LDE225 A stratified multi-arm Phase 2 study evaluating the efficacy and safety of LDE225 in patients with advanced/metastatic sarcomas

Funding

Commercial sector/Industry,Novartis

Scientific enquiries

Ms Linda Cowan

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 de .... 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.
Read more

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 tumou .... 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
Read more

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 i .... 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.
Read more