| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or advanced soft tissue sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Malign tumor of the soft tissue |
|
| 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 |
To show that progression-free survival in the pazopanib group
is not inferior to that in the doxorubicin group |
|
| E.2.2 | Secondary objectives of the trial |
-To show that the rate of neutrophil granulocytopenia grade 4 is smaller in the pazopanib group than in the doxorubicin group
-To show that the rate of febrile neutropenia is smaller in the pazopanib group than in the doxorubicin group
Other secondary objectives are to demonstrate treatment effects on OS, ORR, PFR at 12 and 26 weeks, QoL, geriatric assessment, safety and tolerability, and time to onset of response, and to investigate predictive biomarkers. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent and willingness to comply with treatment and follow-up. Procedures conducted within 3 weeks as part of routine clinical management (e.g. blood count, imaging) and obtained prior to signing consent may be used for screening or baseline purposes if they are conducted as specified in the protocol
2. Male and female patients age ≥ 60 years at day of inclusion
3. Histologically confirmed diagnosis of metastatic or advanced STS of intermediate or high grade with disease progression within 6 months prior to study inclusion:
• Fibrosarcoma
• Pleomorphic high grade sarcoma (“malignant fibrous histiocytoma”)
• Leiomyosarcoma
• Liposarcoma
• Malignant glomus tumor
• Rhabdomyosarcoma, alveolar or pleomorphic (excluding embryonal)
• Vascular sarcoma (epithelioid haemangioendothelioma, angiosarcoma)
• Synovial sarcoma
• Not otherwise specified (NOS)
• Malignant peripheral nerve sheath tumors
• Other types of sarcoma (not listed as ineligible), if approved by the study coordinator.
Excluding: Uncertain differentiation (epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, malignant mesenchymoma, PEComa), chondrosarcoma, Ewing sarcoma/PNET, chordoma, malignant solitary fibrous tumors, embryonal rhabdomyosarcoma, osteosarcoma, gastro-intestinal stromal tumors, dermatofibrosarcoma protuberans, inflammatory myofibroblastic sarcoma (low-grade), neuroblastoma, malignant mesothelioma, and mixed mesodermal tumors of the uterus
(Study inclusion is based on local histopathological diagnosis).
4. ECOG performance status of 0-2 (Appendix D)
5. Evidence of progressive disease prior to start of treatment with measurable disease according to RECIST 1.1 (Appendix A)
6. Preferably archived tumor tissue of the most recent histology or, if not available, tumor block or 8 representative unstained sections on slides must be provided for all subjects for biomarker analysis within first month of treatment for central review
7. Adequate organ system function (see Table 1)
8. Male patients with female partners of childbearing potential must meet one of the following criteria:
• At least 6 weeks after surgical sterilization by vasectomy with documentation of azoospermia
• Correct use of two reliable contraception methods for 14 days before exposure to IMP, through the dosing period, and for at least 21 days after the last dose of IMP. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or of an intrauterine device or system (IUD/IUS) with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom, or condom).
• Complete sexual abstinence for 14 days before exposure to IMP, through the dosing period, and for at least 21 days after the last dose of IMP.
9. Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception as defined below during the study and for 14 days following the last dose of investigational product.
|
|
| E.4 | Principal exclusion criteria |
1. Prior malignancy
Excluding: Subjects who have had another malignancy and have been disease-free for 2 years, or subjects with a history of completely resected non-melanomatous skin carcinoma, or successfully treated in situ carcinoma or incidental prostate cancer (tumor node metastasis (TNM) stage T1a or T1b) are eligible.
2. History or clinical evidence of CNS metastases
Excluding: Subjects who have previously-treated CNS metastases (radiotherapy, surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants 12 weeks prior to study inclusion. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases.
3. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including but not limited to:
• Active peptide ulcer disease
• Known intraluminal metastatic lesion(s) with risk of bleeding
• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease) or other gastrointestinal conditions with increased risk of perforation
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning of study treatment
4. Clinically significant gastrointestinal abnormalities that may affect absorption of IMP including but not limited to:
• Malabsorption syndrome
• Major resection of the stomach or small bowels
5. Presence of uncontrolled infection
6. Corrected QT interval (QTc) > 480 msecs using Bazett’s formula
7. History of any one or more of the following cardiovascular conditions within the past 6 months:
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Coronary artery bypass graft surgery
• Symptomatic peripheral vascular disease
8. Class III or IV congestive heart failure as defined by NYHA (Appendix E)
9. Poorly controlled hypertension (SBP of ≤ 150 mmHg or DBP of ≤95 mmHg is acceptable provided that BP will be treated and monitored at least weekly. The goal is to attain controlled hypertension within 4 weeks of start of treatment, which is defined as grade ≤1 hypertension CTCAE Version 4.0; Appendix F)
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. BP must be re-assessed twice with an interval of at least 1h before start of IMP and should be ≤140/90 mmHg for a subject to be eligible for the study. However, BP of ≤150/95 mmHg is acceptable provided the above measures are employed
10. History of cerebrovascular accident including TIA, pulmonary embolism, or untreated DVT within the past 6 months
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
11. Major surgery or trauma within 28 days before first dose of IMP and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major)
12. Evidence of active bleeding or bleeding diathesis
13. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
14. Hemoptysis in excess of 2.5 mL once within 8 weeks of first dose of IMP
15. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures
16. Unable or unwilling to discontinue use of prohibited medications (see Section 5.5.5) for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of IMP and for the duration of the study
17. Treatment with any of the following anti-cancer therapies:
• Radiation therapy, surgery, or tumor embolization within 14 days prior to the first dose of IMP
OR
• Chemotherapy, immunotherapy, biologic therapy, investigational therapy, or hormonal therapy within 14 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of IMP
18. Any ongoing toxicity from prior anti-cancer therapy that is CTCAE > grade 1 and/or that is progressing in severity except alopecia
19. Prior systemic therapy for metastatic or advanced disease. Neoadjuvant or adjuvant chemotherapy is allowed, unless disease progression occurred within 6 months following end of treatment (see 5.4.2 for specifics)
20. Current participation in any other clinical trial and/or participation in another clinical trial within 30 days before the study begins
21. Known hypersensitivity to any component of IMPs
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free-Survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression-Free-Survival (PFS) calculated as time from date of randomization until the date of first objective documentation of disease progression, treatment failure, or death due to any cause, whichever occurs first |
|
| E.5.2 | Secondary end point(s) |
1. Rates of neutrophil granulocytopenia grade 4
2. Rates of febrile neutropenia
Further secondary endpoints:
3. Progression-Free-Rate (PFR)
4. Overall-Survival (OS)
5. Objective Response Rate (ORR) according to RECIST v1.1
6. QoL
7. Geriatric assessments will be made according to EORTC ETF
8. Biomarker assessment to predict PFR
9. Safety and tolerability
10. Time to onset of response
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.-2.: Day 1 - End of Trial (4 weeks after last IMP dose)
3.: After 12 and 26 weeks from date of randomization
4.: Date of randomization to date of death (from any cause).
5.: After 12 and 26 weeks from date of randomization
6.: QLQ-C30 will be collected at baseline, after 3, 6, 9, 12, 15, 19, and 26 weeks from date of randomization and EOT. Thereafter, assessment will be performed every 12 weeks until progression.
7.: At baseline, after 12 and 26 weeks, and then every 12 weeks until progression
8.: At 26 weeks from date of randomization
9.: Time from date of randomization until the date of first objective documentation of disease progression, treatment failure, or death due to any cause, whichever occurs first
10.: After 6, 12, 19 and 26 weeks from date of randomization
|
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 13 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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