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Trial registered on ANZCTR


Registration number
ACTRN12618000357257
Ethics application status
Approved
Date submitted
15/02/2018
Date registered
9/03/2018
Date last updated
15/02/2019
Date data sharing statement initially provided
15/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 5 substudy 10: Eribulin
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of eribulin in patients with advanced CD31 positive angiosarcoma and selected CD31 positive sarcomas.
Secondary ID [1] 293953 0
CTC0141-addendum 5
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 5
Linked study record
ACTRN12616000908437

Health condition
Health condition(s) or problem(s) studied:
Cancer
306453 0
Sarcoma 306825 0
Angiosarcoma 306826 0
Condition category
Condition code
Cancer 305542 305542 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 305933 305933 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eribulin may be administered directly as an intravenous injection over 2 to 5 minutes or, at the discretion of the investigator, diluted in up to 100 mL 0.9% saline for intravenous infusion over 2 to 5 minutes. Eribulin will be administered at a dose of 1.4 mg/m^2 on days 1 and 8 of a 21 day cycle. Subsequent cycles will continue until disease progression is documented, the patient experiences intolerable toxicity or withdraws for another reason.
Intervention code [1] 300256 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 304721 0
The primary end point is disease control defined as:
1. Objective tumour response, based on complete and partial responses using cancer specific response criteria or
2. Time to progressive disease exceeds the documented time to progressive disease on the last treatment prior to substudy entry by at least 1.3 times (TTP2/TTP1 > 1.3). Or exceeds 6 months if TTP1 is not evaluable.

Where disease evaluation is not based on CT scans alternative validated guidelines, such as Gynecologic Cancer Intergroup (GCIG) and Prostate Cancer Working Group 2 (PCWG2) criteria will be employed.

Where radiological progression cannot be assessed, evidence for clinical progression will be documented. These data will be collected from patient questionnaires, such as quality of life per the QLQ-C30 version 3 or The Brief Pain Inventory, or clinical reports to supplement the primary outcome.
Timepoint [1] 304721 0
CT, MRI or PET scans for disease evaluation will take place every 6 weeks until end of treatment and then every 4 weeks until disease progression.
Secondary outcome [1] 342935 0
Overall survival (OS) (death from any cause).
Timepoint [1] 342935 0
For the duration of the study.
Secondary outcome [2] 342936 0
Safety and tolerability of treatment (rates of adverse events)
Timepoint [2] 342936 0
Clinical assessments and blood tests will be performed before each treatment with eribulin in order to identify adverse events from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [3] 342937 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and the Brief Pain Inventory.
Timepoint [3] 342937 0
Before every treatment during the study and every 4 weeks during follow-up after treatment until disease progression.

Eligibility
Key inclusion criteria
The Cancer Molecular Screening and Therapeutics (MoST) Program - A framework protocol for multiple, parallel, signal-seeking clinical studies of novel molecularly targeted therapies for patients with advanced cancer and unmet clinical need is registered under ACTRN12616000908437.

Inclusion Criteria – molecular screening
1. Male or female patients, aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid cancer of any histologic type or an earlier diagnosis of a poor prognosis cancer.
2. Sufficient and accessible tissue for molecular screening.
3. Patients receiving their last line of standard treatment or who have received and failed all standard anticancer therapy (where standard therapy exists) or have documented unsuitability for any further standard anticancer therapy Poor prognosis cancers or cancers with low expected response rate to standard treatment (in the opinion of the investigator and based on available evidence) may be screened on an earlier line of treatment.
a. Failure is defined as either progression of disease (clinical or radiological) or intolerance to standard therapy resulting in the discontinuation of the therapy.
b. Documented unsuitability for further standard therapy includes known hypersensitivity, organ dysfunction or other patient factors that would make therapy unsuitable in the judgement of the responsible investigator.
4. ECOG performance status 0, 1 or 2
5. Willing and potentially able to comply with study requirements, including treatment, timing and/or nature of required assessments; It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase.

To be eligible for treatment in a substudy, patients must continue to meet all of the inclusion criteria and none of the exclusion criteria specified for entry into molecular screening at the time of registration to a treatment substudy. In addition, they must meet all the inclusion criteria and none of the exclusion criteria in the substudy addendum at the time of registration.

Inclusion Criteria – substudy
1. Confirmation of molecular eligibility by the molecular tumour board;
2. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
3. Clinical or radiological progression on or following last anticancer therapy;
4. Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug):
a. bone marrow function; and haemoglobin greater than or equal to 9g/dL (5.6mmol/L);
5. Participants must have normal organ and marrow function as defined below:
a. leukocytes greater than or equal to 3.0 x 109 L
b. absolute neutrophil count greater than or equal to 1.0 x 10^9 L
c. platelets greater than or equal to 100 x 10^9 L
d. AST(SGOT)/ALT(SGPT) less than or equal to 2.5 × institutional upper limit of normal
e. creatinine clearance greater than or equal to 50 mL/min (Cockcroft and Gault formula – see section 6 for detail)
6. CD31-positive (CD31+) metastatic, unresectable or locally advanced angiosarcoma OR metastatic or locally advanced CD31 positive sarcomas including malignant and progressive epithelioid hemangioendothelioma (EHE).
7. Participants must have measurable disease by RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan, MRI, or calipers by clinical exam.
8. Life expectancy of greater than 3 months

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The Cancer Molecular Screening and Therapeutics (MoST) Program - A framework protocol for multiple, parallel, signal-seeking clinical studies of novel molecularly targeted therapies for patients with advanced cancer and unmet clinical need is registered under ACTRN12616000908437.

Exclusion Criteria – molecular screening
1. Suitable for standard therapy or accepted standard care, if the patient has not been previously treated;
2. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may contraindicate participation and/or interact with the investigational product(s);
3. Other co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol;
4. For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer. Subjects with stable neurological function, on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to study entry are eligible.
5. History of another malignancy within 2 years prior to registration unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible;
6. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a barrier method of contraception (double barrier, if required).

Exclusion criteria – substudy
1. Contraindications to investigational product, as listed in the substudy addendum and outlined in the Investigator Brochure appended to each substudy module;
2. Known history of hypersensitivity to active or inactive components of investigational product;
3. Previous treatment with the same agent or same class of agent;
4. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
-Radiation therapy, surgery or tumour embolization within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions;
-Immunotherapy within 28 days prior to the first dose of study treatment;
-Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5 half-lives of a drug, prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer);
5. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment;
6. Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C), immunotherapy within 3 weeks, targeted therapies (e.g. small molecule inhibitors such as pazopanib) within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Clinically insignificant or clinically stable adverse events from prior therapy (e.g. immunotherapy related hypothyroidism or insulin-dependent diabetes stable on medication or TKI-related hypertension or rash etc.) are allowed.
7. Participants with known brain metastases and/or leptomeningeal disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
8. Contraindications to eribulin, including known hypersensitivity to any of the components of eribulin;
9. Prior treatment with eribulin. Prior taxanes are allowed.
10. History of allergic reactions attributed to compounds of similar chemical or biologic composition to eribulin.
11. Ongoing or active infection, symptomatic congestive heart failure (NYHA Class II), unstable angina pectoris or myocardial infarction within 6 months of enrolment, serious or life-threatening cardiac arrhythmia, subjects with a high probability of Long QT syndrome or QTcF prolongation of greater than or equal to 501 mcsec on at least two separate ECG following correction of any electrolyte imbalance
12. HIV-positive participants on combination antiretroviral therapy

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
As described in the framework protocol (ACTRN12616000908437), substudies with greater than or equal to 3 out of 16 responding patients, will in general be sufficiently interesting to investigate further. As a general rule, substudies with less than 3 out of 16 responses will be considered to not support the molecular hypothesis behind the substudy.

If some activity is recognised in a 16 patient substudy cohort but further information is needed to inform development of phase II testing, iterative substudies may be opened to enrich for patients that harbour a specific common biomarker or histologic cancer subtype. Each such iteration would constitute a new substudy for the purposes of this framework.

The sample size and guiding definitions of what constitutes an interesting signal are determined empirically as the investigators considered these numbers of patients as sufficient for signal-seeking purpose.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 9962 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 9963 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 9964 0
St George Hospital - Kogarah
Recruitment hospital [4] 13160 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 18803 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 18804 0
2050 - Camperdown
Recruitment postcode(s) [3] 18805 0
2217 - Kogarah
Recruitment postcode(s) [4] 25715 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 298582 0
Government body
Name [1] 298582 0
Office for Health and Medical Research
Address [1] 298582 0
Locked Bag 961
North Sydney NSW 2059
Country [1] 298582 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 297736 0
None
Name [1] 297736 0
Address [1] 297736 0
Country [1] 297736 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299547 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 299547 0
Translational Research Centre
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 299547 0
Australia
Date submitted for ethics approval [1] 299547 0
24/01/2018
Approval date [1] 299547 0
11/04/2018
Ethics approval number [1] 299547 0

Summary
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. The purpose of this is to investigate whether gene or CD31 protein profiles may be used to select the best treatment for participants with advanced cancer.

Who is it for?

You may be eligible for this study if you are over 18 years old and have CD31 positive advanced and/or metastatic angiosarcoma OR have CD31 positive advanced and/or metastatic sarcomas.

Study details

All participants will be given eribulin via intravenous administration on Day 1 and Day 8 of a 21 day cycle. Participants will continue to be given the medication in 21 day cycles until the disease has progressed or there are adverse reactions that are not tolerated or the participant withdraws for any reason.

Participants will undergo assessments at 6 weekly intervals or as clinically indicated in order to evaluate tumour response. Safety and tolerability of treatment and health related quality of life during treatment will also be assessed via clinical assessment, blood tests and questionnaires prior to each treatment with eribulin.

It is hoped that this study will help increase treatment options for participants with advanced metastatic cancer. We cannot guarantee that participants will receive any benefits from this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80806 0
Prof David Thomas
Address 80806 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 80806 0
Australia
Phone 80806 0
+ 61 (0)2 9355 5770
Fax 80806 0
+61 (0)2 9355 5872
Email 80806 0
d.thomas@garvan.org.au
Contact person for public queries
Name 80807 0
Dr Lucille Sebastian
Address 80807 0
NHMRC Clinical Trials Centre Level 6
Chris O'Brien Lifehouse
119–143 Missenden Road
Camperdown NSW 2050
Country 80807 0
Australia
Phone 80807 0
+61 (0)2 9562 5000
Fax 80807 0
Email 80807 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 80808 0
Prof David Thomas
Address 80808 0
Garvan Institute of Medical Research
The Kinghorn Cancer Centre
370 Victoria St Darlinghurst NSW 2010
Country 80808 0
Australia
Phone 80808 0
+ 61 (0)2 9355 5770
Fax 80808 0
+61 (0)2 9355 5872
Email 80808 0
d.thomas@garvan.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent will be required
What supporting documents are/will be available?
No other documents available
Summary results
No Results