Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT01576666

Collaborator

(none)

120

Enrollment

Locations

Arm

Duration (Months)

5.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Dose Escalation Safety Preliminary Efficacy Advanced Solid Tumors Metastatic Breast Cancer Advanced Pancreatic Adenocarcinoma Metastatic Colorectal Cancer Recurrent Glioblastoma Multiforme Gastric Cancer Gastroesophageal Junction Cancer Triple Negative Metastatic Breast Cancer Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer	Drug: LDE225 Drug: BKM120	Phase 1

Detailed Description

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. 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.

In the dose escalation part of the study, four groups of patients with the following tumor types will be enrolled: recurrent GBM, metastatic breast cancer, metastatic CRC and advanced pancreatic adenocarcinoma. 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. In the dose expansion part of the study, five groups of patients (approximately 15 patients per group) with the following tumor types will be enrolled: recurrent GBM, triple negative metastatic breast cancer, hormone receptor positive (ER+/PR+, and Her2-) metastatic breast cancer, gastric/gastroesophageal junction cancer, and a combined maximum of 15 patients with metastatic CRC or advanced pancreatic adenocarcinoma. The dose expansion will enroll approximately 75 patients. Accounting for patients who may withdraw or who may not meet the eligibility criteria, it is expected that this study will enroll approximately 120 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 triple negative metastatic breast cancer, hormone receptor positive (ER+/PR+, and Her2-) metastatic breast cancer, advanced pancreatic adenocarcinoma, metastatic CRC, recurrent GBM and gastric/gastroesophageal junction cancer patients. Patients will be treated daily on 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).

Study Design

Study Type:

Interventional

Actual Enrollment :

120 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official 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

Study Start Date :

Jul 1, 2012

Actual Primary Completion Date :

Apr 1, 2015

Actual Study Completion Date :

Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LDE225 and BKM120 in combination LDE225 and BKM120 in combination	Drug: LDE225 Drug: BKM120

Arm

Intervention/Treatment

Experimental: LDE225 and BKM120 in combination

LDE225 and BKM120 in combination

Drug: LDE225

Drug: BKM120

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Number of Patients with Adverse Events and Serious Adverse Events [Following signing of the informed consent form, up to and including 30 days following the last dose]
Adverse and serious adverse events, changes in hematology and chemistry values, and assessment of physical and/or neurological examinations, vital signs, and electrocardiograms
Objective response rate (ORR) [4 months]
ORR is the proportion of patients with best overall response of complete or partial response. ORR will be used to evaluate preliminary efficacy of the combination therapy. Tumors will be assessed using Investigator read CT/MRI assessments evaluated as per RECIST 1.1, except for patients with glioblastoma multiforme (GBM) who will be assessed per the RANO Criteria.
Early progression rate (EPR) [6 months]
EPR is the proportion of patients with progressive disease within 6 months of the start of treatment. EPR will be used to evaluate preliminary efficacy of the combination therapy. Tumors will be assessed using Investigator read CT/MRI assessments evaluated as per RECIST 1.1, except for patients with GBM who will be assessed per the RANO Criteria. AMENDMENT #2 change: EPR duration modified to 6 months for recurrent GBM patients per the convention for that tumor type
Plasma pharmacokinetics (PK) parameters [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)]
Plasma PK parameters of LDE225 and plasma PK parameters of BKM120.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female adult patients (> 18 years)
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.
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.
Measurable disease as assessed by RECIST 1.1 for non-GBM tumors and by RANO criteria for GBM.
ECOG (WHO) performance status 0-2
Adequate bone marrow and organ function
Patient is able to swallow and retain oral medication
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:

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:

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).
Patient has a score ≥12 on the PHQ-9 questionnaire. 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:

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.
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).
NEW Inclusion criterion: Recurrent GBM patient has a Karnofsky performance status (KPS) score ≥ 70.
NEW Inclusion criterion:ECOG (WHO) performance status 0-1 (only applies to patients enrolled under Amendment 2 and any later protocol versions).

Updated Exclusion Criteria:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars Sinai Medical Center SC	Los Angeles	California	United States	90048
2	University of California San Francisco UCSF (SC)	San Francisco	California	United States	94101
3	H. Lee Moffitt Cancer Center & Research Institute Moffitt 4	Tampa	Florida	United States	33612
4	Dana Farber Cancer Institute Dana SC	Boston	Massachusetts	United States	02215
5	Mayo Clinic - Rochester Division of Hematology	Rochester	Minnesota	United States	55905
6	Duke University Medical Center Duke - Baker	Durham	North Carolina	United States	27710
7	Willamette Valley Clinical Studies Williamette Valley Cancer	Eugene	Oregon	United States	97404
8	Northwest Cancer Specialists Northwest Cancer	Portland	Oregon	United States	97210
9	Fox Chase Cancer Center FCCC	Philadelphia	Pennsylvania	United States	19111-2497
10	Texas Oncology Midtown Texas Oncology	Dallas	Texas	United States	75251
11	Sammons Cancer Center - Texas Oncology SC-2	Dallas	Texas	United States	78246
12	University of Texas/MD Anderson Cancer Center SC-3	Houston	Texas	United States	77030-4009
13	University of Utah / Huntsman Cancer Institute Huntsman	Salt Lake City	Utah	United States	84103
14	Novartis Investigative Site	Parkville	Victoria	Australia	3050
15	Novartis Investigative Site	Wilrijk		Belgium	2610
16	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 1Z2
17	Novartis Investigative Site	Essen		Germany	45147
18	Novartis Investigative Site	Ancona	AN	Italy	60126
19	Novartis Investigative Site	Milano	MI	Italy	20133
20	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
21	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
22	Novartis Investigative Site	Glasgow		United Kingdom	G12 0YN
23	Novartis Investigative Site	Sutton		United Kingdom	SM2 5PT