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Trial registered on ANZCTR
Registration number
ACTRN12621001183875
Ethics application status
Approved
Date submitted
27/07/2021
Date registered
3/09/2021
Date last updated
14/07/2024
Date data sharing statement initially provided
3/09/2021
Type of registration
Prospectively registered
Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 16 substudy 37: Pamiparib
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Scientific title
Single arm, open label, signal seeking, phase II trial of pamiparib in patients with relapsed/ refractory myeloid haematological malignancy with aberrant germline or somatic DNA repair pathway function.
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Secondary ID [1]
302761
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CTC0141- addendum 16
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Universal Trial Number (UTN)
U1111-1182-6652
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Trial acronym
MoST Addendum 16
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Linked study record
This record is an addendum to the MoST framework protocol (ACTRN12616000908437). The MoST framework protocol consists of 1/ molecular screening (genomic analysis to determine whether participants are suitable for a sub-study) and 2/ sub-study design structure (study treatment for specific genomic expression/participant population). Additionally, the sub-study shares the same study objectives and outcomes as the framework. Hence, this is a substudy that is linked to ACTRN12616000908437.
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Health condition
Health condition(s) or problem(s) studied:
Cancer
319709
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Condition category
Condition code
Cancer
317641
317641
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0
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Leukaemia - Acute leukaemia
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Cancer
317654
317654
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0
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Leukaemia - Chronic leukaemia
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Cancer
320588
320588
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0
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Thrombocythaemia
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Cancer
320589
320589
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0
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Other cancer types
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Pamiparib is the study intervention in this trial.
Pamiparib will be administered in the form of capsules taken orally at a dose of 60 mg twice daily continuously until disease progression, unacceptable toxicity, participant withdrawal or at the discretion of the investigator.
Pamiparib may be reduced to 40mg twice daily if participants experience intolerable toxicity. If participants continue to experience intolerable toxicity, pamiparib dosage may be further reduced to 20mg twice daily. If a third dose reduction is required, the participant should come off study treatment.
Participants will be asked to return unused drug and empty drug containers at each return visit. The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each participant.
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Intervention code [1]
319042
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Treatment: Drugs
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Comparator / control treatment
No control group
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Control group
Uncontrolled
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Outcomes
Primary outcome [1]
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The primary outcome is to evaluate the clinical activity of pamiparib based on complete and partial responses using myeloid haematology specific response criteria (e.g. ELN guidelines for acute myeloid leukemia, modified International Working Group response criteria for myelodysplastic syndrome).
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Assessment method [1]
325685
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Timepoint [1]
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Bone marrow aspirates will be collected for treatment response assessment prior to treatment at Day 1 Cycle 2, Day 1 Cycle 4 and Day 1 Cycle 7, and at progression.
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Secondary outcome [1]
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Overall survival (OS)
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Assessment method [1]
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Timepoint [1]
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For the duration of the study. From the date of registration to date of death from any cause, or the date of last known follow-up alive.
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Secondary outcome [2]
388772
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Overall survival at 6 months
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Assessment method [2]
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Timepoint [2]
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At 6 months from participant registration to date of death from any cause (or the date of last known follow-up alive within 6 months from registration).
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Secondary outcome [3]
388773
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Progression free survival (PFS). PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first. Participants who do not progress or die will be censored on the date of their last clinical assessment or tumour assessment. Disease progression is defined according to myeloid haematology specific response criteria guidelines.
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Assessment method [3]
388773
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Timepoint [3]
388773
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Bone marrow aspirates will be collected for treatment response assessment prior to treatment at Day 1 Cycle 2, Day 1 Cycle 4 and Day 1 Cycle 7, and at progression.
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Secondary outcome [4]
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Progression free survival at 6 months. The proportion of participants on study who are alive and progression free at 6 months. The disease progression is defined according to myeloid haematology specific response criteria guidelines.
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Assessment method [4]
388774
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Timepoint [4]
388774
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At 6 months post participant registration. Bone marrow aspirates will be collected for treatment response assessment prior to treatment at Day 1 Cycle 2, Day 1 Cycle 4, and at progression. All data collected prior to 6 months post participant registration will be used.
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Secondary outcome [5]
388775
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Time to treatment failure. This is defined as the interval from the date of registration to date of permanently ceasing study treatment for any reason. The entered data in the trial database will be used to evaluate this outcome. Participants who are still on study treatment at time of analysis will be censored on the date of their last reported study treatment.
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Assessment method [5]
388775
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Timepoint [5]
388775
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Time to treatment failure analysis is performed at 12 months from last patient registration.
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Secondary outcome [6]
388776
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Safety and tolerability of treatment (rates of adverse events). All adverse events (AEs), including event grading as per NCI CTCAE criteria, will be captured from the first dose of study treatment until 30 days after cessation of study treatment. Reported AEs by participants will be documented by study site staff and subsequently transcribed onto the study electronic data capture (EDC) system. In order to evaluate the safety and tolerability of the study treatment, the entered AE types, frequency and severity in the EDC will be analysed.
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Assessment method [6]
388776
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Timepoint [6]
388776
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Adverse events will be recorded from the first dose of study treatment until 30 days after the cessation of study treatment.
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Secondary outcome [7]
388777
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Health-related quality of life during treatment. The EORTC QLQ-C30 and The Brief Pain Inventory Forms will be used to evaluate this composite outcome.
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Assessment method [7]
388777
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Timepoint [7]
388777
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Every 4 weeks from first dose of study treatment until participants stop treatment due to intolerable toxicity or withdraw for another reason (apart from disease progression). After treatment discontinuation, the health-related quality of life will be assessed at every 8 weeks until disease progression is recorded.
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Eligibility
Key inclusion criteria
Inclusion criteria - participants from Pan cancer subprogram
1. Adults, aged 18 years and older, with pathologically confirmed high grade haematological malignancy of any myeloid subtype, including but not limited to AML, MDS and MPN or an earlier diagnosis of a poor prognosis cancer.
2. Confirmation of molecular eligibility by the molecular tumour board to have germline or somatic DNA repair pathway mutation (e.g. BRCA1/2, ATM, RAD1/2, PALB2), and/or BRCA mutational signature.
3. ECOG performance status 0-2.
4. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
5. Measurable disease assessed within 28 days prior to registration. Percentage bone marrow infiltration or circulating myeloid blast cells may be used as a surrogate for measurable disease.
6. 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; platelets greater than or equal to 100 x 10^9/L, ANC greater than or equal to 1.5 x 10^9/L, and haemoglobin greater than or equal to 9g/dL (5.6mmol/L),; except where bone marrow function is reduced as a result of the underlying disease;
b. liver function; ALT/AST less than or equal to 3 x ULN and total bilirubin less than or equal to 1.5xULN; patients with Gilberts syndrome less than or equal to 4 x ULN
c. renal function; serum creatinine calculated GFR (glomerular filtration rate) greater than 30ml/min
7. Sufficient and accessible tissue (Bone marrow aspirate) less than 3 months old for exploratory objectives
8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
9. Signed, written informed consent to participation in the specific treatment substudy.
10. Life expectancy of at least 12 weeks
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Previous treatment with a PARP inhibitor;
2. Known history of hypersensitivity or contraindication to pamiparib;
3. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s) as assessed by the treating physician;
4. 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;
5. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. Radiation therapy, 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;
b. Immunotherapy within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment;
c. Chemotherapy, biologic therapy, or hormonal therapy within 7 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);
d. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
6. Administration of any investigational treatment within 28 days prior to receiving the first dose of pamiparib
7. Any unresolved toxicity (greater than CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy);
8. Known history of active tuberculosis
9. Receipt of live attenuated vaccination within 30 days prior to study entry
10. 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 (double if required) barrier method of contraception.
11. Has difficulty with or is unable to swallow oral medication, or has gastrointestinal disease that would limit the absorption of oral medication
12. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
13. Eligible for participation in another MoST substudy based on identification of an actionable mutation. Patients who have previously participated in another MoST substudy may subsequently participate in this study, all other inclusion and exclusion criteria being satisfied.
14. Any of the following cardiovascular criteria:
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, within 28 days prior to registration
b. Symptomatic pulmonary embolism within 28 days prior to registration
c. Any history of acute myocardial infarction within 6 months prior to registration
d. Any history of heart failure meeting New York Heart Association Classification III or IV within 6 months prior to registration
e. Any event of ventricular arrhythmia greater than or equal to Grade 2 in severity within 6 months prior to registration
f. Any history of cerebral vascular accident within 6 months prior to registration
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
16 participants will be recruited in this substudy of the Molecular Screening and Therapeutic (MoST) program.
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.
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Recruitment
Recruitment status
Stopped early
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Data analysis
No data analysis planned
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Reason for early stopping/withdrawal
Other reasons/comments
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Other reasons
Futility
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Date of first participant enrolment
Anticipated
15/07/2022
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Actual
17/11/2022
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Date of last participant enrolment
Anticipated
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Actual
18/12/2023
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Date of last data collection
Anticipated
30/09/2024
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Actual
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Sample size
Target
16
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Accrual to date
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Final
12
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Recruitment in Australia
Recruitment state(s)
QLD,SA,TAS,WA
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Recruitment hospital [1]
17996
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The Royal Adelaide Hospital - Adelaide
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Recruitment hospital [2]
17997
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Royal Brisbane & Womens Hospital - Herston
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Recruitment hospital [3]
22572
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Linear Clinical Research - Nedlands
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Recruitment hospital [4]
22574
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Royal Hobart Hospital - Hobart
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Recruitment postcode(s) [1]
31956
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4029 - Herston
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Recruitment postcode(s) [2]
31955
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5000 - Adelaide
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Recruitment postcode(s) [3]
37824
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6009 - Nedlands
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Recruitment postcode(s) [4]
37826
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7000 - Hobart
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Funding & Sponsors
Funding source category [1]
307180
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Government body
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Name [1]
307180
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Office for Health and Medical Research
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Address [1]
307180
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Locked Bag 961, North Sydney NSW 2059
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Country [1]
307180
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Australia
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Funding source category [2]
307184
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Charities/Societies/Foundations
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Name [2]
307184
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Leukaemia Foundation
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Address [2]
307184
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Level 4, 44 Hampden Road
Artarmon NSW 2064
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Country [2]
307184
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Australia
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Funding source category [3]
307632
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Charities/Societies/Foundations
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Name [3]
307632
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Tour de Cure
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Address [3]
307632
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PO Box 6121
Frenchs Forest
NSW 2086
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Country [3]
307632
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Australia
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Primary sponsor type
University
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Name
The University of Sydney
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Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
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Country
Australia
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Secondary sponsor category [1]
307786
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None
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Name [1]
307786
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Address [1]
307786
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Country [1]
307786
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
307293
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St Vincent's Hospital Human Research Ethics Committee
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Ethics committee address [1]
307293
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Translational Research Centre 97-105 Boundary Street Darlinghurst, NSW 2010
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Ethics committee country [1]
307293
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Australia
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Date submitted for ethics approval [1]
307293
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19/11/2020
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Approval date [1]
307293
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25/03/2021
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Ethics approval number [1]
307293
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Summary
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12515000908437. This substudy will evaluate the activity of pamiparib in participants with acute myloid leukaemia or myelodysplastic syndrome with DNA repair pathway mutation (e.g. BRCA1/2), and/or BRCA mutational signature. Who is it for? You may be eligible to join the study if you are aged 18 years and older, with acute myeloid leukaemia or myelodysplastic syndrome. Your cancer will need to harbour DNA repair pathway mutations (e.g. BRCA1/2), and/or BRCA mutational signature. Study details: Participants will receive pamiparib, to be taken orally at a dose of 60 mg twice daily. Pamiparib will be given to participants continuously as long as they and their doctor agree there is a benefit from treatment. Participants will undergo clinical assessments at 4 weekly intervals from first treatment until end of treatment.. Safety and tolerability of treatment will be assessed at 4 weekly intervals. Health related quality of life during treatment will be assessed at 4 weekly intervals and then every 8 weeks after end of treatment until progression. We cannot guarantee that participants will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who have limited treatment options available to them. It is hoped that pamiparib will be well tolerated and will improve outcomes for future patients, however there may be no clear benefit from participation in this study.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
106718
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Prof Steven Lane
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Address
106718
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QIMR Berghofer Medical Research Institute
300 Herston Road
Brisbane QLD 4006
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Country
106718
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Australia
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Phone
106718
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+61 7 3845 3766
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Fax
106718
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Email
106718
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steven.lane@qimrberghofer.edu.au
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Contact person for public queries
Name
106719
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Sarah Finlayson
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Address
106719
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NHMRC Clinical Trials Centre
Medical Foundation Building
Level 6, 92-94 Parramatta Road
Camperdown NSW 2050
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Country
106719
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Australia
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Phone
106719
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+61 295625000
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Fax
106719
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Email
106719
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most.study@sydney.edu.au
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Contact person for scientific queries
Name
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Steven Lane
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Address
106720
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QIMR Berghofer Medical Research Institute
300 Herston Road
Brisbane QLD 4006
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Country
106720
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Australia
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Phone
106720
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+61 7 3845 3766
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Fax
106720
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Email
106720
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steven.lane@qimrberghofer.edu.au
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent is required for data sharing
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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
No additional documents have been identified.
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