| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic soft tissue sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 |
| The primary objective of the trial is to evaluate whether nintedanib given as second-line therapy for advanced, inoperable and/or metastatic STS prolongs progression-free survival when compared with ifosfamide. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to evaluate the efficacy of nintedanib as compared to ifosfamide in terms of progression-free rate at 12 weeks, overall survival, objective response rate, patient benefit rate, response duration, total duration of treatment with nintedanib safety, Health related Quality of Life and Health Economics. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
♦ Histologically proven advanced, inoperable (medical or surgical) and/or metastatic malignant STS of intermediate or high grade
♦ Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial.
♦ Prior to study enrolment, all patients need to have confirmed RECIST 1.1 disease progression based on local investigator's assessment.
♦ Presence of measurable disease according to RECIST 1.1.
♦One (and no less or more than one) line of previous systemic chemotherapy for advanced, inoperable and/or metastatic malignant STS.
♦ Note: Patients treated in first line with doxorubicin/olaratumab or
doxorubicin/placebo +/- olaratumab/placebo maintenance qualify for the trial and such treatment will be considered as one line according to the protocol.
♦ Age 18 years or older
♦ WHO performance status (PS) 0-2.
♦ Life expectancy of at least 3 months.
♦ Adequate bone marrow, liver and renal function and coagulation parameters
♦ Normal cardiac function, 12 lead electrocardiogram without clinically relevant abnormalities. No Class III or IV congestive heart failure, angina pectoris, myocardial infarction within 1 year before registration/randomization, clinically significant cardiac arrhythmia or pericardial effusion.
♦Absence of active or uncontrolled infections in particular if requiring systemic antibiotics or antimicrobial therapy.
♦ Absence of serious illnesses or medical conditions, including a history of chronic alcohol abuse, active and chronic hepatitis B or C, chronic infection with HIV or clinically relevant liver cirrhosis.
♦ Absence of active gastrointestinal disorders or abnormalities that interfere with absorption of the study drug.
♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration/randomization in the trial.
♦ Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to randomization.
♦ Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and after the last study treatment as follows:
♦ Nintedanib: for at least 3 months after the last dose
♦ Ifosfamide: for at least 1 year after the last dose
♦ A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
♦ Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
♦ Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable).
♦ Intrauterine device (IUD)
♦ Intrauterine hormone-releasing system (IUS)
♦ Bilateral tubal occlusion
♦ Vasectomised partner
♦ Sexual abstinence (not accepted for Switzerland)
Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy.
♦ Female subjects who are breast feeding should discontinue nursing prior to randomization and until 6 months after the last study treatment.
♦ Sexually active male participants must use a barrier method of contraception (e.g., condom) during the study treatment period and for at least 3 months (nintedanib) or 6 months (ifosfamide) after the last study treatment.
♦ Before patient registration/randomization, written informed consent must be obtained according to international conference on harmonisation/Good clinical practice (ICH/GCP) and national/local regulations. |
|
| E.4 | Principal exclusion criteria |
♦History of central nervous system metastasis or leptomeningeal tumor spread.
♦Active brain metastases
♦Other anti-cancer therapy within 28 days prior to randomization.
♦Treatment with another investigational agent within 28 days prior to randomization.
♦Treatment with another investigational agent concomitantly with the trial.
♦Known hypersensitivity to or known specific contraindications for the use of nintedanib or ifosfamide.
♦Known hypersensitivity to peanut or soy bean.
♦Child Pugh B or C hepatic impairment.
♦Uncontrolled arterial hypertension defined at baseline as blood pressure ≥ 150/100 mmHg despite adequate medical therapy.
♦Use of therapeutic anticoagulation or anti-platelet therapy
♦Known inherited predisposition for bleeding or thromboembolism.
♦History of clinically significant hemorrhagic or thromboembolic event in the past 6 months.
♦previous encephalopathy of any cause or other significant neurological condition.
♦acute or chronic, clinically relevant inflammation of urinary bladder.
♦major injuries and/or surgery within the past 28 days prior to randomization with incomplete wound healing and/or planned surgery during the on-treatment study period.
♦persistence of clinically relevant therapy-related toxicity from previous chemotherapy and/or radiotherapy. Grade 1 or 2 adverse events (AEs) are acceptable.
♦history, within the past five years, of malignancies other than STS
♦active alcohol or drug abuse. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary end-point is progression-free survival defined according to RECIST 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor evaluations for the assessment of PFS will be done every 6 weeks during the first 48 weeks and every 12 weeks thereafter |
|
| E.5.2 | Secondary end point(s) |
Secondary end-points include:
♦ Progression-free rate at 12 weeks (binary)
♦ Overall survival
♦ Objective response rate
♦ Clinical benefit rate
♦ Response duration
♦ Total duration of treatment with nintedanib (including treatment beyond RECIST progression)
♦ Safety (Common Toxicity Criteria CTCAE 4.0)
♦ Health related quality of life (QLQ-C30)
♦ Health economics (EQ-5D-5L, health care resource utilities) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
♦ Progression-free rate at 12 weeks
♦ OS every 3 weeks during treatment, every 12 weeks thereafter until death
♦ ORR Tumor evaluations for the assessment of ORR will be done every 6 weeks during the first 48 weeks and every 12 weeks thereafter
♦ Total duration of treatment with nintedanib: every 3 weeks until end of treatment
♦ Safety every 3 weeks during treatment + 30 days after the last dose of study treatment
♦ Health related quality of life: within 7 days before randomization; every 3 weeks during the treatment period only for limited period, it changes to link to tumor assessments
♦ Health economics: within 7 days before randomization; every 3 weeks during the treatment period only for limited period, it changes to link to tumor assessments
|
|
| 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 | No |
| 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 | 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 | No |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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