Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612000533897
Ethics application status
Approved
Date submitted
17/05/2012
Date registered
21/05/2012
Date last updated
6/05/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of the efficacy and safety of LDE225 in the treatment of patients with advanced or metastatic sarcomas
Scientific title
A stratified multi-arm Phase 2 study evaluating the efficacy and safety of LDE225 in patients with advanced/metastatic sarcomas
Secondary ID [1] 280505 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sarcoma 286484 0
Condition category
Condition code
Cancer 286744 286744 0 0
Sarcoma (also see 'Bone') - soft tissue

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
LDE225; 4 x 200mg capsule once daily, orally; until disease progression
Intervention code [1] 284870 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 287138 0
Achievement of complete response or partial response during the first 12 weeks of treatment or maintenance of stable disease until 12 weeks after commencement of treatment per RECIST 1.1 guidelines.
Timepoint [1] 287138 0
At 12 weeks after treatment commencement.
Secondary outcome [1] 297462 0
Objective response as defined by complete response and partial response according to RECIST 1.1 criteria at anytime over the course of treatment.
Timepoint [1] 297462 0
At 7and 13 weeks after treatment commencement, then every 8 weeks until completion of treatment due to disease progression.
Secondary outcome [2] 297463 0
Progression-free survival measured from date of commencement of treatment with LDE225 until disease progression or death from any cause.
Timepoint [2] 297463 0
Up to 2 years post commencement of treatment.
Secondary outcome [3] 297464 0
Duration of Response defined for patients who achieve an objective response and measured from the date objective response is documented until the date of progression.
Timepoint [3] 297464 0
Up to 2 years post commencement of treatment.
Secondary outcome [4] 297465 0
Frequency and severity of adverse events, new or worsened laboratory results, and other safety data from other investigations.
Adverse events may include, but are not limited to, changes to blood test results, physical signs and symptoms, and changes to radiological imaging results. They may be assessed via physical assessment, blood tests, and radiological imaging.
Timepoint [4] 297465 0
Up to 25 months post commencement of treatment.
Secondary outcome [5] 297466 0
Changes in pain levels (assessed by a linear analogue self-assessment scale).
Timepoint [5] 297466 0
Baseline, and at 6 and 12 weeks after treatment commencement.
Secondary outcome [6] 297467 0
Metabolic response based on 18FDG-PET
Timepoint [6] 297467 0
Baseline and at 5 weeks after treatment commencement.
Secondary outcome [7] 297468 0
Efficacy of LDE225 (objective response rate, progression-free survival, and duration of response) as a function of pathway mutations and Hh target gene amplification/expression in tumour biopsies.
Timepoint [7] 297468 0
Baseline, then at 5 weeks after treatment commencement, then at every 8 weeks from 13 weeks after treatment commencement, until completion of treatment due to disease progression.

Eligibility
Key inclusion criteria
1. At least 18 years of age at the time of study entry
2. All participants must have histologically confirmed metastatic or unresectable sarcoma,
(a) with a strong preclinical rationale for Hh pathway activation.
Cohort 1: Metastatic osteosarcoma
Cohort 2: Metastatic or unresectable chondrosarcoma
Cohort 3: An open cohort including other subtypes of patients for which there is a biological rationale, with a particular emphasis on patients with Ewing’s sarcoma, desmoplastic small round cell tumour (DSRCT) and rhabdomyosarcoma (RMS). Patients entering this cohort need to be discussed with the Trial Management Committee prior to enrolment to ensure that an appropriately enriched cohort is included.
(b) with no known curative treatment options according to the judgment of the investigator and
(c) for whom an investigational systemic therapy would be considered appropriate.
3. Measurable disease per RECIST 1.1 criteria.
4. ECOG performance status 0 – 2.
5. Participants must have adequate organ and marrow function as defined below:
* Haemoglobin greater than or equal to 90 g/L
* Absolute neutrophil count greater than or equal to 1.5 x 109/L
* Platelets greater than or equal to 80 x 109/L
* ALT and AST less than or equal to 2.5 x upper limit of normal (ULN), or less than or equal to 5 x ULN if liver metastases are present
* Total serum bilirubin less than or equal to 1.5 x ULN
* Serum creatinine less than or equal to 1.5 x ULN, or 24-hour clearance greater than 50ml/min
* Creatine phosphokinase (CK) less than 1.5x ULN
6. Participants must be suitable for oral drug administration
7. A tumour paraffin tissue block or 20 - 30 unstained slides from the tumour tissue block must be available for the purpose of biomarker and predictive marker analyses. Obtaining archived tumour material or unstained slides from an archived tumour block will suffice to meet this requirement. The availability of the tumour tissue block must be confirmed at screening for a patient to be considered eligible.
8. Female patients of childbearing potential (see below) must:
8(i). be on highly effective contraception. Highly effective contraception methods include
* total abstinence, or
* sterilisation, or
* combination of any two of the following (a+b, or a+c, or b+c)
(a) Use of oral, injected or implanted hormonal methods of contraception. Hormonal contraceptives include any marketed contraceptive agent that includes an oestrogen and/or a progestin.
(b) Placement of an intrauterine device (IUD)
(c) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/ vaginal suppository
8(ii) have a negative pregnancy test performed within the 7 days before start of treatment.
8(iii) Highly effective contraception for females of child bearing potential should be maintained throughout the study and for 3 months after study drug discontinuation.
9. Female patient not of child-bearing potential. Women are considered not of child bearing potential if they have had either
* 12 months of natural (spontaneous) amenorrhoea with an appropriate clinical profile (eg. age appropriate, history of vasomotor symptoms), or
* have had a surgical bilateral oophorectomy (with or without hysterectomy), or
* tubal ligation at least 6 weeks ago.
In the case of oophorectomy alone, a woman is considered not of child-bearing potential only once the reproductive status has been confirmed by follow up hormone level assessment.
10. Sexually active males must use a condom during intercourse while taking the drug and for 6 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid.
11. Ability to understand and the willingness to sign a written informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who have had any systemic cytotoxic/ biologic or investigational therapies within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study entry or who have not recovered from the side effects of such earlier therapy.
2. Participants who have had radiotherapy and/or major surgery within 2 weeks prior to study entry
3. Concurrent use of any other anti-cancer therapies or study agents.
4. Prior treatment with a smoothened (Smo) antagonist, systemic LDE225, or other Hh pathway inhibitors.
5. Impaired cardiac function or clinically significant heart disease, including any one of the following:
a. Angina pectoris within 3 months
b. Acute myocardial infarction within 3 months
c. QTc > 450 msec for males and > 470 msec for females on the screening ECG
d. A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
e. Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
6. Raised (>1.5 x ULN) or potentially raised plasma creatine phosphokinase (CK):
a. Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting LDE225 treatment. If it is essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may be used with extra caution.
b. Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on LDE225 treatment.
7. Presence of brain or central nervous system metastases.
8. Uncontrolled intercurrent illness or social situations that would limit compliance with study requirements.
9. Patients who are receiving treatment with medications known to be moderate and strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment with LDE225.
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, not using highly effective contraception (see Inclusion criterion #9).
12. Patients anticipated to require major surgery within the first 12 weeks of treatment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
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
Multi-arm study with patients grouped into the following cohorts:
Cohort 1: Metastatic osteosarcoma
Cohort 2: Metastatic or unresectable chondrosarcoma
Cohort 3: An open cohort including other subtypes of patients for which there is a biological rationale, with a particular emphasis on patients with Ewing’s sarcoma, desmoplastic small round cell tumour (DSRCT) and rhabdomyosarcoma (RMS). Patients entering this cohort need to be discussed with the Trial Management Committee prior to enrolment to ensure that an appropriately enriched cohort is included.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
29/09/2012
Actual
13/09/2012
Date of last participant enrolment
Anticipated
30/04/2015
Actual
16/04/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
84
Accrual to date
Final
46
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC
Recruitment hospital [1] 5745 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 5746 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [3] 5747 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 13214 0
3002 - East Melbourne
Recruitment postcode(s) [2] 13215 0
5000 - Adelaide
Recruitment postcode(s) [3] 13216 0
4102 - Woolloongabba
Recruitment outside Australia
Country [1] 4321 0
New Zealand
State/province [1] 4321 0
site in NZ
Country [2] 7862 0
Singapore
State/province [2] 7862 0

Funding & Sponsors
Funding source category [1] 285264 0
Commercial sector/Industry
Name [1] 285264 0
Novartis
Country [1] 285264 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Sarcoma Study Group
Address
Australasian Sarcoma Study Group,
Peter MacCallum Cancer Centre
Locked Bag 1, A'Beckett St VIC 8006
Country
Australia
Secondary sponsor category [1] 284127 0
None
Name [1] 284127 0
Address [1] 284127 0
Country [1] 284127 0
Other collaborator category [1] 260803 0
University
Name [1] 260803 0
Monash Institute of Medical Research
Address [1] 260803 0
27 - 31 Wright St,
Clayton VIC 3168
Country [1] 260803 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287281 0
Ethics committee address [1] 287281 0
Ethics committee country [1] 287281 0
Date submitted for ethics approval [1] 287281 0
11/05/2012
Approval date [1] 287281 0
11/05/2012
Ethics approval number [1] 287281 0
Ethics committee name [2] 294975 0
Metro South Hospital and Health Service Human Research Ethics Committee
Ethics committee address [2] 294975 0
Ipswich Road, Woollongabba QLD 4102
Ethics committee country [2] 294975 0
Australia
Date submitted for ethics approval [2] 294975 0
Approval date [2] 294975 0
24/08/2012
Ethics approval number [2] 294975 0
Ethics committee name [3] 294976 0
Peter MacCallum Cancer Centre Ethics Committee Secretariat
Ethics committee address [3] 294976 0
Peter MacCallum Cancer Centre Ethics Committee Secretariat
10 St Andrews Pl
East Melbourne VIC 3002
Ethics committee country [3] 294976 0
Australia
Date submitted for ethics approval [3] 294976 0
Approval date [3] 294976 0
03/09/2012
Ethics approval number [3] 294976 0
Ethics committee name [4] 294977 0
Royal Adelaide Hospital Research Ethics Committee
Ethics committee address [4] 294977 0
Royal Adelaide Hospital Research Ethics Committee
North Terrace
Adelaide, SA 5000
Ethics committee country [4] 294977 0
New Zealand
Date submitted for ethics approval [4] 294977 0
Approval date [4] 294977 0
26/09/2012
Ethics approval number [4] 294977 0
Ethics committee name [5] 294978 0
SingHealth Centralised Institutional Review Board B
Ethics committee address [5] 294978 0
Singapore Health Services Pte Ltd,
31 Third Hospital Avenue,
#03-03 Bowyer Block C,
Singapore 168753
Ethics committee country [5] 294978 0
Singapore
Date submitted for ethics approval [5] 294978 0
Approval date [5] 294978 0
02/04/2013
Ethics approval number [5] 294978 0

Summary
Brief summary
The purpose of this study is to evaluate the efficacy and safety of LDE225 as a treatment for patients with metastatic sarcoma who can not be treated by surgery.
Who is it for? You may be eligible for this study if you are aged 18 years or above, have a histologically confirmed diagnosis of metastatic or unresectable sarcoma with no known curative treatment options, and give your consent to take part. The full inclusion criteria details can be found in the relevant section of this form.
Trial details: In this study, you will receive the drug LDE225 in the form of 4x200mg capsules daily, taken orally until your disease progresses. You will be required to attend regular clinic visits for routine tests and assessments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34189 0
Dr Jayesh Desai
Address 34189 0
Department of Medical Oncology
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne VIC 3002
Country 34189 0
Australia
Phone 34189 0
+61 3 9342 7560
Fax 34189 0
Email 34189 0
[email protected]
Contact person for public queries
Name 17436 0
Dr Dr. Denise Caruso
Address 17436 0
Australasian Sarcoma Study Group,
Peter MacCallum Cancer Centre,
Locked Bag 1, A'Beckett St VIC 8006
Country 17436 0
Australia
Phone 17436 0
+61 3 9656 3605
Fax 17436 0
+61 3 9656 5875
Email 17436 0
[email protected]
Contact person for scientific queries
Name 8364 0
Ms Linda Cowan
Address 8364 0
Centre for Biostatistics & Clinical Trials,
Peter MacCallum Cancer Centre,
Locked Bag 1, A'Beckett St VIC 8006
Country 8364 0
Australia
Phone 8364 0
+61 3 9656 3637
Fax 8364 0
Email 8364 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSonidegib: First Global Approval.2015https://dx.doi.org/10.1007/s40265-015-0458-y
N.B. These documents automatically identified may not have been verified by the study sponsor.