A study of the experimental drug BKM120 with paclitaxel in patients with HER2 negative, locally advanced or metastatic breast cancer, with or without PI3K activatio

• Conditions: This study will evaluate whether the addition of daily BKM120 to weeklypaclitaxel is effective and safe in treating patients with HER2- locallyadvanced or metastatic breast cancer.; MedDRA version: 15.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2011-005932-24-IT
• Lead Sponsor: OVARTIS FARMA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2012-09-03
• Last Update Posted: 18 January 2016

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Female
• Target Recruitment: 200

Inclusion Criteria

1. Patient is an adult, female = 18 years old at the time of informed consent
2. Patient has histologically and/or cytologically confirmed diagnosis of breast cancer
3. Patient has radiologic evidence of inoperable locally advanced, or metastatic breast cancer
4. Patient has HER2 negative disease (based on most recently analyzed biopsy) defined as a negative immunohistochemistry, fluorescent, non-florescent chromogenic or silver in situ
hybridization (respectively FISH/CISH/SISH) test or an IHC status of 0, 1+ or 2+ (if IHC 2+, a negative SISH/FISH/CISH test is required) by local laboratory testing
5. Patient has a known PI3K pathway status (activated or non-activated based on results from a Novartis designated laboratory prior to the start of treatment)
A representative archival or fresh tumor biopsy must be shipped to a Novartis
designated laboratory for profiling and results obtained prior to randomization
through IRT
• Note: one block or = 15 unstained slides are required to determine the PI3K activation
status. Whenever possible = 20 unstained slides is preferred.
6. Patient has a known ER/PgR status (either positive or negative) by local laboratory testing
7. Patient has measurable or non-measurable disease according to RECIST 1.1 criteria
8. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status = 1
which the investigator believes is stable at the time of screening
9. Patient has adequate bone marrow and organ function as defined by the following
laboratory values:
a. Absolutely Neutrophil Count (ANC) = 1.5 x 109/L
b. Platelets = 100 x 109/L
Hemoglobin = 9.0 g/dL
d. INR = 1.5
e. Potassium and calcium (corrected for albumin), within normal limits for the
institution
f. Serum creatinine = 1.5 x ULN and/or creatinine clearance > 45 mL/min
g. Total serum bilirubin within normal range (or = 1.5 x ULN if liver metastases are
present; or total bilirubin = 3.0 x ULN with direct bilirubin within normal range in
patients with well documented Gilbert’s Syndrome, which is defined as presence of
several episodes of unconjugated hyperbilirubinemia with normal results from CBC
count (including normal reticulocyte count and blood smear), normal liver function
test results, and absence of other contributing disease processes at the time of
diagnosis (see Appendix in the final protocol)]
h. Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) within normal
range (or < 3.0 x ULN if liver metastases are present)
i. Fasting plasma glucose (FPG) = 120mg/dL or = 6.7 mmol/L
j. HbA1c = 8 %
10. Patient is able to swallow and retain oral medication
11. Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 120
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 80

Exclusion Criteria

1. Patient has received previous treatment with a PI3K inhibitor
2. Patient has received any prior systemic therapies (except endocrine therapy) for the
inoperable locally advanced (recurrent or progressive) or metastatic disease. Study
treatment in this study must be the patient’s first chemotherapy treatment for inoperable
locally advanced or metastatic disease. Any number of prior endocrine therapies is
permitted)
• Note: Adjuvant/neoadjuvant therapy will be counted as prior line of therapy for
metastatic/recurrent disease if the patient had a progression/recurrence within 6
months after completion of the therapy (12 months for taxane-based therapy).
3. Patient has symptomatic CNS metastases
• Patients with asymptomatic CNS metastases may participate in this trial. The patient
must have completed any prior local treatment for CNS metastases = 28 days prior to
the start of study treatment (including radiotherapy and/or surgery) and must have
completed corticosteroid therapy.
4. Patient has a concurrent malignancy or malignancy within 3 years of study enrollment,
(with the exception of adequately treated, basal or squamous cell carcinoma, nonmelanomatous
skin cancer or curatively resected cervical cancer)
5. Patient has 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 before enrollment, may be continued
6. Patient has received wide field radiotherapy = 4 weeks or limited field radiation for
palliation = 2 weeks prior to starting study drug or who have not recovered to grade 1 or
better from related side effects of such therapy (exceptions include alopecia, bone marrow
and organ functions (limits described in Inclusion 7))
7. Patient is currently receiving increasing or chronic treatment (> 5 days) with
corticosteroids or another immunosuppressive agent, as chronic administration of
corticosteroids (> 5 days) can induce CYP3A4.
The following uses of corticosteroids are permitted: single doses; standard
premedication for paclitaxel; Topical applications (e.g., rash), inhaled sprays (e.g.,
obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
8. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin
(LMWH), or fondaparinux is allowed
9. Patient is currently receiving treatment with drugs known to be moderate or strong
inhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued strong
inducers for at least one week and must have discontinued strong inhibitors before the
treatment is initiated. Switching to a different medication prior to randomization is
allowed. Please refer to the Table 14-1 in Appendix 1 for a list of strong and moderate
inhibitors and inducers of CYP3A4.
10. Patient has a known hypersensitivity to paclitaxel or other products containing Cremophor
11. Patient has a contraindication to use the paclitaxel standard pre-treatment such as
corticosteroids
12. Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects
13. Patient has a score = 12 on the PHQ-9 questionnaire.
Further exclusion criteria are listed in the protocol

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the treatment effect of BKM120 once daily plus weekly<br>paclitaxel versus BKM120 matching placebo once daily plus weekly<br>paclitaxel on progression-free survival (PFS);Secondary Objective: To evaluate BKM120 once daily plus weekly paclitaxel versus BKM120<br>matching placebo once daily plus weekly paclitaxel with respect to<br>• Overall survival (OS)<br>• Overall response rate (ORR)<br>• Duration of response (DOR)<br>• Time to response<br>• Clinical benefit rate<br>• Safety<br>• To characterize the pharmacokinetics of BKM120 given in combination<br>with paclitaxel;Primary end point(s): PFS in the PI3K pathway activated sub-population and full population.;Timepoint(s) of evaluation of this end point: When a total of 125 PFS events have occurred (about 18-22 months);<br>Estimated average 6-9 months for each patient.