Therapeutic Goods Administration
Date of first round CER: 28 June 2013Date of second round CER: 30 September 2013
AusPAR Attachment 2
Extract from the Clinical Evaluation Report for denosumab
Proprietary Product Name: Xgeva
Sponsor: Amgen Australia Pty Ltd
About the Therapeutic Goods Administration (TGA)
- The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices.
- The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.
- The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.
- The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.
- To report a problem with a medicine or medical device, please see the information on the TGA website
About the Extract from the Clinical Evaluation Report
- This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities.
- The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted.
- For the most recent Product Information (PI), please refer to the TGA website
Copyright
© Commonwealth of Australia 2014
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <>.
Therapeutic Goods Administration
Contents
List of abbreviations
1.Introduction
2.Clinical rationale
3.Contents of the clinical dossier
3.1.Scope of the clinical dossier
3.2.Paediatric data
3.3.Good clinical practice
4.Pharmacokinetics
4.1.Studies providing pharmacokinetic data
4.2.Evaluator’s overall conclusions on pharmacokinetics
5.Pharmacodynamics
5.1.Studies providing pharmacodynamic data
6.Dosage selection for the pivotal studies
7.Clinical efficacy
7.1.Pivotal efficacy studies
7.2.Evaluator’s conclusions on clinical efficacy for GCTB
8.Clinical safety
8.1.Studies providing evaluable safety data
8.2.Patient exposure
8.3.All adverse events (irrespective of relationship to study treatment)
8.4.Laboratory tests
8.5.Post-marketing experience
8.6.Safety issues with the potential for major regulatory impact
8.7.Other safety issues
8.8.Evaluator’s overall conclusions on clinical safety
9.First round benefit-risk assessment
9.1.First round assessment of benefits
9.2.First round assessment of risks
9.3.First round assessment of benefit-risk balance
10.First round recommendation regarding authorisation
11.Clinical questions
11.1.Pharmacokinetics
11.2.Pharmacodynamics
11.3.Efficacy
11.4.Safety
12.Second round evaluation of clinical data submitted in response to questions
12.1.Question one
12.2.Question two
13.Second round benefit-risk assessment
14.Second round recommendation regarding authorisation
15.References
List of abbreviations
Abbreviation / MeaningAE / Adverse Event
ALT / Alanine Transaminase
AST / Aspartate Transaminase
ARTG / Australian Register of Therapeutic Goods
BSAP / Bone specific alkaline phosphatase
CT / X-Ray Computed Tomography
EMA / European Medicines Agency
EORTC / European Organisation for Research and Treatment of Cancer
FDA / Food and Drug Administration
GCTB / Giant Cell Tumour of Bone
LDH / Lactate Dehydrogenase
MRI / Magnetic resonance imaging
ONJ / Osteonecrosis of the jaw
PET / Positron Emission Tomography
PI / Product Information
RANK / Receptor activator of nuclear factor κB
RANK-L / Receptor activator of nuclear factor κB ligand
RECIST / Response evaluation criteria in solid tumours
SAE / Serious Adverse Event
sCTX / Serum C-telopeptide
TGA / Therapeutic Goods Administration
TRAP-5b / Tartrate-resistant acid phosphatase 5 b
uNTX / Urinary N-telopeptide
1.Introduction
The currently approved dose regimen for patients with bone metastases from solid tumours is 120 mg subcutaneously every 4 weeks.
For the new indication, the sponsor is proposing essentially the same regimen, but is proposing the addition of two loading doses of 120 mg each on days 8 and 15 of the initial 4-week period.
The sponsor is proposing changes to the Pharmacology, Clinical Trials, Precautions, Adverse Effects and Dosage and Administration sections of the Product Information (PI), based on the clinical studies submitted in support of the new indication. No other changes to the PI are proposed.Details are beyond the scope of the AusPAR.
2.Clinical rationale
Giant cell tumour of bone (GCTB) is considered to be a benign but locally very destructive neoplasm. The neoplastic cells are thought to arise from primitive mesenchymal stromal cells. These neoplastic cells secrete RANK-L, which stimulates the differentiation and activation of osteoclast-like giant cells. The histological appearance of GCTB is therefore that of a mixture of mononuclear cells (thought to be derived from primitive mesenchymal stromal cells) and the osteoclast giant cells. Contrary to the name of the tumour, the giant cells are not considered to be neoplastic.[1]
GCTB generally occurs in long bones, most commonly around the knee (distal femur, proximal tibia) but also frequently in the distal radius, proximal humerus and proximal fibula. It can also occur in the pelvic bones, sacrum and in the vertebrae. The peak frequency is in the second to fourth decades of life and is slightly more common in females. It is very rare in children unless skeletally mature (that is, with closed epiphyses). On X-ray it appears as a lytic lesion. If left untreated the tumour causes progressive bone destruction. GCTB can also spread to the lungs. In these cases the histology of the pulmonary lesions is identical to that of the primary benign tumour2 and these lesions are therefore considered to be “benign metastases”.
Current treatment of GCTB generally relies on surgical management (curettage of bone, complete resection where possible). Radiotherapy is also considered effective in situations where surgery is not possible.[2] The disease is not considered responsive to chemotherapy. Bisphosphonates may reduce the risk of recurrence following surgery.
Although considered a benign tumour, it has a capacity to undergo malignant transformation. Such transformation is generally only seen in tumours that recur after radiotherapy or surgery. Giant cell tumours that display malignant behaviour de novo are considered to be a form of sarcoma and a separate clinical entity to GCTB.
The clinical rationale for use of denosumab in GCTB is summarised by the sponsor as follows:
‘In patients with GCTB, the inhibition of RANK-L secreted by the stromal component of the tumor by denosumab significantly reduces or eliminates the osteoclast-like, tumor-associated giant cells. Consequently, osteolysis and the progression of the giant cell tumor are reduced, and proliferative stroma is replaced with nonproliferative, differentiated, densely woven new bone, resulting in improved clinical outcomes.’
There are currently no other medicines registered for the treatment of GCTB.
As described above, previous applications for denosumab have been approved by the TGA for use in patients with metastases to bone and for the treatment of bone loss associated with osteoporosis and androgen deprivation therapy.
The following guideline published by the European Medicines Agency (EMA) and adopted by the TGA is considered relevant to the current application:
- Guideline On The Evaluation Of Anticancer Medicinal Products In Man (CPMP/EWP/205/95/Rev.3/Corr.)[3]
Compliance with this guideline will be considered in the relevant sections of this report.
3.Contents of the clinical dossier
3.1.Scope of the clinical dossier
The hard copy of the submission consisted of 15 volumes (6,000 pages) of clinical data. The covering letter gave an assurance that the hard copy and electronic versions of the submission were identical. This reviewer used the electronic version.
The submission contained the following clinical information:
- Clinical study reports for 2 open-label, single-arm studies (20062004 and 20040215) examining the efficacy and safety of denosumab in the treatment of GCTB;
- An integrated analysis of efficacy;
- An integrated analysis of safety;
- Literature references.
- The sponsor’s Clinical Overview, Summary of Clinical Efficacy and Summary of Clinical Safety.
3.2.Paediatric data
One of the two submitted clinical trials (20062004) included 10 skeletally mature adolescents (aged between 12 and 18 years). The two trials did not include subjects who were not skeletally mature as GCTB is extremely rare in such subjects.
3.3.Good clinical practice
The study reports for the two submitted clinical trials included assurances that they were conducted in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practices (GCP) guidelines and any regulations applicable in the countries where the trials were conducted. Study protocols, consent forms et cetera were reviewed by independent ethics committees.
4.Pharmacokinetics
4.1.Studies providing pharmacokinetic data
One of the submitted studies (20040215) included data on trough serum levels of denosumab in 37 subjects receiving the drug for GCTB.
4.2.Evaluator’s overall conclusions on pharmacokinetics
The trough level data from Study 20040215 demonstrated that denosumab trough levels do not decline with long-term, 4-weekly dosing in subjects with GCTB, and that use of a loading dose on Days 8 and 15 results in rapid attainment of steady-state levels.
5.Pharmacodynamics
5.1.Studies providing pharmacodynamic data
Study 20040215 included data on the effect of denosumab treatment on markers of bone resorption. Results are summarised in the efficacy section of this evaluation report.
6.Dosage selection for the pivotal studies
The sponsor chose to use essentially the same dosage regimen as is currently approved for the treatment of bone metastases120 mgsubcutaneously (SC) every 4 weeks. In a previously submitted Phase II dose ranging Study (20040113) in subjects with breast cancer and bone metastasis, this regimen was associated with the maximum reduction of the bone turnover marker uNTX/Cr (uNTX corrected for urine creatinine) by Week 13 compared with the other dosing regimens tested.
According to the current Australian PI, in patients with bone metastases the half-life of denosumab is approximately 28 days and steady state is achieved after 6 months. The sponsor considered it desirable to achieve target levels within the first month of treatment for patients with GCTB, on the grounds that this may be associated with improved clinical outcomes. For this reason, two loading doses, at Days 8 and 15, were added to the established 4-weekly regimen.
Comment:Given the rapidly progressive nature of GCTB, the sponsor’s justification for the use of the two loading doses is considered acceptable. The PK data from Study 20040215 demonstrated that steady state levels associated with 4-weekly dosing were achieved early with the use of the loading doses.
7.Clinical efficacy
The two submitted studies both provided efficacy data. Although both were single arm, non-comparative Phase II trials, they are both considered pivotal to the submission.
7.1.Pivotal efficacy studies
7.1.1.Study 20040215
7.1.1.1.Study design, objectives, locations and dates
This study was an openlabel, singlearm, Phase II trial. The primary objective of the study was to evaluate the efficacy of denosumab in subjects with recurrent or unresectable GCTB. Secondary objectives included evaluation of safety, pharmacokinetics (trough levels of denosumab), pharmacodynamics (bone markers) and the development of antidenosumab antibodies.
The study was conducted in 8 centres in Australia, France and the United States. The first subject enrolled in July 2006. The submission included two study reports:
- The ‘primary analysis’ (data cut-off of 7 April 2008, report dated 2 April 2009); and
- A ‘final’ report (data cut-off of 16 November 2010, report dated of 19 June 2011).
The study has been published.[4]
Comment: The EMA guideline on anticancer agents generally encourages the use of randomised controlled trials, even in rare tumours. The sponsor justified the use of an open single-arm design on the grounds that there is no active comparator recognised as standard of care, and use of placebo was not considered ethical. Given the aggressive nature of the disease, the justification for not using a placebo arm is considered acceptable.
7.1.1.2.Inclusion and exclusion criteria
It is noted that the study restricted enrolment to patients with unresectable or recurrent disease. The proposed indication in Australia does not restrict use to this population.In the published version of the study the term ‘unresectable’ is explained as meaning: ‘for example, resection could not be done without nerve damage or substantial impairment of joint function.’
7.1.1.3.Study treatments
All patients received denosumab 120 mg subcutaneously (SC) on days 1, 8, 15 and 29 and once every 4 weeks thereafter. There were no dosage adjustments allowed during the study. Treatment was continued until one of the following occurred:
- The subject had a complete tumour resection;
- Disease progression occurred;
- Either the sponsor or the investigator recommended discontinuation;
- The subject decided to discontinue; or
- The subject received bisphosphonates, calcitonin or interferon alfa-2a.
Daily supplementation with greater than or equal to 500 mg of calcium and 400 IU or more of vitamin D was strongly recommended, except in the case of pre-existing hypercalcemia.
7.1.1.4.Efficacy variables and outcomes
The main efficacy variables were:
- Histopathology. Samples (obtained via biopsy or at the time of any surgical resection) were to be obtained prior to the administration of the first dose of denosumab and again at some time between weeks 9 and 25. All samples were evaluated both locally and by a blinded central laboratory.
- Tumour imaging (CT or MRI). At baseline, a bone lesion was identified as the target lesion. It was required to be at least 10 mm in its longest diameter and suitable for accurate repeated measurements by CT or MRI. The longest diameter was used as the measurement by which subsequent progression or objective response would be characterised. Imaging was then performed at weeks 13 and 25 and every 12 weeks thereafter. Positron emission tomography (PET) scans were performed at the same time points for additional evaluation of tumour response and bone repair.
The primary efficacy outcome was the proportion of patients who achieved a ‘response’. Response was defined as one of the following:
- For subjects who had histopathology samples available:
–At least 90% elimination of giant cells relative to baseline, or
–Complete elimination of giant cells in cases where giant cells represented less than 5% of tumor cells at baseline.
- For subjects who did not have histopathology samples available, a response was defined as lack of progression of the target lesion (by CT or MRI) at Week 25 compared with baseline. Progression was defined as a greater than or equal to 20% increase in longest diameter of the target lesion.
Other efficacy outcomes included:
- Changes in concentrations of bone turnover markers, urinary N-telopeptide (uNTx) and serum C-telopeptide (sCTx), compared with baseline;
- The percent change of measurable lesions from baseline in subjects who had multiple lesions and were unable to undergo palliative resection;
- The number and percentage of subjects who had bone calcification, or bone repair in lesions, or clinical benefit.
7.1.1.5.Randomisation and blinding methods
There was no randomisation in the study. Patients and investigators were not blinded to treatment.
7.1.1.6.Analysis populations
The efficacy analysis set (also referred to as evaluable subjects) included those subjects who had a baseline histology assessment and at least 1 post-dose histology assessment between Weeks 5 and 25; or a baseline radiology assessment and at least 1 post-dose radiology assessment between Weeks 5 and 25. Evaluable subjects had to be on study for at least 28 days after administration of the first dose of denosumab.
The safety analysis set included all subjects who received at least one dose of denosumab.
7.1.1.7.Sample size
A response rate of greater than 11% was chosen as clinically meaningful, and a true response rate of 30% was anticipated. The planned sample size was 35 subjects. With this sample size, if a successful result was defined as an observed response rate of 23% or more, the study had a probability of less than 0.05 of concluding denosumab was efficacious when the true response rate was less than 11%. If the true response rate was at least 30%, then the probability of concluding denosumab is not efficacious was less than 0.15.
7.1.1.8.Statistical methods
Descriptive statistics were used. Frequencies and percentages were provided for all categorical variables. Continuous variables were summarized using mean, standard deviation (SD), and minimum and maximum values. Median and other selected percentiles were substituted for mean and SD for parameters exhibiting a lack of normality. For parameters that were required by the protocol to have multiple baseline measurements, the mean of the baseline records was used for calculation of changes from baseline. Otherwise, the baseline value was the observation recorded just before the first dose of denosumab. No imputation of missing values was used.
For the primary endpoint of response rate, 95% confidence intervals were calculated.
7.1.1.9.Participant flow
A total of 37 subjects were enrolled and all received at least one dose of denosumab. At the final analysis, 10 subjects (27%) had proceeded to complete resection and another 12 subjects (32%) had been rolled over into Study 20062004.