective therapy, agents with more acceptable toxicity profiles, and drugs that could be administered without significant demand on time and activity for individual patients receiving these drugs.

This is a phase I trial of 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. This study will attempt to estimate the Maximum Tolerated Dose of the combination of irinotecan and BKM120.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Irinotecan + BKM120; Irinotecan + BKM120 at the assigned cohort dose level.	Drug: Irinotecan; IV over 90 minutes on day 1 of each cycle (every 2 weeks) at the cohort assigned dose level; Other Names: Camptostar; Drug: BKM120; BKM120, oral, daily starting with cycle 1/day 2 at the cohort defined dose level

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose	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).	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
area under the plasma concentration versus time curve (AUC) of irinotecan	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.	up to 25.5 hours post dose of irinotecan
Change in tumor size	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.	baseline, and every 8 weeks
Peak Plasma Concentration (Cmax) of irinotecan	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.	up to 25.5 hours post-dose of irinotecan
biological half-life of irinotecan	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.	up to 25.5 hours post dose of irinotecan
Peak Plasma Concentration (Cmax) of BKM120	The Cmax of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.	up to 25.5 hours post-dose of irinotecan
area under the plasma concentration versus time curve (AUC) of BKM120	The AUC of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.	up to 25.5 hours post dose of irinotecan
Biological half life of BKM120	The biological half life of BKM120 will be measured at Cycle 2/Day 1 for pharmacokinetic characterization of BKM120.	up to 25.5 hours post dose of irinotecan

Collaborators and Investigators

• Sponsor: University of Kansas Medical Center
• Investigators: Principal Investigator: Joaquina Baranda, MD, University of Kansas Medical Center

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: February 18, 2011
• First Submitted That Met QC Criteria: February 24, 2011
• First Posted (Estimate): February 25, 2011

Study Record Updates

• Last Update Posted (Estimate): January 6, 2017
• Last Update Submitted That Met QC Criteria: January 4, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: colorectal cancer; irinotecan; BKM120
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Irinotecan
• Other Study ID Numbers: 12480