Pharmacodynamic Study of BKM120 in Breast Cancer

NCT01513356 | Completed Early Phase 1

• 1 other identifier: CBKM120XES01T
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

BKM120 is a potent and highly specific oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, currently under investigation in a first-in-man study in patients with advanced solid tumors (wild type and PIK3CA-mutated). Consistent, dose-dependent pharmacodynamic activity has been demonstrated and clear signs of anti-tumor activity have been seen with BKM120.

Conditions

Breast Cancer

Keywords

breast; cancer; BKM120

Outcome Measures

Primary Outcomes (1)

• - To determine the grade of inhibition of PI3K/mTOR pathways, in pre-surgery setting with BKM120

  Biomarkers assessments must be performed at baseline and at the end of study treatment. The following biomarkers will be assessed: PI3K, KRAS, pAkt and -RPS6p

  28 days

Secondary Outcomes (2)

• Number, grade and relationship of adverse events with BKM120

  28 days

• Potential predictive biomarkers (PI3K mutation, KRAS, pAkt and RPS6p) for a pathologic complete response relating to BKM120

  28 days

Study Arms (1)

CBKM120

EXPERIMENTAL

BKM120 will be administered on a continuous once daily dosing schedule at a dose of 100 mg (p.o.)during 28 days

Drug: BKM120

Interventions

BKM120 DRUG

BKM120 will be administered on a continuous once daily dosing schedule at a dose of 100 mg (p.o.)until progression of disease or unacceptable toxicity or a maximum of 4 weeks.

CBKM120

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• ER+ / HER2 negative breast cancer patients
• WHO performance status £ 2
• Previously untreated histologically confirmed invasive, non-metastatic, breast carcinoma with a tumor size ≥ 1,5cm and non urgent surgical treatment
• Activated Pi3K pathway in breast cancer trucut biopsy
• Documentation of negative pregnancy test for patients of child bearing potential within 7 days prior to start study treatment. Sexually active pre-menopausal patients must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on study.
• Patients must meet the following laboratory criteria within 7 days prior to start the study treatment:
• Hematology
• Neutrophil count of \> 1200/mm3
• Platelet count of \> 100,000/ mm3
• Hemoglobin \> 90g/L
• Biochemistry
• AST/SGOT and ALT/SGPT \< 2.5 x upper limit of normal (ULN) or \< 5.0 x ULN if the transaminase elevation is due to liver metastases
• Total bilirubin \< 1.5 x ULN \[Patients with Gilbert Syndrome must have total bilirubin \< 3 ULN\]
• Cholesterol \< ULN - 7.75 mmol/L and Triglycerides \< ULN - 2.5 x ULN (with lipid-lowering drugs permitted)

You may not qualify if:

• Patients who have received prior treatment with a P13K inhibitor
• Patients with a known hypersensitivity to BKM120 or to its excipients
• Patients with a history of photosensitivity reactions to other drugs
• Patients with the following mood disorders as judged by the Investigator or a psychiatrist, or as 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 homicidal ideation (immediate risk of doing harm to others)
• ≥ CTCAE grade 3 anxiety The psychiatric judgment overrules the mood assessment questionnaire result/investigators judgment.
• 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
• Patients with diabetes mellitus requiring insulin treatment, history of gestational diabetes mellitus
• Impaired cardiac function or clinically significant cardiac diseases
• LVEF \< 45% as determined by MUGA scan or ECHO
• Complete left bundle branch block
• ST depression or elevation of ≥ 1.5 mm in 2 or more leads
• Congenital long QT syndrome
• History or presence of ventricular arrhythmias or atrial fibrillation
• Clinically significant resting bradycardia (\< 50 beats per minute)

Sponsors & Collaborators

• Sofia Perea, Director Clinical Trials Unit.: lead
• Novartis: collaborator

Study Sites (1)

Hospital Madrid Norte Sanchinarro- CIOCC

Madrid, Madrid, 28050, Spain

Location

Related Publications (8)

• Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, Demanse D, De Buck SS, Ru QC, Peters M, Goldbrunner M, Baselga J. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012 Jan 20;30(3):282-90. doi: 10.1200/JCO.2011.36.1360. Epub 2011 Dec 12.

  PMID: 22162589 BACKGROUND

• Park E, Park J, Han SW, Im SA, Kim TY, Oh DY, Bang YJ. NVP-BKM120, a novel PI3K inhibitor, shows synergism with a STAT3 inhibitor in human gastric cancer cells harboring KRAS mutations. Int J Oncol. 2012 Apr;40(4):1259-66. doi: 10.3892/ijo.2011.1290. Epub 2011 Dec 8.

  PMID: 22159814 BACKGROUND

• Koul D, Fu J, Shen R, LaFortune TA, Wang S, Tiao N, Kim YW, Liu JL, Ramnarian D, Yuan Y, Garcia-Echevrria C, Maira SM, Yung WK. Antitumor activity of NVP-BKM120--a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res. 2012 Jan 1;18(1):184-95. doi: 10.1158/1078-0432.CCR-11-1558. Epub 2011 Nov 7.

  PMID: 22065080 BACKGROUND

• Maira SM. PI3K inhibitors for cancer treatment: five years of preclinical and clinical research after BEZ235. Mol Cancer Ther. 2011 Nov;10(11):2016. doi: 10.1158/1535-7163.MCT-11-0792. No abstract available.

  PMID: 22072802 BACKGROUND

• Leung E, Kim JE, Rewcastle GW, Finlay GJ, Baguley BC. Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells. Cancer Biol Ther. 2011 Jun 1;11(11):938-46. doi: 10.4161/cbt.11.11.15527. Epub 2011 Jun 1.

  PMID: 21464613 BACKGROUND

• Brunner-Kubath C, Shabbir W, Saferding V, Wagner R, Singer CF, Valent P, Berger W, Marian B, Zielinski CC, Grusch M, Grunt TW. The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells. Breast Cancer Res Treat. 2011 Sep;129(2):387-400. doi: 10.1007/s10549-010-1232-1. Epub 2010 Nov 3.

  PMID: 21046231 BACKGROUND

• Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, Wang S, Garcia-Echeverria C, Maira SM. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22299-304. doi: 10.1073/pnas.0905152106. Epub 2009 Dec 10.

  PMID: 20007781 BACKGROUND

• Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008 Jul;7(7):1851-63. doi: 10.1158/1535-7163.MCT-08-0017. Epub 2008 Jul 7.

  PMID: 18606717 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms; Neoplasms

Interventions

NVP-BKM120

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director Clinical Research Unit

Study Record Dates

• First Submitted: December 21, 2011
• First Posted: January 20, 2012
• Study Start: October 1, 2012
• Primary Completion: February 1, 2014
• Study Completion: February 1, 2014
• Last Updated: April 2, 2014

Record last verified: 2014-04

Locations

ES (1)