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Trial registered on ANZCTR


Registration number
ACTRN12615000292572
Ethics application status
Approved
Date submitted
11/03/2015
Date registered
27/03/2015
Date last updated
24/04/2020
Date data sharing statement initially provided
24/04/2020
Date results information initially provided
24/04/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
An open-label, single-arm, phase I/II, multicentre study to evaluate the safety and efficacy of the combination of dabrafenib, trametinib and palliative radiotherapy in patients with unresectable (stage IIIc) and metastatic (stage IV) BRAF V600E/K mutation-positive cutaneous melanoma.
Scientific title
An open-label, single-arm, phase I/II, multicentre study to evaluate the safety and efficacy of the combination of dabrafenib, trametinib and palliative radiotherapy in patients with unresectable (stage IIIc) and metastatic (stage IV) BRAF V600E/K mutation-positive cutaneous melanoma.
Secondary ID [1] 286339 0
02.14
Universal Trial Number (UTN)
Trial acronym
RT & Combi in metastatic melanoma - CombiRT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic melanoma 294455 0
Condition category
Condition code
Cancer 294761 294761 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective study combining dabrafenib, trametinib and palliative radiotherapy (RT).

Eligible subjects are patients who have been on dabrafenib (150 mg oral twice daily) and trametinib (2mg oral once daily) for more than 2 weeks, as the current standard management for advanced stage melanoma.
Palliative RT will be delivered to symptomatic or bulky (>2cm) soft tissue, nodal or bony metastases concurrently with dabrafenib and trametinib. Up to 3 areas of disease can be irradiated at the same time.
The following dose levels for palliative RT are shown below:
Level 1: 20 Gray in 5 fractions
Level 2: 30 Gray in 10 fractions
Level 3: 40 Gray in 16 fractions
The RT technique, dose, frequency and duration (ranging from 1-4 weeks) of treatment will be determined by your treating radiation oncologist, depending on the location and size of the lesion(s).

Following RT, dabrafenib and trametinib alone will be continued until disease progression according to RECIST 1.1 criteria.
Intervention code [1] 291393 0
Treatment: Other
Comparator / control treatment
All patients enrolled will receive palliative RT in combination with dabrafenib and trametinib.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 294518 0
Establish a toxicity profile for patients receiving dabrafenib and trametinib in combination with RT, assessed by monitoring adverse events and radiotherapy toxicities (e.g. skin inflammation, fatigue, soreness in mouth/eyes, nausea/vomiting, hair loss, joint pain).
Timepoint [1] 294518 0
Baseline to 12 months post radiotherapy treatment
Secondary outcome [1] 313549 0
Assess patients’ pain using a visual analog scale.
Timepoint [1] 313549 0
Baseline, weekly during RT, 4 weeks post RT and then every 8 weeks until study completion (patient passes away, withdraws consent, lost to follow up or completion of 12 months post RT follow up).
Secondary outcome [2] 313550 0
Assess overall disease response by measuring progression free survival and overall survival (composite outcome)
Timepoint [2] 313550 0
Time from enrolment until the earliest date of disease progression or death due to any cause. 0-12 months
Secondary outcome [3] 313551 0
Evaluate local treatment response and the time to local progression in the irradiated index lesion(s) using RECIST 1.1 criteria - composite outcome
Timepoint [3] 313551 0
Baseline to 12 months post radiotherapy treatment

Eligibility
Key inclusion criteria
1. Greater than or equal to 18 years of age.
2. Signed written informed consent.
3. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive as determined by a BRAF mutation assay.
Note: For Stage IIIC disease, the decision that the disease is unresectable should be formally endorsed by the melanoma multidisciplinary tumour board of the local institution.
4. Have received dabrafenib and trametinib for 2 weeks or more prior to enrolment in the study (i.e. first fraction of palliative RT), and is still continuing with dabrafenib and trametinib.
5. Symptomatic or bulky (greater than 2 cm in diameter) soft tissue, nodal or bony metastases requiring palliative RT.
6. Have measurable disease according to RECIST 1.1 criteria.
Note: patients with bony metastases that are not measurable by RECIST 1.1 criteria are allowed in this study.
7. All anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 1 of the protocol) must be less than or equal to Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.03; NCI, 2009) at the time of study enrolment.
8. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
9. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrolment and agree to use effective contraception, from 14 days prior to enrolment throughout the treatment period, and for 4 months after the last dose of study treatment.
10. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
11. Adequate baseline organ function (as defined in Table 1 of the protocol).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Treatment with Ipilimumab or any other anti-CTLA-4 monoclonal antibody therapy within the past 4 weeks.
2. Treatment with anti-PD-1 or anti-PD-L1 monoclonal antibody therapy within the past 4 weeks.
3. Known ocular or primary mucosal melanoma.
4. Four (4) or more lesions requiring palliative RT at the time of study enrolment.
5. Symptomatic brain metastases or those treated < 3 months previously
6. Clear evidence of systemic disease progression on dabrafenib and trametinib.
7. Systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) within the last 4 weeks. Prior interferon treatment in the adjuvant setting is allowed.
Note: Tamoxifen and aromatase inhibitors are allowed in the adjuvant setting of breast cancer.
8. Current use of a prohibited medication as described in Section 8.2.
9. History of malignancy other than disease under study within 3 years of study enrolment with exceptions below, or any malignancy with confirmed activating RAS mutation.
Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility.
Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer.
10. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
11. A history of known Human Immunodeficiency Virus (HIV).
12. A history or evidence of cardiovascular risk including any of the following:
a. A QT interval corrected for heart rate using the Bazett’s formula (QTcB) = 480 msec;
b. A history or evidence of current clinically significant uncontrolled arrhythmias;
c. A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to enrolment;
d. A history or evidence of current = Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines;
e. Patients with intra-cardiac defibrillators;
f. Abnormal cardiac valve morphology (= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study;
g. Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy;
h. Known cardiac metastases.
13. A history of retinal vein occlusion (RVO).
14. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
15. Pregnant or nursing females.
16. Previous RT to the same lesion or area due to receive the current course of palliative RT.
Note: patients who had previous RT to other areas are eligible to the study if the previous RT was completed more than 8 weeks prior.
17. A history of autoimmune diseases which are known to increase radiation toxicity, including systemic lupus erythematosus and scleroderma.
18. Genetic syndromes exhibiting increased radiosensitivity (e.g. ataxia telangiectasia).

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)
Patient registration/enrolment will be performed via an online registration system. Sites will receive confirmation of patient enrolment via email.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable as this trial is not randomised. All patients will receive active treatment.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/05/2015
Actual
6/06/2016
Date of last participant enrolment
Anticipated
Actual
23/09/2019
Date of last data collection
Anticipated
30/06/2020
Actual
Sample size
Target
30
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment postcode(s) [1] 9379 0
2145 - Westmead
Recruitment postcode(s) [2] 9380 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 9381 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 23515 0
2170 - Liverpool
Recruitment postcode(s) [5] 23516 0
2076 - Wahroonga

Funding & Sponsors
Funding source category [1] 290914 0
Commercial sector/Industry
Name [1] 290914 0
GlaxoSmithKline (GSK)
Country [1] 290914 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Melanoma and Skin Cancer Trials
Address
The Oncology Unit, South Block, Alfred Hospital
55 Commercial Road, Victoria 3004
Country
Australia
Secondary sponsor category [1] 289594 0
Other Collaborative groups
Name [1] 289594 0
Melanoma Institute Australia
Address [1] 289594 0
The Poche Centre
40 Rocklands Road
North Sydney NSW 2060
Country [1] 289594 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292514 0
St Vincent's Hospital Sydney Human Research Ethics Committee
Ethics committee address [1] 292514 0
Research Office
Level 6, de Lacy Building
St Vincent’s Hospital
390 Victoria Street
Darlinghurst NSW 2010
Ethics committee country [1] 292514 0
Australia
Date submitted for ethics approval [1] 292514 0
30/01/2015
Approval date [1] 292514 0
02/06/2015
Ethics approval number [1] 292514 0
HREC/15/SVH/36

Summary
Brief summary
This study aims to investigate the side effects, safety, and effectiveness of combining dabrafenib and trametinib with radiotherapy in treatment of BRAF V600E/K mutation-positive melanoma.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have received dabrafenib and trametinib (for 2 weeks or more prior to enrolment) for treatment of BRAF V600E/K mutation-positive melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic).

Study details:
Melanoma that has spread to other parts of the body may benefit from radiotherapy to help reduce symptoms from melanoma. Previous studies have shown that melanoma may be sensitive to radiotherapy and that it can help to improve quality of life. All participants in this study will receive palliative radiotherapy concurrently with their dabrafenib and trametinib treatment. The radiotherapy dose, frequency and duration will be determined by your treating radiation oncologist and dependent on the location and size of your tumours. Up to 3 areas of disease can be irradiated at the same time. Regular follow up visits will be performed up to 12 months to monitor patient response and any toxicities experienced. CT scans will also be performed every 8 weeks to monitor response to treatment.
Trial website
https://www.masc.org.au/trials.aspx?cat=1
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55682 0
Dr Tim Wang
Address 55682 0
Radiation Oncology Network
Crown Princess Mary Cancer Center, Westmead
PO Box 143
Westmead NSW 2145
Country 55682 0
Australia
Phone 55682 0
+612 9845 8888
Fax 55682 0
Email 55682 0
[email protected]
Contact person for public queries
Name 55683 0
MASC Trials
Address 55683 0
Melanoma and Skin Cancer Trials
The Oncology Unit, South Block, Alfred Hospital
55 Commercial Road, Victoria 3004
Country 55683 0
Australia
Phone 55683 0
+612 9911 7200
Fax 55683 0
Email 55683 0
[email protected]
Contact person for scientific queries
Name 55684 0
MASC Trials
Address 55684 0
Melanoma and Skin Cancer Trials
The Oncology Unit, South Block, Alfred Hospital
55 Commercial Road, Victoria 3004
Country 55684 0
Australia
Phone 55684 0
+612 9911 7200
Fax 55684 0
Email 55684 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7758Study protocol  [email protected]



Results publications and other study-related documents

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

Update to Study Results
Doc. No.TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
4518Study results articleYes https://www.ctro.science/article/S2405-6308(21)000... [More Details] 368156-(Uploaded-29-11-2021-11-47-26)-Journal results publication.pdf

Documents added automatically
No additional documents have been identified.