E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Ewing’s sarcoma and other sarcoma subtypes |
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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 | 10015560 |
E.1.2 | Term | Ewing's sarcoma |
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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 |
1. To determine the overall objective response rate of R1507 in patients with recurrent or refractory osteosarcoma, synovial sarcoma, rhabdomyosarcoma and other sarcomas of the following subtypes: alveolar soft part sarcoma, desmoplastic small round cell tumor, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, and myxoid liposarcoma. 2. To determine the progression-free survival at 18 weeks from start of treatment of patients with progressive, recurrent or refractory Ewing’s sarcoma (Ewing’s family of tumors) treated with R1507. 3. To determine the safety and response rate for patients with recurrent or refractory Ewing’s sarcoma/Ewing’s family of tumors regardless of prior therapy or time to progression when treated with R1507 on an every three week schedule. |
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E.2.2 | Secondary objectives of the trial |
1. To estimate the duration of response, time to progression, failure-free survival , OS, PFS rate at 18 weeks from start of treatment and overall PFS of pts with recurrent or refractory, Ewing’s sarcoma nonprimary cohort, osteosarcoma, synovial sarcoma, rhabdomyosarcoma and other sarcomas who were treated with R1507. 2. To determine the overall objective response rate, response duration, time to progression, failure-free survival, overall PFS and OS of pts with progressive, recurrent or refractory Ewing’s sarcoma/Ewing’s family of tumors primary cohort treated with R1507. 3. To define the population pharmacokinetic profile of R1507 in selected study patients. 4. To define the tolerability and adverse event profile of R1507 in sarcoma pts.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must have histologically or cytologically confirmed one of the histologies shown below and should be stratified into one of the seven treatment cohorts defined below Ewing’s sarcoma (Ewing’s family of tumors, ESFT) cohorts - Primary cohort: Ewing’s sarcoma primary cohort (defined as those patients who have relapsed < 24 months from diagnosis, and received at least 2 prior chemotherapy programs (one initial and a second for 1st relapse) and are unresectable) - Secondary cohort: Ewing’s sarcoma non-primary cohort ((defined as those patients who have relapsed > 24 months from diagnosis or have only received only 1 prior chemotherapy program) - Expanded cohort: Patients with recurrent or relapsed Ewing’s sarcoma regardless of number of prior number of salvage regimens and regardless of time to relapse. The dose and schedule of R1507 in this cohort will differ from that of all other cohorts, as will the PK, PD, safety, and HAHA assessments. *Osteosarcoma *Synovial sarcoma *Rhabdomyosarcoma *Other sarcomas of the following subtypes: • Alveolar soft part sarcoma • Desmoplastic small round cell tumors • Extraskeletal myxoid chondrosarcoma • Clear cell sarcoma • Myxoid Liposarcoma 2. Patients must have had histological verification of malignancy by central pathology review (to be completed within 6 weeks of study entry). 3.All patients must have recurrent or refractory tumors with no known curative treatment options according to the judgment of the investigatorand must have documented progressive disease by WHO criteria (see Appendix B). 4. Age >2 years - For patients enrolled in the expanded Ewing’s sarcoma cohort 3 only, age must be ≥ 2 and ≤ 21 years. 5. Life expectancy of at least 6 weeks. 6. Karnofsky performance status of > 70% 7. Patients must have measurable disease defined as lesions that can be measured in 2 dimensions by medical imaging techniques such as CT or MRI. Ascites, pleural fluid, bone marrow disease, lesions seen on PET scan will not be considered measurable. -For patients enrolled in all cohorts with the exception of expanded Ewing’s sarcoma cohort 3, lesions that are situated in a previously irradiated area will not be considered measurable. (see section 11.1.1) -For patients enrolled in the expanded Ewing’s sarcoma cohort 3 only, lesions that are situated in an area of prior irradiation that have progressed and are measurable by WHO criteria will be considered measurable . (see section 11.1.1). 8. Adequate organ function requirements (see protocol for definition) 9. Prior Therapy -Time elapsed from previous therapy must be > 3 weeks. Patients must be recovered (toxicities < grade 1 except for alopecia) from the effects of any prior surgery, radiotherapy or systemic therapy, including any investigational therapy. - Patients who have undergone autologous hematopoietic stem cell transplantation (HSCT) will be eligible once they have recovered from all toxicities from therapy (< grade 1 except for alopecia). Patients who have received allogeneic HSCT will be eligible 6 months after the procedure provided there is no evidence of active graft-versus-host disease and immunosuppressive treatment has been discontinued for at least 30 days. - Patients with central nervous system (CNS) disease are eligible for enrollment if they have received prior radiotherapy or surgery to sites of CNS metastatic disease, have been off glucocorticoids for at least 4 weeks, have no overt evidence of neurological deficit and are > 6 weeks from completion of brain irradiation. 10. Females of childbearing potential as well as fertile males and their partners must agree to use an effective form of contraception during the study and for 120 days following the last dose of study medication. An effective form of contraception is use of an oral contraceptive, a double barrier method, or commitment to sexual abstinence.
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E.4 | Principal exclusion criteria |
1) Clinically significant unrelated systemic illness (such as serious infections requiring active systemic therapy; cardiovascular disease [congestive heart failure, recent myocardial infarction, unstable angina, inadequately controlled hypertension], poorly controlled diabetes; hepatic renal or other organ dysfunction) which would, in the judgment of the treating physician, compromise the patient’s ability to tolerate the investigational agent or be likely to interfere with the study procedures or results. 2) Known hypersensitivity to any of the components of R1507 or prior hypersensitivity reactions to monoclonal antibodies (refer to section 8.3 for study drug formulation). 3) Concomitant use of any other investigational agent(s). An investigational therapy is defined as treatment for which there is currently no approved indication from regulatory authorities. Prior use of investigational agent(s) is acceptable if at least 3 weeks have elapsed since last dose and no future doses are planned. 4) Current or previous treatment (within the past 6 months) with chronic, pharmacologic doses of corticosteroids, immunosuppressive agents or medications that inactivate or may interfere with the pharmacologic activity of R1507. 5) Current or prior therapy with IGF inhibitor (monoclonal or specific kinase inhibitor). 6) Pregnant patients or patients who are breast feeding. Subjects capable of pregnancy (post menarche and not post-menopausal, defined as over 12 months since final menstrual period) must have a negative pregnancy test within 7 days prior to first dose. 7) History of solid organ transplant. 8) Other malignant disease diagnosed within the previous 5 years, excluding intra-epithelial cervical neoplasia or non-melanoma skin cancer. 9) Active central nervous system disease
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E.5 End points |
E.5.1 | Primary end point(s) |
• For Ewing’s sarcoma (primary cohort): a one-sided 97.4% confidence interval will be calculated around the 18-week progression-free survival rate. • For osteosarcoma, rhabdomyosarcoma, synovial sarcoma, Ewing’s sarcoma (non-primary cohort), expanded Ewing’s sarcoma: a one-sided 98% confidence interval will be calculated around the objective response rate. • For “other” sarcomas: a one-sided 98% confidence interval will be calculated around the objective response rate.
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
To explore changes in PET scans in patients treated with R1507. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | 36 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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
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The trial has a survival endpoint and therefore will continue as long as a patient having received treatment on trial survives |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |