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A Phase Ib, Multi-center, Open Label, Dose Escalation Study of Oral LDE225 in Combination With BKM 120 in Patients With Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Dose Escalation, Safety, Preliminary Efficacy, Advanced Solid Tumors, Metastatic Breast Cancer, Advanced Pancreatic Adenocarcinoma, Metastatic Colorectal Cancer, Recurrent Glioblastoma Multiforme

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Trial Information

A Phase Ib, Multi-center, Open Label, Dose Escalation Study of Oral LDE225 in Combination With BKM 120 in Patients With Advanced Solid Tumors


The primary purpose of this study is to determine a combination maximum tolerated dose (MTD)
and/or recommended dose for expansion (RDE) of LDE225 and BKM120 when co-administered orally
in patients with advanced solid tumors (specifically, metastatic breast cancer, advance
pancreatic adenocarcinoma, metastatic colorectal cancer (CRC) and recurrent glioblastoma
multiforme (GBM)).

Adult patients, aged > 18 years with advanced solid tumors that have progressed despite
standard therapy or for which no standard therapies exist will be eligible for this study.
The study population will be limited to patients with the following tumor types: metastatic
breast cancer, pancreatic adenocarcinoma, metastatic CRC and recurrent GBM. It is
anticipated that approximately 45 patients will be enrolled in the dose escalation part.
Approximately 15 GBM patients (maximum of 2 patients per dose level) will be enrolled to
previously well-tolerated doses during dose escalation if no slot is available in a cohort
under active testing. The dose expansion will enroll 30 patients (at least 15 patients with
recurrent GBM). Accounting for patients who may withdrawal or who may not meet the
eligibility criteria, it is expected that this study will enroll approximately 80 patients.

This is a multi-center, open-label, dose finding, phase Ib study to determine the MTD and/or
RDE for the combination of LDE225 plus BKM120, followed by an expansion part to further
assess safety and preliminary efficacy of the combination in patients with advanced solid
tumors that are frequently associated with dysregulated Hh and/or PI3K pathways,
specifically metastatic breast cancer, pancreatic adenocarcinoma, metastatic CRC and
recurrent GBM. Patients will be treated daily on a 28-day cycles. Dose escalation will be
dependent on the available toxicity information (including adverse events that are not
DLTs), PK, PD, and efficacy information, as well as the recommendations from the Bayesian
Logistic Regression Model (BLRM).


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.

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).

Exclusion Criteria:

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)

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Dose Limiting Toxicities

Outcome Description:

Dose Limiting Toxicities (DLTs) during the first 6 weeks (42 days) of the combination treatment of LDE225 and BKM120.

Outcome Time Frame:

6 weeks (42 days)

Safety Issue:

Yes

Principal Investigator

Novartis Pharmceuticals

Investigator Role:

Study Director

Investigator Affiliation:

Novartis Pharmceuticals

Authority:

United States: Food and Drug Administration

Study ID:

CLDE225X2114

NCT ID:

NCT01576666

Start Date:

July 2012

Completion Date:

March 2015

Related Keywords:

  • Dose Escalation
  • Safety
  • Preliminary Efficacy
  • Advanced Solid Tumors
  • Metastatic Breast Cancer
  • Advanced Pancreatic Adenocarcinoma
  • Metastatic Colorectal Cancer
  • Recurrent Glioblastoma Multiforme
  • Dose escalation
  • Maximum Tolerated Dose
  • MTD
  • Safety Expansion
  • Safety
  • Preliminary Efficacy
  • Objective Response Rate
  • Early progression rate
  • PI3K activation
  • Combination Treatment
  • Hedgehog Signaling Pathway
  • Smoothened inhibitor
  • Phosphoinositide-3' kinase
  • Phosphatase signaling pathway
  • Advanced solid tumors
  • metastatic breast cancer
  • advanced pancreatic adenocarcinoma
  • metastatic colorectal cancer
  • recurrent glioblastoma multiforme
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Breast Neoplasms
  • Colorectal Neoplasms
  • Glioblastoma
  • Neoplasms

Name

Location

US Oncology Central MonitoringDallas, Texas  75246
Willamette Valley Clinical Studies Williamette Valley CancerEugene, Oregon  97404
University of Utah / Huntsman Cancer Institute HuntsmanSalt Lake City, Utah  84103
H. Lee Moffitt Cancer Center/University of South Florida Moffitt 4Tampa, Florida  33612
University of California San Francisco UCSF (SC)San Francisco, California  
Sammons Cancer Center Sammons Cancer Center SC-2Dallas, Texas  78246
Cedars Sinai Medical Center SCLos Angeles, California  90048
Dana Farber Cancer Institute Dana SCBoston, Massachusetts  02115
Mayo Clinic - Rochester Division of HematologyRochester, Minnesota  55905
Duke University Medical Center Duke - BakerDurham, North Carolina  27710
Northwest Cancer Specialists Main SitePortland, Oregon  97210
Fox Chase Cancer Center FCCCPhiladelphia, Pennsylvania  19111-2497
MD Anderson Cancer Center/University of Texas SC-3Houston, Texas  77030-4009
Texas Oncology, P.A. SCFort Worth, Texas  76104
University of California at Los Angeles Dept. of Neuro-OncologyLos Angeles, California  90095