| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| locally advanced (unresectable) or metastatic soft tissue sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| locally advanced (unresectable) or metastatic soft tissue sarcoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10041299 |
| E.1.2 | Term | Soft tissue sarcomas |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Progression-free survival rate after 3 months (PFSR3), assessed by applying RECIST 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
· Progression-free survival (PFS)
· Objective response rate (ORR) (i.e. CR or PR)
· Disease control rate (DCR) (i.e. CR, PR or SD)
· Overall survival (OS)
· Assessment of adverse events according to CTCAE 4.03
· Study therapy discontinuation rate due to cardiac toxicity
(i.e. due to LVEF reduction by more than 20% or LVEF <45%)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must have histologically confirmed soft tissue sarcoma (STS)
Note: Evidence of disease progression at study entry is required.
2. Treated in any order (neoadjuvant, adjuvant or for metastatic disease) with an anthracycline containing chemotherapy
(The participant may have had any number of prior systemic cytotoxic therapies for advanced/metastatic disease. All previous anticancer treatments must be completed ≥ 3 weeks (21 days) prior to first dose of study drug.)
3. No progression on prior therapy with anthracyclines or within three months after stopping this therapy
4. Signed written informed consent
5. Men and women aged ≥ 18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Locally advanced (unresectable) or metastatic disease
8. Presence of measurable or non-measurable but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1, Eisenhauer et al., 2009)
9. Adequate haematologic, organ, and coagulation within 2 weeks (14 days) prior to enrollment:
• Absolute neutrophil count (ANC) ≥ 1,500/mm3; G-CSF is not permitted within 2 weeks (14 days) prior to enrollment
• Platelet count ≥ 100,000/mm3
• Creatinine clearance ≥ 45 mL/min (calculated by using the Cockcroft-Gault formula (refer to study protocol Appendix 4)
• Total bilirubin ≤ upper limit of normal (ULN). In patients with Gilbert’s Syndrome, total bilirubin should be < 3 mg/dL
• AST/ALT ≤ 3.0 x upper limit of normal (ULN); in case of liver involvement, AST/ALT ≤ 5.0 x are acceptable
• Haemoglobin ≥ 9 g/dl. If haemoglobin <9 g/dl, blood transfusion is permitted. If haemoglobin cannot be enhanced to ≥ 9 g/dl, patient cannot be included into the study
• International Normalized Ration (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN
• Partial thromboplastin time (PTT or aPTT) ≤ 1.5 x ULN if not on anticoagulant therapy. For patients receiving anticoagulants, coagulation parameters within the intended or expected range for their therapeutic use are allowed.
• If routine urinalysis ≥2+ proteinuria, patient must have ≤1000 mg protein on a 24-hour urine, or urine protein/creatinine ratio ≤1 on spot urine
10. Left ventricular ejection fraction (LVEF) ≥50% assessed within 28 days prior to enrollment
11. Females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to enrollment (refer to study protocol Appendix 3)
12. Females of child-bearing potential and males and must agree to use highly effective contraceptive precautions during the trial and up to 6 months following the last dose of study drug (refer to study protocol Appendix 3)
13. The participant has, in the opinion of the investigator, a life expectancy of at least 3 months
|
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of GIST or Kaposi sarcoma
2. Active central nervous system (CNS) or leptomeningeal metastasis (brain metastasis) at the time of enrollment. Participants with a history of a CNS metastasis previously treated with curative intent (for example, stereotactic radiation or surgery) that have not progressed on follow-up imaging, have been asymptomatic for at least 60 days and are not receiving systemic corticosteroids and or/anticonvulsants, are eligible. Participants with signs or symptoms of neurological compromise should have appropriate radiographic imaging performed before enrollment to rule out brain metastasis
3. Prior radiotherapy of the mediastinal/pericardial area or whole pelvis radiation
4. The participant has symptomatic congestive heart failure (CHF), or severe cardiac arrhythmia
5. The participant has unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction within 6 months of enrollment
6. The participant has a QTcB interval calculated using Bazett's formula interval of >450 milliseconds (msec) for males and >470 msec for females on screening electrocardiogram (ECG)
7. Females who are pregnant or breastfeeding
8. Known allergy to any of the treatment components including a history of allergic reactions attributed to compounds of chemical or biological composition similar to olaratumab, dexrazoxane or doxorubicin
9. The participant has a known active fungal, bacterial, or viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required)
10. Known history of active bleeding (defined as within 14 days of first dose of study drug) or pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or known esophageal varices)
11. History of another primary cancer, with the exception of
i) curatively treated non-melanomatous skin cancer or ii) curatively treated cervical carcinoma in situ or iii) other primary nonhaematologic malignancies or solid tumor treated with curative intent, no known active disease and no treatment administered during the last 3 years prior to enrollment
12. Electively planned or required major surgery during the course of the clinical trial
13. Any condition that, in the opinion of the investigator, would compromise the well-being of the participant or the study or prevent the participant from meeting or performing study requirements
14. On-treatment participation in another clinical study in the period 30 days prior to start of study treatment and during the study
15. Legal incapacity or limited legal capacity.
16. Any condition that requires concomitant vaccination with yellow fever vaccine
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival rate after 3 months (PFSR3) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 3 months from the first dosing date of any study medication |
|
| E.5.2 | Secondary end point(s) |
Safety parameters:
· Olaratumab plus doxorubicin treatment and dosage used
· Treatment duration (number of cycles)
· General description of grade 3/4 adverse events
· Reason for discontinuation of treatment
· Discontinuation rate due to cardiac toxicity
(i.e. due to LVEF reduction by more than 20% or LVEF <45%)
Efficacy parameters:
• PFS:
PFS is defined as the time from the first dosing date of any study medication to the date of the first objectively documented tumor progression, as determined by investigators (per RECIST v1.1), or death due to any cause. Subjects who die without a reported prior progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their last tumor assessment. Subjects who did not have any on study tumor assessments and did not die will be censored on the first dosing date of study medication. Subjects who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy.
• ORR: Objective Response Rate (ORR) defined as the number and percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented tumor progression per RECIST v1.1 or the date of subsequent therapy or death date, whichever occurs first. For participants without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination.
• DCR: Disease Control Rate (DCR) defined as the number and percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD), recorded between the date of first dose and the date of the initial objectively documented tumor progression per RECIST v1.1 or the date of subsequent therapy or death date, whichever occurs first. For participants without documented progression or subsequent therapy, all available response designations will contribute to the DCR determination.
• OS: OS is defined as the time from date of the first dosing date of any study medication to the date of death (due to any cause). Subjects who are alive will be censored at the last known alive dates.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be evaluated at the end of study |
|
| 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 | 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 | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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