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Trial registered on ANZCTR


Registration number
ACTRN12615001291572
Ethics application status
Approved
Date submitted
18/11/2015
Date registered
26/11/2015
Date last updated
12/04/2019
Date data sharing statement initially provided
5/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A two stage, open-label, phase II trial assessing the efficacy of a single oral agent AZD4547 in malignant mesothelioma.
Scientific title
A two stage, open-label, phase II trial assessing the efficacy of a single oral agent AZD4547 in malignant mesothelioma.
Secondary ID [1] 287873 0
None
Universal Trial Number (UTN)
U1111-1176-4052
Trial acronym
FRAME
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Mesothelioma 296758 0
Condition category
Condition code
Cancer 296991 296991 0 0
Lung - Mesothelioma
Cancer 297063 297063 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In mesothelioma we have established that Fibroblast Growth Factor (FGF)-9 plays a key role in the pathobiology of the tumour and that targeting the downstream actions of FGF-9 significantly reduces tumour growth.
AZD4547 is A FGF receptor inhibitor that will be used in patients with malignant mesothelioma that has progressed despite first or second line chemotherapy.
The selected starting dose of AZD4547 to be used as monotherapy will be 80 mg twice daily in a continuous dosing schedule. This will be taken orally as a tablet. Participants may continue to receive AZD4547 as long as they are continuing to show clinical benefit, as judged by the investigators, and in the absence of discontinuation criteria such as:
1. Progressive disease (PD) is documented by a site investigator.
2. Unacceptable toxicity as determined by the patient or site investigator
3. Delay of day 1 treatment for 21 days due to toxicity.
4. The investigator determines that continuation of treatment is not in the patient’s best interest.
5. New occurrence of an exclusion criterion affecting patient safety, e.g. pregnancy or psychiatric illness.
6. Required use of a concomitant treatment that is not permitted.
7. Failure to comply with the protocol, e.g. repeatedly failing to attend scheduled assessments. If a patient has failed to attend scheduled assessments in the study, the Investigator must determine the reasons and document the circumstances as completely and accurately as possible in the medical records and CRF.
8. The patient declines further study treatment, or withdraws their consent to participate in the study.

The use of AZD4547 will be a continuous schedule and as such there is no maximum duration of use unless there is evidence of disease progression as judged by the investigators.

Participants will be followed up every 3 weeks by a medical specialist where adherance to the drug and adverse events related to the drug will be evaluated. Adverse events will be assessed by clinical history/examination, laboratory tests, vital signs, electrocardiogram, ophthalmological assessment and radiological investigations.
Intervention code [1] 293241 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296592 0
To determine the progression free survival at 6 months using AZD4547 in patients with malignant pleural mesothelioma who have previously undergone first line chemotherapy. CT scan of the chest & abdomen will be used to assess disease progression.
Timepoint [1] 296592 0
6 months
Secondary outcome [1] 318824 0
To determine progression free survival on AZD4547. CT scan of the chest & abdomen will be used to assess disease progression.
Timepoint [1] 318824 0
Until disease progression. This will be assessed radiologically with a CT scan every 6 weeks for the first 6 months and then on a 3 monthly basis until disease progression.
Secondary outcome [2] 318825 0
To determine objective tumour response to AZD4547. This will be assessed using the Modified RECIST criteria.
Timepoint [2] 318825 0
3 years or until disease progression.
Secondary outcome [3] 318826 0
To determine overall survival on AZD4547. Overall survival is defined as the interval from the date of registration to date of death from any cause. This will be assessed through clinical records.
Timepoint [3] 318826 0
From the date of registration to date of death from any cause.
Secondary outcome [4] 318827 0
To determine treatment duration on AZD4547 assessed by review of study records.
Timepoint [4] 318827 0
From date of first dose of study drug to the date of last dose of study drug
Secondary outcome [5] 318828 0
Safety and tolerability of AZD4547
Adverse events (AE) and Serious adverse events (SAE) to the trial drug will be assessed every clinic visit which will occur every 3 weeks.
Adverse events will be recorded from the start of the first dose of study drug throughout the treatment and follow-up phases until 30 days after the last dose of study treatment.
All AEs occurring during the study will be documented in the source records and on the respective Case Report Form (CRF), regardless of the assumption of a causal relationship
For each AE (including SAEs), the following aspects must be captured in the CRF:
1) A description of the AE in medical terms according to NCI CTCAE Version 4.0
2) The grade as assessed by the investigator according to the definitions in NCI CTCAE
version 4.0
3) The causal relationship to the study treatment as assessed by the site investigator

Examples of adverse events

1 ) High Phosphate - If a patient has a doubling of phosphate from baseline or a corrected calcium:phosphate product >4.5 mmol2/L2 then the patient may remain on study treatment but phosphate chelation therapy (non-calcium containing agent) should be initiated, and clinical chemistry monitored weekly until resolution of the parameter to below the intervention limit. Investigators must seek appropriate specialist medical consultation (renal or metabolic) to advise on the prescription and titration of phosphate chelation agents and to raise the patient’s awareness of low phosphate diets. Complication of high phosphate is mineralisation of the heart.
Management - regular blood test (at each clinic visit), troponin, electrocardiogram and cardiac imaging done ( 3 monthly)

2) Ophthalmic toxicity - If patients have toxicities regarding the anterior aspect of the eye (dry eyes, punctuate keratopathy and keratitis) such events must be clinically managed to prevent secondary consequences eg, secondary infections following corneal abrasions. Lubricating eye drops/replacement tears should be used; if there is any indication of extra eyelash growth or eyelashes rubbing on the cornea then these eyelashes should be removed. It is anticipated that patients will report any visual disturbances or discomfort relating to the eye in advance of any significant pathology such as ulceration occurring. The decision to continue on study treatment if mild corneal changes in the eye examination are observed will be left to the Investigator’s discretion, since a patient may indicate a wish to tolerate minor discomfort if there is perceived clinical benefit from the therapy. A patient should also be immediately withdrawn from AZD4547 if corneal ulceration occurs, and appropriate expert ophthalmologic consultation should be initiated.
Ophthalmology assessment will be done in a 3 monthly basis while on the study drug

3) Renal toxicity - Patients will be excluded from this study if they have serum creatinine >1.5 times the upper limit of normal concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation). Serum creatinine and blood urea nitrogen should be included in the standard clinical chemistry safety bloods and should be assessed on a regular basis as per the individual study plan.

4) Stomatitis/dry mouth - In cases of stomatitis particular attention should be given to prophylaxis, maintaining a high standard of oral hygiene with the regular use of antibacterial mouthwashes during the study.

5) Dermatological toxicity - These include events of dry skin, alopecia, hair changes, trichomegaly and changes to the nails and nail beds
Timepoint [5] 318828 0
3 weekly for the duration of treatment of the study drug. (6 months or until disease progression)

Eligibility
Key inclusion criteria
Histologically or cytologically malignant pleural mesothelioma
1. Provision of signed and dated, written informed consent prior to any study specific procedures.
2. Male or female aged 25 years or older.
3. Histologically or cytologically confirmed diagnosis of mesothelioma.
4. Progression after first line chemotherapy with pemetrexed and a platinum-based drug (cisplatin and/or carboplatin).
5. Evidence of measurable disease. Measurable disease must be outside a previous radiotherapy field, unless it has been documented to progress after radiotherapy.
6. ECOG performance status 0-1, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose.
7. Females should be using adequate contraceptive measures (see restrictions), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
*Post-menopausal defined as:
a. Aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
b. Aged under 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and with LH and FSH levels in the postmenopausal range.
*Documentation of irreversible surgical sterilisation by hysterectomy, and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal ligation.
8. Male patients should be willing to use barrier contraception, ie condoms.
Minimum age
25 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any prior chemotherapy other than pemetrexed and a platinum compound.
2. Concurrent treatment with any experimental drugs or other anti-cancer therapy.
3. Prior exposure to any of the following: Prior exposure to an FGFR inhibitor and/orPrior treatment in this or another AZD4547 study, or randomisation in a study in which AZD4547 is/was under investigation.
- AZD4547 in the present study (ie, dosing with AZD4547 previously initiated in this study).
- Potent inhibitors or inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort). Refer to Section 7.7 of this document for an example list of applicable drugs.
- Any chemotherapy, immunotherapy or anticancer agents within 3 weeks before the first dose of study treatment.
- Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment.
- Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks before the first dose of study treatment.
- Other concomitant anti-cancer therapy except corticosteroids.
4. Any of the following ophthalmological criteria:
- Current evidence or previous history of RPED.
- Previous laser treatment or intra-ocular injection for treatment of macular degeneration.
- Current evidence or previous history of dry or wet age-related macular degeneration.
- Current evidence or previous history of retinal vein occlusion.
- Current evidence or previous history of retinal degenerative diseases (eg, hereditary).
- Current evidence or previous history of any other clinically relevant chorioretinal defect.

5. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD4547.
6. With the exception of alopecia, any unresolved toxicities from prior therapy with a Common Terminology Criteria for Adverse Events (CTCAE) grade >1 at the time of starting study treatment.
7. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
8. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive electrocardiograms (ECGs).
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.

9. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
- Absolute neutrophil count < 1.5 x 109/L.
- Platelet count < 100 x 109/L.
- Haemoglobin < 90 g/L (can be transfused to meet inclusion criterion).
- Alanine aminotransferase > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases/invasion or > 5 times ULN in the presence of liver metastases or liver invasion.
- Aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases/liver invasion or > 5 times ULN in the presence of liver metastases or liver invasion.
- Total bilirubin > 1.5 times ULN.
- Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN.
- Corrected total calcium > ULN (corrected for albumin using a standard formula that will be specified in the protocol).
- Total phosphate > ULN.

10. Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication.

11. History of hypersensitivity to active or inactive excipients of AZD4547 or other drugs formulated in Cremaphor EL (polyoxyethylated castor oil or other drugs with a similar chemical structure or class to AZD4547.

12. Patients with a history of another primary malignancy within 5 years prior to starting study treatment, except adequately treated basal or squamous cell carcinoma of the skin, carcinoma of the cervix in situ and the disease under study.
13. Known spinal cord compression, brain metastases or leptomeningeal disease (baseline CT brain or MRI is only required if there is clinical suspicion of central nervous system involvement).
14. Serious medical or psychiatric conditions, which might prevent management according to the protocol.
15. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
The two stage design allows for earlier rejection of an inactive agent at stage 1, with proceeding to stage 2 allowing us to reduce the confidence intervals around efficacy for an agent with potential activity.
It is a two stage design.

We will enrol 26 patients in the first of the two stages. If fewer than 7 (i.e. 27%) of the 26 patients were observed to have progression-free survival of more than or equal 6 months, the study will be terminated and declared negative. Otherwise, recruitment will continue to complete the second stage (to a total of 55 evaluable patients).

AZD4547 will be considered worthwhile for further testing in mesothelioma if 17 or more of the 50 evaluable patients (i.e. 34%) enjoyed a progression-free survival for more than or equal 6 months. To achieve 50 progression events, 55 patients will be accrued, allowing 10% of patients to be non-evaluable at 6 months follow-up.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The progression free survival at six months (PFS6) will be evaluated to determine if the anti-tumour activity of AZD4547 in mesothelioma is sufficient to justify further study.

Null hypothesis: PFS6 25% in the treatment group, as estimated from PFS of patients following first-line chemotherapy. Alternative hypothesis: PFS6 of 45% in treatment group.

A Simon’s optimal two-stage design will be examined with the following assumptions; a PFS6 of 45% is considered of interest while a PFS6 of 25% is not. Observing a total of 50 progression events will provide 90% power to achieve this if the true PFS6 rate for AZD4547 is 45% and less than 10% chance of a false signal if the true PFS6 rate is less than25%,with a one-sided a equals to 0.10 and with a probability of early termination 0.68.

Because the trial is designed to assess whether AZD4547 shows sufficient promise to warrant further investigation, a one-sided a equals to 0.10 (rather than two-sided a equals to 0.05) is proposed.

We will enrol 26 patients in the first of the two stages. If fewer than 7 (i.e. 27%) of the 26 patients were observed to have progression-free survival of at more than or equal 6 months, the study will be terminated and declared negative. Otherwise, recruitment will continue to complete the second stage (to a total of 55 evaluable patients).

AZD4547 will be considered worthwhile for further testing in mesothelioma if 17 or more of the 50 evaluable patients (i.e. 34%) enjoyed a progression-free survival for more than to equal to 6 months. To achieve 50 progression events, 55 patients will be accrued, allowing 10% of patients to be non-evaluable at 6 months follow-up.

The modified Intent To Treat (mITT) analysis set will include all dosed patients who have a RECIST assessment at baseline and at least 1 further assessment following commencement of dosing with study drug, or who has died or discontinued prior to the data cut-off. The mITT analysis set will be used for outputs that present tumour responses. The subset of the mITT patients who have a response (CR/PR) will be used for the summary of duration of response.

Safety analysis set
All patients who receive at least 1 dose of any study drug (eg, AZD4547) will be included in the safety analysis set.

Full analysis set
All eligible patients who receive at least 1 dose of any study drug (eg, AZD4547) will be included in the full analysis set and will be used to summarise demographics and disposition in addition to safety

Biomarker analysis set
All patients that provide biological samples for exploratory biomarkers research will be included in this analysis set.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
This was set up as a two stage study requiring successful completion of stage 1 to continue to stage 2. Fewer than 7 (i.e. 27%) of the 26 patients were observed to have progression-free survival of 6 months, therefore the study has been terminated and declared negative.
Date of first participant enrolment
Anticipated
15/03/2016
Actual
7/04/2016
Date of last participant enrolment
Anticipated
30/12/2018
Actual
8/05/2018
Date of last data collection
Anticipated
Actual
22/01/2019
Sample size
Target
55
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 4621 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 12211 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 292371 0
Government body
Name [1] 292371 0
Dust Disease Board
Country [1] 292371 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Institute of Respiratory Health
Address
Ground Floor, E Block,
Sir Charles Gairdner Hospital,
Hospital Ave,
Redlands, 6009 WA.
Country
Australia
Secondary sponsor category [1] 291058 0
None
Name [1] 291058 0
Address [1] 291058 0
Country [1] 291058 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293845 0
Sir Charles Gairdner Group
Ethics committee address [1] 293845 0
Level 2, A Block,
Hospital Avenue,
Redlands, 6009 WA
Ethics committee country [1] 293845 0
Australia
Date submitted for ethics approval [1] 293845 0
24/11/2015
Approval date [1] 293845 0
10/02/2016
Ethics approval number [1] 293845 0
2015-170

Summary
Brief summary
This primary purpose of this study is to evaluate the safety and efficacy of AZD4547 for the treatment of malignant mesothelioma which has progressed following first line chemotherapy. You may be eligible to participate in this study if you are aged 25 years or over, and have been diagnosed with mesothelioma which has progressed following first or second line chemotherapy with pemetrexed and cisplatin and/or carboplatin.

Study details
All participants in this study will receive two oral doses of the study drug, AZD4547 per day for 6 months, with appointments with study staff every 3 weeks throughout this period to monitor side effects and adherence to the medication. Researchers will examine disease progression and survival at 6 months, as well as side effect data from the three-weekly appointments to determine the efficacy and safety of the drug.

Information from this study will then be used to inform researchers on whether continued study of this drug is both worthwhile and safe, in the hope that it may provide a safe and effective second line therapy for mesothelioma in patients whose disease has progressed following first line chemotherapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61494 0
Prof Y. C. Gary Lee
Address 61494 0
Pleural Medicine Unit/Department of Respiratory Medicine
B, Block, Ground Floor,
Sir Charles Gairdner Hospital,
Hospital Avenue,
Nedlands, 6009 WA.
Country 61494 0
Australia
Phone 61494 0
+61893461754
Fax 61494 0
+61893461555
Email 61494 0
[email protected]
Contact person for public queries
Name 61495 0
Y. C. Gary Lee
Address 61495 0
Pleural Medicine Unit/Department of Respiratory Medicine
B, Block, Ground Floor,
Sir Charles Gairdner Hospital,
Hospital Avenue,
Nedlands, 6009 WA.
Country 61495 0
Australia
Phone 61495 0
+61893461754
Fax 61495 0
+61893461555
Email 61495 0
[email protected]
Contact person for scientific queries
Name 61496 0
Y. C. Gary Lee
Address 61496 0
Pleural Medicine Unit/Department of Respiratory Medicine
B, Block, Ground Floor,
Sir Charles Gairdner Hospital,
Hospital Avenue,
Nedlands, 6009 WA.
Country 61496 0
Australia
Phone 61496 0
+61893461754
Fax 61496 0
+61893461555
Email 61496 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseIncreased interdigitation zone visibility on optical coherence tomography following systemic fibroblast growth factor receptor 1-3 tyrosine kinase inhibitor anticancer therapy.2021https://dx.doi.org/10.1111/ceo.13940
N.B. These documents automatically identified may not have been verified by the study sponsor.