| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | histological evidence of progressive or metastatic bone or soft tissue sarcomas | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10039494 | | E.1.2 | Term | Sarcoma NOS | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | To evaluate preliminary efficacy of RAD001 in progressive or metastatic alveolar soft part sarcoma (ASPS). Efficacy is defined as the proportion of patients showing complete response, partial response or stable disease at 16 weeks.
To evaluate preliminary efficacy of RAD001 in patients with gastorintestinal stromal tumor (GIST) after failure or intolerance of treatment with imatinib or sunitinib in 1st or 2nd line. Efficacy is defined as the proportion of patients showing complete response, partial response or stable disease at 16 weeks.
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| E.2.2 | Secondary objectives of the trial | •To evaluate the tolerability and safety profile of RAD001 in these patient populations.
•To evaluate the objective tumor response rate based on RECIST-criteria (complete response [CR] and partial response [PR]) at 16 weeks.
•To evaluate duration of response.
•To evaluate progression-free survival (PFS) at 16 weeks.
•To evaluate overall survival (OS).
•To evaluate PFS at month 12 for patients with data available from follow-up observation (optional).
•To evaluate OS at 12 months for patients with data available from follow-up observation (optional).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | •Histological evidence of progressive or metastatic bone or soft tissue sarcoma.
The following tumor types are included:
alveolar soft part sarcoma (ASPS)
malignant fibrous histiocytoma;
liposarcoma;
synovial sarcoma;
malignant paraganglioma;
fibrosarcoma;
leiomyosarcoma;
angiosarcoma including haemangiopericytoma;
malignant peripheral nerve sheath tumor;
STS, not otherwise specified;
miscellaneous sarcoma including mixed mesodermal tumors of the uterus;
osteosarcoma;
Ewing’s sarcoma;
rhabdomyosarcoma;
gastrointestinal stromal tumor (only after failure or intolerance of imatinib or sunitinib in 1st and 2nd line).
Objective progression of disease may be documented by RECIST criteria. Any of the following would be sufficient according to RECIST:
a 20% increase in the sum of unidimensionally measured target lesions;
a new lesion;
unequivocal increase in non-measurable disease.
•At baseline, a CT or MRI scan must demonstrate measurable disease by RECIST criteria, i.e. the presence of at least one measurable lesion. Measurable disease lesions must be accurately measured in at least one dimension with longest diameter 20mm using conventional techniques or 10mm with spiral CT scan (with minimum lesion size no less than double the slice thickness). (see post-text supplement 1).
•At least one measurable lesion outside of the field of any prior radiation therapy (according to RECIST criteria). Prior radiotherapy to a single index lesion is not allowed.
•Adult male or female patients (≥18 years of age). In countries outside Germany patients at the age of ≥ 16 can also be included into the trial.
•Patients must have disease not amenable to surgery, radiation, or combined modality therapy with curative intent.
•Adequate bone marrow function as shown by: absolute neutrophil count (ANC) > 1,500/µl, Platelets ≥ 100,000/µl, Hb > 9g/dL.
•Adequate renal function as shown by: a serum creatinine value < 1.5 x upper limit of normal (ULN).
•Adequate liver function as shown by:
•serum bilirubin ≤ 1.5 x ULN;
•INR < 1.3 x ULN (or < 3 on anticoagulants);
•ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases).
•ECOG performance status 0 – 2.
•Fully recovered from any previous surgery, prior chemotherapy or radiation therapy (at least 4 weeks since major surgery or prior myelosuppressive chemotherapy). Prior radiotherapy to a single index lesion is not allowed. With the exception of alopecia, patients must have resolution of all acute toxic effects of any prior surgery, radiotherapy, or chemotherapy to NCI CTC (Version 3.0) grade ≤ 1.
•Signed informed consent to participate in the study must be obtained from patients after they have been fully informed of the nature and potential risks by the investigator (or his/her designee) with the aid of written information. | |
| E.4 | Principal exclusion criteria | •Anticancer therapy within 3 weeks of enrollment including chemotherapy, hormonal therapy, immunotherapy, or radiotherapy.
•The following tumor types will not be included:
gastrointestinal stromal tumor (except for patients after treatment with imatinib or sunitinib in 1st and 2nd line);
chondrosarcoma;
malignant mesothelioma;
neuroblastoma.
•Prior therapy with RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus).
•neurotoxicity ≥ grade 2 CTC.
•Radiation of the lung.
•Patients taking drugs known to inhibit or induce isoenzyme CYP3A (Table 6-4) are excluded unless the drugs are medically necessary and no substitutes are available. If there are no acceptable substitutes, special precautions should be taken in these patients (section 6.3.5).
•Patients with any concurrent major medical condition liable to compromise the patient's participation in the study (e.g. known HIV infection, uncontrolled diabetes, serious cardiac dysrhythmia or condition, New York Heart Association classification of III or IV, congestive cardiac failure, myocardial infarction within 6 months, unstable angina, chronic or acute renal or liver disease, uncontrolled serious infections including abscess or fistulae, etc.).
•Patients with a history of another malignancy prior to study entry, except curatively treated non-melanotic skin cancer or carcinoma in-situ cervical cancer unless in complete remission or no evidence of disease and off all therapy for that disease for a minimum of 5 years.
•No symptomatic brain metastasis. Patients with asymptomatic brain metastases can be entered, if this is deemed to be in the best interest of the patient by the responsible physician. Previously radiated brain lesions will be defined non evaluable for response.
•Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
•History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures.
•Patients committed to an institution by order of the authorities or court decision.
•Female patients who are pregnant or breast feeding or patients of reproductive potential not employing an effective method of birth control. Because oral, implantable or injectable contraceptives may be affected by cytochrome P450 interactions, an appropriate method of birth control should be used throughout the trial in both sexes. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 48 hours prior to the administration of study medication.
Definition of women of child-bearing potential (WOCBP): all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: Acceptable methods of contraception may include total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. Appropriate contraception is defined as surgical sterilization (e.g. bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap).Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | To evaluate preliminary efficacy of RAD001 in bone and soft tissue sarcoma. Efficacy is defined as complete response, partial response or stable disease at 16 weeks. | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
