Study to Assess Safety, Tolerability and Preliminary Efficacy of BKM120, PI3K Kinase Inhibitor, With Advanced Leukemias

Study Description

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Brief Summary:

The goal of this clinical research study is to find the highest tolerable dose of BKM120 that can be given to patients with relapsed or refractory leukemia. The safety of BKM120 will also be studied.

Condition or disease	Intervention/treatment	Phase
Leukemia	Drug: BKM120	Phase 1

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	16 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I Open-label Study to Assess the Safety, Tolerability and Preliminary Efficacy of BKM120, PI3K Kinase Inhibitor, in Patients With Advanced Leukemias
Study Start Date :	July 2012
Actual Primary Completion Date :	October 2016
Actual Study Completion Date :	October 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: BKM120; Oral BKM120 starting dose 80 mg once daily.	Drug: BKM120; Starting dose 80 mg tablets by mouth daily for a 28 day cycle.

Outcome Measures

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Primary Outcome Measures :

1. Maximum Tolerated Dose of BKM 120 [ Time Frame: 28 days, Cycle 1 ]

   Maximum tolerated dose (MTD) defined as highest dose in which 1/6 or less subjects experience a dose limiting toxicity (DLT) during the first course of treatment.

   Toxicity assessed using the NCI Common Toxicity Criteria for Adverse Events, version 4.0.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Age 18 years old or older
2. Relapsed/refractory leukemias for which no standard therapy options are anticipated to result in a durable remission: Acute myelogenous leukemia (AML) by World Health Organization (WHO) classification or acute lymphoblastic leukemia (ALL) relapsed or refractory to standard chemotherapy; unsuitable for standard chemotherapy or unwilling to undergo standard chemotherapy. Philadelphia chromosome (Ph) positive ALL eligible if failed prior tyrosine-kinase inhibitor therapy. Age =/> 60 years with AML not candidates for or have refused standard chemotherapy, excluding subjects with acute promyelocytic leukemia (APL) or with favorable cytogenetic abnormalities [inv16, t(8;21)].
3. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2
4. Serum total bilirubin </= 2 x ULN or direct bilirubin </=ULN for patients with total bilirubin levels > 2 x ULN, unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis. Aspartate aminotransferase or alanine aminotransferase within normal range (or =/< 3.0 x upper limit of normal (ULN) if due to leukemic involvement); serum creatinine =/< 1.5 x ULN or 24-hour clearance =/> 50 mL/min; serum amylase </= ULN; serum lipase</= ULN.
5. Fasting glucose =/< 120 mg/dL (6.7 mmol/L).
6. Total calcium (corrected for serum albumin) within normal limits (8.8 - 10.5 MG/DL). This is MD Anderson Cancer Center (MDACC) lab standard. Supplements for calcium allowed to meet eligibility criteria.
7. Magnesium >/= the lower limit of normal (1.8 MG/DL). Supplements for magnesium allowed to meet eligibility criteria
8. Potassium within normal limits (3.5 - 5.0 milliequivalent (MEq)/L). Supplements for potassium allowed to meet eligibility criteria
9. international normalized ratio (INR) =/< 2
10. Women of childbearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum or urine pregnancy test within 48 hours prior to the start of study drug
11. Patients should be able to take oral medications.

Exclusion Criteria:

1. Patients who have received myelosuppressive chemotherapy </= to 4 weeks prior to starting study drug (with the exception of Hydroxyurea which will be allowed during Course 1 of treatment).
2. Patients who have received targeted anticancer therapy ≤ 2 week (for non myelosuppressive therapy) prior to starting study drug.
3. central nervous system (CNS) disease
4. Patient has active cardiac disease including any of the following: Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO), corrected QT interval (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 arrythmias requiring a pacemaker or not controlled with medication, Conduction abnormality requiring a pacemaker, Valvular disease with document compromise in cardiac function, Symptomatic pericarditis
5. Patient has 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 Documented congestive heart failure (New York Heart Association functional classification III-IV) Documented cardiomyopathy
6. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., e.g., uncontrolled infection, such as persistent fever despite antibacterial therapy) that could cause unacceptable safety risks or compromise compliance with the protocol. Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusion capacity of lung for carbon monoxide (DLco), O2 saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates.
7. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus
8. Patients with acute or chronic liver, renal disease or pancreatitis
9. Patients with diarrhea >/= CTCAE grade 2
10. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with unresolved diarrhea will be excluded as previously indicated
11. 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 darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
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: a. 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 homicidal ideation (immediate risk of doing harm to others) b. >/= CTCAE grade 3 anxiety c. Meets the cut-off score of >/= 10 in the Patient Health Questionnaire PHQ-9 or a cut-off of >/= 15 in the General Anxiety Disorder GAD-7 mood scale, respectively, or 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 who have received prior treatment with a PI3K inhibitor
14. Patients with a known hypersensitivity to BKM120 or to its excipients
15. 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 4-7 or a list of prohibited QT prolonging drugs with risk of Torsades de Pointes
16. Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. If treatment with such an inhibitor is in the best interest of the patient, extreme caution should be taken with its concomitant use. Please refer to Table 4-6 for a list of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment with weak inhibitors of CYP3A is allowed)
17. Patients receiving chronic treatment with steroids or another immunosuppressive agent
18. 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
19. Patients who have undergone major surgery </= 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
20. Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant
21. Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Double barrier contraceptives must be used through the trial by both sexes. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Women of child-bearing potential must have a negative serum or urine pregnancy test ≤ 48 hours prior to initiating treatment.
22. Known diagnosis of human immunodeficiency virus (HIV) infection
23. History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix and squamous cell carcinoma in situ of the skin.
24. Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Novartis

Investigators

Principal Investigator:	Marina Konopleva, MD, PHD	M.D. Anderson Cancer Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

University of Texas MD Anderson Cancer Center Website 

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT01396499 History of Changes
Other Study ID Numbers:	2010-0874; NCI-2011-01610 ( Registry Identifier: NCI CTRP )
First Posted:	July 18, 2011
Last Update Posted:	November 1, 2016
Last Verified:	October 2016

Keywords provided by M.D. Anderson Cancer Center:

Leukemia; Acute leukemias; Relapsed/refractory leukemias; Acute myelogenous leukemia	AML; Acute lymphoblastic leukemia; ALL; BKM120

Additional relevant MeSH terms:

Leukemia; Neoplasms by Histologic Type; Neoplasms