| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
| Patient with high risk soft tissue cancer |
|
| 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 |
Primary objective:
To compare the effectiveness, as measured by PFS according to RECIST v 1.1, of maintenance pazopanib
given as a continuous daily dose over maximally 24 months versus placebo maintenance in patients with
high-risk retroperitoneal or visceral soft tissue sarcomas who show no evidence of disease after multimodal
treatment including neo- and/or adjuvant doxorubicin / ifosfamide chemotherapy with regional hyperthermia,
tumor resection and radiotherapy, if indicated. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
Key secondary objectives:
· To describe the toxic effects of pazopanib given in a continuous daily schedule
· To determine LPFS, DPFS and OS of treated patients
Other secondary objectives are to assess health related quality of life (QOL) as assessed by EORTC QLQC30,
and to investigate predictive biomarkers. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must provide written informed consent prior to performance of study-specific procedures or
assessments and must be willing to comply with treatment and follow up.
Note: Informed consent may be obtained prior to start of the specified screening window.
Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood count,
imaging study such as bone scan) and obtained prior to signing of informed consent may be utilized
for screening or baseline purposes provided these procedures are conducted as specified in the
protocol
2. Age ≥ 18 years
3. Patients must have histological evidence of high-grade soft tissue sarcoma (grade 2 – 3) according
to the FNLCC grading system, tumor size ≥ 5 cm and deep localization, excluding the following
tumor types:
· Embryonal rhabdomyosarcoma
· Chondrosarcoma (excluding extraskeletal myxoid chondrosarcoma)
· Osteosarcoma (excluding extraskeletal osteosarcoma)
· Ewing tumors / primitive neuroectodermal tumor (PNET)
· Gastro-intestinal stromal tumors (GIST)
· Dermatofibrosarcoma protuberans
4. Patients who had undergone previous surgery with inadequate margins (tumour-free margins ≤1 cm
or margins contaminated) are eligible if thermochemotherapy has been started within 8 weeks of
surgery. The decision of a re-resection after 4 cycles of thermochemotherapy will be made by the multidisciplinary tumor board.
5. Unstained slides and ideally tumour blocks must be available for histological central review
6. Completed 4 to 8 cycles of thermochemotherapy with doxorubicin and ifosfamide at least 21 days
but no more than 42 days prior to study entry
7. No evidence of disease following completion of first-line thermochemotherapy and within ≤ 21 days
of study entry
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. No other prior chemotherapy except thermochemotherapy with doxorubicin and ifosfamide
10. Adequate organ system function as defined in Table 2
11. 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 in section 7.1.11 Inclusion criteria during the study and for 14 days following the last dose of investigational product.
12. Male patients with female partners of childbearing potential must meet one of the following criteria:
o At least 6 weeks after surgical sterilization by vasectomy with documentation of azoospermia
o 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 an IUD/IUS with a barrier method (diaphragm, cervical cap, Lea
contraceptive, femidom, or condom).
o 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. |
|
| E.4 | Principal exclusion criteria |
1. No prior or concurrent second primary malignant tumors (except adequately treated in situ
carcinoma of cervix, or basal cell carcinoma).
2. No symptomatic or known Central nervous system (CNS) metastases at baseline.
3. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal
bleeding including, but not limited to:
· Active peptic ulcer disease
· Known intraluminal metastatic lesion/s with risk of bleeding
· Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn’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 study treatment.
4. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational
product including, but not limited to:
· Malabsorption syndrome
· Major resection of the stomach or small bowel.
5. Corrected QT interval (QTc) > 480 msecs
Note: Correction method should be reported in CRF
6. 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
· Class III or IV congestive heart failure, as defined by the New York Heart Association
(NYHA) (See Appendix D)
7. 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 IMP which is defined as grade ≤1 hypertension CTCAE Version 4.0)
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 treatment 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.
8. NYHA II at Screening for Patients > 65 years
9. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or
untreated deep venous thrombosis (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
10. Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence
of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered
to be major surgery).
11. Evidence of active bleeding or bleeding diathesis.
12. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the
risk of pulmonary hemorrhage
Note: Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are excluded;
however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is
acceptable (CT with contrast is strongly recommended to evaluate such lesions).
· Large protruding endobronchial lesions in the main or lobar bronchi are excluded; however,
endobronchial lesions in the segmented bronchi are allowed.
· Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor
infiltrations in the wall of the bronchi are allowed.
13. Recent hemoptysis (≥½ teaspoon of red blood within 8 weeks before first dose of study drug).
14. 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.
15. Unable or unwilling to discontinue use of prohibited medications listed in section 9.3.3 for at least 14
days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the
duration of the study.
16. Treatment with any of the following anti-cancer therapies:
· radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of
pazoapnib OR
· chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal
therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose
of pazopanib
17. Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is
longer prior to receiving the first dose of study treatment
18. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in
severity, except alopecia. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
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.5.1.1 | Timepoint(s) of evaluation of this end point |
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) |
Secondary endpoints:
Key secondary endpoints:
· Rates of grade 3 or 4 toxicities during pazopanib or placebo maintenance
· Local progression-free survival (LPFS), defined as time from randomization to the date of local tumor
relapse or death, whichever occurred first and irrespective of any occurrence of distant metastases
· Distant progression-free survival (DPFS), defined as time from randomization to the date of
metastasis formation whichever occurred first.
· Overall survival (OS) will be calculated from date of randomization to date of death (from any cause).
Patients alive will be censored at time of last follow-up.
Further secondary endpoints:
· QoL: Quality of life questionnaire (QLQ-C30; Appendix B) will be collected at baseline (day -21 to 1),
after 3, 6, 9, 12, 15, 18, 21 and 24 months from date of randomization and 3 months after last dose
(end of treatment (EOT)).
· Biomarker assessment to predict PFS at 2 years from date of randomization |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to E.5.2 Secondary Endpoints |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
- Biomarker assessment
- QoL assessment |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 4 |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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