Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01576666




Registration number
NCT01576666
Ethics application status
Date submitted
10/04/2012
Date registered
12/04/2012
Date last updated
19/12/2020

Titles & IDs
Public title
Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors
Scientific title
A Phase Ib, Multi-center, Open Label, Dose Escalation Study of Oral LDE225 in Combination With BKM 120 in Patients With Advanced Solid Tumors
Secondary ID [1] 0 0
2011-005016-28
Secondary ID [2] 0 0
CLDE225X2114
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dose Escalation 0 0
Safety 0 0
Preliminary Efficacy 0 0
Advanced Solid Tumors 0 0
Metastatic Breast Cancer 0 0
Advanced Pancreatic Adenocarcinoma 0 0
Metastatic Colorectal Cancer 0 0
Recurrent Glioblastoma Multiforme 0 0
Gastric Cancer 0 0
Gastroesophageal Junction Cancer 0 0
Triple Negative Metastatic Breast Cancer 0 0
Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 0 0 0 0
Stomach
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - LDE225
Treatment: Drugs - BKM120

Experimental: LDE225 and BKM120 in combination - LDE225 and BKM120 in combination


Treatment: Drugs: LDE225


Treatment: Drugs: BKM120
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose Limiting Toxicities
Timepoint [1] 0 0
6 weeks (42 days)
Secondary outcome [1] 0 0
Number of Patients with Adverse Events and Serious Adverse Events
Timepoint [1] 0 0
Following signing of the informed consent form, up to and including 30 days following the last dose
Secondary outcome [2] 0 0
Objective response rate (ORR)
Timepoint [2] 0 0
4 months
Secondary outcome [3] 0 0
Early progression rate (EPR)
Timepoint [3] 0 0
6 months
Secondary outcome [4] 0 0
Plasma pharmacokinetics (PK) parameters
Timepoint [4] 0 0
In 28-day cycles: Cycle 1/Day 1 and Day 15; Cycle 2/Day 1 and Day 15; then on Day 1 of each additional cycle up to and including cycle 11 (if applicable)

Eligibility
Key inclusion criteria
1. Male or female adult patients (> 18 years)

2. Patients with histologically/cytologically confirmed diagnosis of the following
advanced tumors that have progressed despite standard therapy or that have no
available established treatments: metastatic breast cancer, pancreatic adenocarcinoma,
metastatic CRC or recurrent GBM will be included.

3. Provision of an archival tumor sample to a Novartis designated laboratory for
molecular profiling. The tumor material submitted for these analyses may have been
obtained at any time during the course of the patient's disease.

4. Measurable disease as assessed by RECIST 1.1 for non-GBM tumors and by RANO criteria
for GBM.

5. ECOG (WHO) performance status 0-2

6. Adequate bone marrow and organ function

7. Patient is able to swallow and retain oral medication

8. Negative serum pregnancy test; non-lactating or post-menopausal women.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Use of other investigational drugs within 30 days of enrollment or 5 half-lives of
enrollment, whichever is longer. 2.History of hypersensitivity to LDE225, BKM120 or to
drugs of similar chemical classes.

3.Patient has received previous treatment with PI3K inhibitors and/or smoothened
inhibitors.

4.Patients with recurrent GBM who have received radiotherapy within 3 months of initiating
study treatment.

5.Patients with primary CNS tumor (except recurrent GBM), uncontrolled or symptomatic CNS
metastasis. However, patients with controlled, asymptomatic or with resected CNS metastases
with no radiological evidence of disease or with stable brain metastasis with no
progression may be are eligible.

6.Patients who have neuromuscular disorders or are on concomitant treatment with drugs that
are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate
and gemfibrozil. If it is essential that the patient remains on a statin to control
hyperlipidemia, only Pravastatin may be used with extra caution.

7.Patients who require the use of warfarin (substrate of CYP2C9) cannot be enrolled as
LDE225 and BKM120 are competitive inhibitors of CYP2C9 based on in-vitro data.

8.Patient is currently being treated with drugs known to be strong inhibitors or inducers
of CYP3A4/5, which cannot be discontinued or switched to a different medication 7 days
prior to starting study treatment and for the duration of the study.

9.Patient has a score =12 on the PHQ-9 questionnaire. A normal evaluation by a psychiatrist
or psychologist can overrule this exclusion).

10.Patients who select responses of "1", "2" or "3" to question number 9 on the PHQ-9
questionnaire regarding potential for suicidal thoughts or ideation (independent of the
total score of the PHQ-9), (a normal evaluation by a psychiatrist or psychologist can
overrule this exclusion).

11.Patient has a GAD-7 mood scale score = 15, (a normal evaluation by a psychiatrist or
psychologist can overrule this exclusion) 12.Patient has a documented medical history of or
active major depression episode, bipolar disorder (I or II), obsessive compulsive disorder,
schizophrenia, a history of suicidal attempts or ideation, or homicidal ideation (e.g. risk
of doing harm to self or others) 13. Patient has =CTCAE grade 3 anxiety 14.Current medical
history of the following:

- Use of a pacemaker

- History of or presence of clinically significant ventricular or atrial tachyarrhythmia

- Clinically significant resting bradycardia (< 45 beats per minute)

- History of clinically documented myocardial infarction

- History of unstable angina pectoris

- History of known structural abnormalities (i.e. cardiomyopathy) 15.Clinically
significant cardio-vascular disease 16.Clinically significant abnormal ECG 17.Left
Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated Acquisition
(MUGA) scan or echocardiogram (ECHO) 18.Patient is currently receiving treatment with
QT prolonging medication known to have a risk to induce Torsades de Pointes, and the
treatment cannot be discontinued or switched to a different medication 7 days prior to
starting the study and for the duration of the study 19.Patients who are not willing
to apply highly effective contraception as defined by the protocol during the study
and through the duration of the study. Note: Hormonal contraception methods (e.g.
oral, injected, implanted) are not allowed as it cannot be ruled out that the study
drug decreases the effectiveness of hormonal contraception 20.Sexually active males
who are unwilling to use a condom during intercourse while taking drug and for 6
months after stopping investigational medications and agree not father a child in this
period.

21.Patients is currently receiving increasing or chronic treatment with
corticosteroids ((= the anti-inflammatory potency of 4mg dexamethasone) or another
immunosuppressive agent.

22.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 23.Patient who
has received chemotherapy, targeted therapy or immunotherapy = 3 weeks (6 weeks for
nitrosourea, mitomycin-C or monoclonal antibodies; 1 week for hormonal anti-cancer
therapy) 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) 24.Patient has impairment of gastrointestinal (GI) function or GI
disease that may significantly alter the absorption of LDE225 and BKM120 (e.g.,
ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome,
or small bowel resection) 25.Patient has a known history of HIV infection (testing not
mandatory)

AMENDMENT 1 CHANGES:

Inclusion Criteria:

3. Provision of an archival tumor sample to a Novartis designated laboratory for molecular
profiling. It is accepted that it may not be possible to obtain all samples prior to
commencing study treatment. It is also accepted that it may not be possible to obtain a
sample (e.g. if sufficient sample does not exist), and in this situation inclusion of the
patient should be discussed with Novartis (as this may not make a patient ineligible).



5. Patients with primary CNS tumor (except recurrent GBM), uncontrolled or symptomatic CNS
metastasis. However, patients with controlled, asymptomatic or with resected CNS metastases
with no radiological evidence of disease or with stable brain metastasis with no
progression may be eligible. The patient must have completed any prior treatment for CNS
metastases (including radiotherapy and/or surgery) = 28 days (> 14 days for stereotactic
radiosurgery).

9. Patient has a score =12 on the PHQ-9 questionnaire. A normal evaluation by a
psychiatrist can overrule this exclusion.

10.Patients who select responses of "1", "2" or "3" to question number 9 on the PHQ-9
questionnaire regarding potential for suicidal thoughts or ideation (independent of the
total score of the PHQ-9), (a normal evaluation by a psychiatrist can overrule this
exclusion).

11.Patient has a GAD-7 mood scale score = 15, (a normal evaluation by a psychiatrist can
overrule this exclusion)

AMENDMENT 2 CHANGES:

Updated Inclusion Criteria:

3. Revised to specify the groups of patients that will be included in the dose escalation
and dose expansion parts (NEW tumor type added here): Patients with
histologically/cytologically confirmed diagnosis of the following advanced tumors that have
progressed despite standard therapy or that have no available established treatments: four
group of patients during the dose escalation part: metastatic breast cancer, advanced
pancreatic adenocarcinoma, metastatic CRC or recurrent GBM and five groups during the dose
expansion part: triple negative metastatic breast cancer, hormone receptor positive
(ER+/PR+, and Her2-) metastatic breast cancer, recurrent GBM, GASTRIC/GASTROESOPHAGEAL
JUNCTION CANCER, advanced pancreatic adenocarcinoma or metastatic CRC will be included.

6. ECOG (WHO) performance status 0-2. ADDED "only applies to patients enrolled under the
original and Amendment 1 protocol versions." 7. Two sub-bullets updated: Potassium, and
calcium, within normal limits for the institution. Out of range values should be clinically
insignificant. Serum Creatinine = 1.5 x ULN and 24-hour creatinine clearance = 50 mL/min
(determined by inputting the serum creatinine result into the Cockcroft-Gault formula).

9. NEW Inclusion criterion: Recurrent GBM patient has a Karnofsky performance status (KPS)
score = 70.

10. NEW Inclusion criterion:ECOG (WHO) performance status 0-1 (only applies to patients
enrolled under Amendment 2 and any later protocol versions).

Updated

12. Patient has a score =12 on the PHQ-9 questionnaire. REMOVED "A normal evaluation by a
psychiatrist can overrule this exclusion." 13.Patients who select responses of "1", "2" or
"3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal
thoughts or ideation (independent of the total score of the PHQ-9). REMOVED "A normal
evaluation by a psychiatrist can overrule this exclusion." 14. Patient has a GAD-7 mood
scale score = 15. REMOVED "A normal evaluation by a psychiatrist can overrule this
exclusion." 15. Patient has a documented medical history of or active major depression
episode, bipolar disorder (I or II), obsessive compulsive disorder, schizophrenia, a
history of suicidal attempts or ideation. ADDED "or homicidal ideation (e.g. risk of doing
harm to self or others), or patients with active severe personality disorders (defined
according to DSM- IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition)
are not eligible. Note: for patients with psychotropic treatments ongoing at baseline, the
dose and the schedule should not be modified within the previous 6 weeks prior to start of
study drug." 23. REMOVED mention of "Double barrier method" term under "Male patient"
section 27. Patient who has received chemotherapy, targeted therapy or immunotherapy = 3
weeks (6 weeks for nitrosourea, or mitomycin-C; or 6 weeks for monoclonal antibodies if
carryover effects are suspected; 1 week for hormonal anti-cancer therapy) 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). ADDED clarification
concerning the washout period for monoclonal antibodies.

Study design
Purpose of the study
Other
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/07/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/04/2015
Sample size
Target
Accrual to date
Final
120
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Parkville
Recruitment postcode(s) [1] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
Minnesota
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Oregon
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Utah
Country [10] 0 0
Belgium
State/province [10] 0 0
Wilrijk
Country [11] 0 0
Canada
State/province [11] 0 0
Alberta
Country [12] 0 0
Germany
State/province [12] 0 0
Essen
Country [13] 0 0
Italy
State/province [13] 0 0
AN
Country [14] 0 0
Italy
State/province [14] 0 0
MI
Country [15] 0 0
Spain
State/province [15] 0 0
Catalunya
Country [16] 0 0
United Kingdom
State/province [16] 0 0
Glasgow
Country [17] 0 0
United Kingdom
State/province [17] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to determine the maximum dose of LDE225 and BKM120 that can be
safely given together to patients and/or the dose that will be used in future studies. This
study will also learn more about how the combination of these two investigational drugs may
work for patients with certain cancers (specifically metastatic breast cancer, advanced
pancreatic adenocarcinoma, metastatic colorectal cancer and recurrent glioblastoma
multiforme).
Trial website
https://clinicaltrials.gov/ct2/show/NCT01576666
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmceuticals
Address 0 0
Novartis Pharmceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01576666