E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10005968 |
E.1.2 | Term | Bone giant cell tumor |
E.1.2 | System Organ Class | 100000004864 |
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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 |
The primary objective of the trial is to evaluate the risk versus benefit of denosumab in maintenance setting in patients requiring long-term use (> 1 year) of denosumab. For that purpose, the treatment schedule with reduced dose density (120mg SC 12-weekly instead of 4-weekly) will be investigated, starting after 1-year (12-15 months) of denosumab full dose, as per current label. The impact on osteonecrosis of the jaw (ONJ) without compromising disease control will be assessed. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess the effect of the reduced dose density schedule on patient clinical and self-reported outcomes, and on the toxicity profile of the treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
* Histologically proven primary or metastatic unresectable GCTB or resectable GCTB but not a candidate for surgery, excluding primary or metastatic GCTB in the jaw.
* Evidence of active disease at time of registration based on local investigator's assessment
Note: Active disease is defined as any lesion increased in size and/or any osteolytic lesion with increased bone disruption and/or increase of tumor-associated symptoms
* Age ≥ 18 years old
* Patient must have received denosumab before entering this trial:
- The duration of treatment with full dose denosumab (120 mg SC ) as per current label must be at least 12 months and patient may have received up to 15 months of denosumab. Note: for patients who temporarily discontinued tratement and then restarted reaching a total treatment duration of 15 months, the Sponsor should be contacted and eligibility evaluated on a per patient basis.
- And patient must have received at least 12 doses of denosumab 120 mg before entering into this trial.
* ECOG/WHO PS 0-2
* Albumin-adjusted serum calcium level ≥ 2.0 mmol/L (8.0 mg/dL)
* 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.
* Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first reduced dose of study treatment.
Note: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
* WOCBP should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 5 months after the last treatment cycle. A highly effective method of birth control is defined as a method which results in a 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
- Vasectomized partner
Note: Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success.
- Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
* Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 5 months after the last study treatment.
* Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
* Currently receiving other GCTB specific treatment (eg, radiation, chemotherapy, or embolization)
* Concurrent bisphosphonate treatment and calcitonin
* Known or suspected current diagnosis of underlying malignancy including high-grade sarcoma, osteosarcoma, fibrosarcoma, malignant giant cell sarcoma
* Known diagnosis of second malignancy within the past 5 years (subjects with definitively treated basal cell carcinoma and cervical carcinoma in situ are permitted)
* Creatinine clearance < 30 mL/min
* Hemoglobin < 10.0 g/dL or 6.2 mmol/L
* Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
* Active dental or jaw condition which requires oral surgery, including tooth extraction
* Non-healed dental/oral surgery
* Planned invasive dental procedure for the course of the study
* Known hypersensitivity to the active substance or to any of the excipients (glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 20)
* Treatment with other investigational device or drug 30 days prior to registration
* Known hypersensitivity to products to be administered during the study (calcium and/or vitamin D)
* Unstable systemic disease including active and uncontrolled infection, uncontrolled hypertension, unstable angina, congestive heart failure, or myocardial infarction within 6 months before registration
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Two co-primary end-points will be assessed at 2 years after enrollment:
1) Progression free survival (PFS) at 2 years
2) Osteonecrosis of the jaw (ONJ) incidence at 2 years |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The two co-primary end-points (progression free survival at 2 years and osteonecrosis of the jaw incidence at 2 years) will be assessed at 2 years after last patient in. |
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E.5.2 | Secondary end point(s) |
Secondary end-points include:
* Progression free survival (overall)
* Overall survival
* Denosumab treatment duration
* ONJ incidence (overall)
* Safety and tolerability (Common Terminology Criteria for Adverse Events (CTCAE) v 5.0)
* Visual Analogue Scale (VAS) pain score. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
* PFS (overall) is counted from patient registration until disease progression
* OS is counted from patient registration until the date of death from any cause
* Denosumab treatment duration is counted from 1) the start to end of protocol denosumab treatment; 2) start of monthly denosumab schedule (prior to patient registration) to end of protocol treatment; and 3) from start of the initial monthly denosumab schedule (i.e. prior to enrollment) to end of all denosumab treatment (including the period of rechallenge with the monthly denosumab dosing schedule upon progression if applicable)
* ONJ incidence (overall) is counted from patient registration until first onset of ONJ
* Safety is assessed from patient registration until 1 year after treatment discontinuation
* VAS pain score
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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 | 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 |
Biobanking
VAS pain questionnaire |
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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 | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 | 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
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End of study occurs when all of the following criteria have been satisfied:
1. One year 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. |
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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 |