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A Phase I Study of BKM120 With mFOLFOX6 in Patients With Advanced Solid Tumors With Expansion Cohorts in KRAS Wild Type Metastatic Colorectal and Metastatic Pancreatic Cancers

Phase 1
18 Years
Open (Enrolling)
Advanced Solid Tumors, Metastatic Colorectal Cancer, Metastatic Pancreatic Cancer

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Trial Information

A Phase I Study of BKM120 With mFOLFOX6 in Patients With Advanced Solid Tumors With Expansion Cohorts in KRAS Wild Type Metastatic Colorectal and Metastatic Pancreatic Cancers

This single arm, multicenter, open-label Phase I clinical trial has been designed to
establish the safety and tolerability of dose escalating BKM120 when combined with mFOLFOX6
and to define the MTD of BKM120 in this combination. Secondary objective will be to
estimate the response rate, Progression Free Survival rate, and Overall Survival rate, after
treatment with the Maximum Tolerated Dose of BKM120 in combination with mFOLFOX6 in patients
with metastatic colorectal cancer (KRAS wild type [WT]) and metastatic pancreatic cancer.
Eligible patients will be treated with BKM120 orally (PO), once per day (QD) in combination
with mFOLFOX6 administered intravenously (IV) every 2 weeks on Days 1 and 15 of each cycle
using a standard 3+3 dose escalation scheme. Each cycle will be repeated every 4 weeks (28
days). FOLFOX6 treatment will be as follows: Oxaliplatin: 85 mg/m2 IV, Leucovorin: 400 mg/m2
IV, 5FU bolus: 400 mg/m2 IV and 5FU infusion: 2400 mg/m2 IV.

In the absence of treatment delays due to adverse events (AEs), treatment may continue
until: disease progression, intercurrent illness that prevents further administration of
treatment, unacceptable AE(s), patient decides to withdraw from the study, or general or
specific changes in the patient's condition render the patient unacceptable for further
treatment in the judgment of the investigator.

Inclusion Criteria:

Inclusion Criteria

1. Age ≥18 years (no upper age limit)

2. Histologically confirmed advanced solid tumor that is refractory to standard therapy
or for which there is no accepted standard therapy. In the initial determination of
the MTD, any solid tumor type is acceptable. For the expansion cohorts, the following
advanced tumor types are eligible, with 15 patients planned for enrollment into each:
untreated mCRC (KRAS WT) and metastatic pancreatic cancer.

3. Measurable or nonmeasurable (but evaluable) disease as determined by Response
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for determination of the
MTD. Measurable disease is required for expansion cohorts.

4. Patients must have normal organ and marrow function as defined below: Absolute
neutrophil count ≥1,500/μL Platelets ≥100,000/μL Hemoglobin > 9g/dL (transfusion
allowed) Total bilirubin within normal range, or ≤1.5 X upper limit of normal (ULN)
if liver metastases are present; or total bilirubin ≤3 x ULN with direct bilirubin
within normal range in patients with well documented Gilbert Syndrome.
AST(SGOT)/ALT(SGPT) within normal limits (WNL), except for patients with tumor
involvement of the liver who must have AST and ALT ≤3 X ULN Serum creatinine ≤1.5 X
ULN OR 24-hour creatinine clearance ≥60 mL/min Amylase and lipase levels WNL Fasting
plasma glucose ≤120 mg/dL (7.8 mmol/L) Magnesium ≥ lower limit or normal (LLN);
potassium WNL INR ≤2

5. Total calcium (corrected for serum albumin) WNL (bisphosphonate use for malignant
hypercalcemia control is not allowed).

6. Brain metastases permitted if: CNS-directed treatment has been given; Off
CNS-directed therapy >3 months; AND CNS disease has been clinically and
radiographically stable for at least 8 weeks and patient not receiving corticosteroid

7. Life expectancy ≥12 weeks

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤1

9. No limit to prior number of cytotoxic chemotherapies provided time since the last
dose of prior therapy (in advance of Day 1 of study treatment): Cytotoxic
chemotherapy ≥ the duration of the most recent cycle of the previous regimen (with a
minimum of 4 weeks for all, except minimum of 6 weeks for nitrosourea, mitomycin-C)
Biologic therapy (e.g. antibodies) ≥4 weeks ≥5 X half-life of a small molecule
therapeutic (e.g. tyrosine kinase inhibitor [TKI])

10. Ability to understand and willingness to sign a written informed consent document

11. Women of childbearing potential (WOCBP) and all men must be willing and able to use
appropriate contraception (double barrier method); WOCBP must have negative pregnancy
test within 48 hours before Day 1 of treatment.

12. Patient must have recovered from all reversible toxicities related to their previous
treatment except for alopecia and grade 1 neuropathy

Exclusion Criteria:

1. Patients with history of prior treatment with a PI3K inhibitor

2. Patients may not be receiving any other investigational agents currently, or within
time limits specified above prior to study Day 1. NOTE: For the mCRC expansion
cohort, patients may not have received a FOLFOX-based adjuvant regimen within 6
months of study entry. If FOLFOX treatment occurred in the adjuvant setting, no more
than grade 1 neuropathy may be present at baseline.

3. Patients with known coagulopathies, and those who require therapeutic
anti-coagulation with coumarin-derivative anticoagulants

4. Patients on strong or moderate CYP3A4 inhibitor(s) or CYP3A4 inducer(s) unable or
unwilling to discontinue during the study period (see Appendix B for list). Please
note that co-treatment with weak inhibitors of CYP3A4 is allowed.

5. Patients who received live vaccines or who have close contact with people who have
received live vaccines within 7 days of day 1 of BKM120 (see Appendix B).

6. 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.

7. Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., G-CSF, GM-CSF) ≤2 weeks prior to starting study drug. Erythropoietin
or darbepoietin therapy, if initiated ≥2 weeks prior to enrollment, may be continued.

8. Patients who are currently receiving treatment with medication with a known risk to
prolong the QT interval or inducing Torsades de Pointes and the treatment cannot
either be discontinued or switched to a different medication prior to starting study
drug. Please refer to table 12B for a list of prohibited QT-prolonging drugs with
risk of Torsades de Pointes.

9. Patients on chronic steroids (or other immunosuppressive agents) unable or unwilling
to discontinue. Note: Topical applications (e.g., for rash), inhaled sprays (e.g.,
for obstructive airway diseases), eye drops, or local injections (e.g.,
intra-articular) are allowed.

10. Presence of acute or chronic liver or renal disease or pancreatitis

11. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus

12. Patients with the following mood disorders as judged by the Investigator or a
psychiatrist, or as a result of patient's mood assessment questionnaire: Medically
documented history of or active major depressive episode, bipolar disorder (I or II),
obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or
ideation, or homicide/homicidal ideation (immediate risk of doing harm to others),
≥CTCAE Grade 3 anxiety Meets the cut-off score of ≥ 10 on the 9-item Patient Health
Questionnaire (PHQ-9) or a cut-off score of ≥15 on the 7-item, Generalized Anxiety
Disorder (GAD-7) mood scale, or who selects a 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) will be excluded from the study unless overruled by
the psychiatric assessment.

13. Patients with diarrhea CTCAE v4 grade ≥2

14. Patient having active cardiac disease including any of the following: Left
ventricular ejection fraction (LVEF) <50% as determined by multiple gated acquisition
scan (MUGA) or echocardiogram (ECHO), QTc >480 msec on screening ECG (using the QTcF
formula), Angina pectoris that requires the use of anti-anginal medication,
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 compromise of cardiac function, Symptomatic pericarditis.

15. Patient having a history of cardiac dysfunction including any of the following:
Myocardial infraction within the last 6 months documented by persistent elevated
cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF
function, History of documented congestive heart failure (CHF) by New York Heart
Association (NYHA) functional classification III-IV, Documented cardiomyopathy.

16. Known diagnosis of human immunodeficiency virus (HIV) infection

17. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection. Significant symptomatic deterioration of lung function. If clinically
indicated, pulmonary function tests including measures of predicted lung volumes,
carbon monoxide diffusing capacity (DLco), and O2 saturation at rest on room air
should be considered to exclude pneumonitis or pulmonary infiltrates.

18. Impaired GI function or GI disease that may significantly impair absorption of BKM120
(e.g., irritable bowel disease [IBD] malabsorption syndrome, small bowel resection,
uncontrolled vomiting, or diarrhea).

19. 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

20. Patients who have undergone major surgery ≤2 weeks prior to starting study drug or
who have not recovered from side effects of such therapy

21. History of allergic reaction attributed to compounds of similar chemical or biologic
composition to BKM120, 5FU, leucovorin, or oxaliplatin

22. Patient is unable or unwilling to abide by the study protocol or cooperate fully with
the investigator

23. Grade ≥2 neuropathy at baseline

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicity (DLT)

Outcome Description:

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications, and occurs within the first cycle of therapy (4 weeks)of BKM120 when administered with mFOLFOX6 in patients with advanced solid tumors including metastatic colorectal cancer (KRAS wild type [WT]) and metastatic pancreatic cancer.

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Autumn McRee, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center; Chapel Hill, NC


United States: Food and Drug Administration

Study ID:

LCCC 1036



Start Date:

May 2012

Completion Date:

July 2014

Related Keywords:

  • Advanced Solid Tumors
  • Metastatic Colorectal Cancer
  • Metastatic Pancreatic Cancer
  • BKM120
  • Advanced Solid Tumors
  • Metastatic
  • Colorectal Cancer
  • Pancreatic Cancer
  • Colorectal Neoplasms
  • Pancreatic Neoplasms
  • Neoplasms



University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center Chapel Hill, North Carolina  27599