LDE225: This phase II trial is evaluating the oral drug LDE225 for the treatment of patients whose sarcoma has spread to other parts of the bodyA stratified multi-arm Phase 2 study evaluating the efficacy and safety of LDE225 in patients with advanced/metastatic sarcomas

Inclusion

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