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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
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.
Secondary ID [1] 302761 0
CTC0141- addendum 16
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 16
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.

Health condition
Health condition(s) or problem(s) studied:
Cancer 319709 0
Condition category
Condition code
Cancer 317641 317641 0 0
Leukaemia - Acute leukaemia
Cancer 317654 317654 0 0
Leukaemia - Chronic leukaemia
Cancer 320588 320588 0 0
Thrombocythaemia
Cancer 320589 320589 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 319042 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325685 0
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).
Timepoint [1] 325685 0
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.
Secondary outcome [1] 388762 0
Overall survival (OS)
Timepoint [1] 388762 0
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.
Secondary outcome [2] 388772 0
Overall survival at 6 months
Timepoint [2] 388772 0
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).
Secondary outcome [3] 388773 0
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.
Timepoint [3] 388773 0
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.
Secondary outcome [4] 388774 0
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.
Timepoint [4] 388774 0
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.
Secondary outcome [5] 388775 0
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.
Timepoint [5] 388775 0
Time to treatment failure analysis is performed at 12 months from last patient registration.
Secondary outcome [6] 388776 0
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.
Timepoint [6] 388776 0
Adverse events will be recorded from the first dose of study treatment until 30 days after the cessation of study treatment.
Secondary outcome [7] 388777 0
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.
Timepoint [7] 388777 0
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.

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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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

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
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.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Futility
Date of first participant enrolment
Anticipated
15/07/2022
Actual
17/11/2022
Date of last participant enrolment
Anticipated
Actual
18/12/2023
Date of last data collection
Anticipated
30/09/2024
Actual
Sample size
Target
16
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
QLD,SA,TAS,WA
Recruitment hospital [1] 17996 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 17997 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 22572 0
Linear Clinical Research - Nedlands
Recruitment hospital [4] 22574 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 31955 0
5000 - Adelaide
Recruitment postcode(s) [2] 31956 0
4029 - Herston
Recruitment postcode(s) [3] 37824 0
6009 - Nedlands
Recruitment postcode(s) [4] 37826 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 307180 0
Government body
Name [1] 307180 0
Office for Health and Medical Research
Country [1] 307180 0
Australia
Funding source category [2] 307184 0
Charities/Societies/Foundations
Name [2] 307184 0
Leukaemia Foundation
Country [2] 307184 0
Australia
Funding source category [3] 307632 0
Charities/Societies/Foundations
Name [3] 307632 0
Tour de Cure
Country [3] 307632 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] 307786 0
None
Name [1] 307786 0
Address [1] 307786 0
Country [1] 307786 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307293 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 307293 0
Ethics committee country [1] 307293 0
Australia
Date submitted for ethics approval [1] 307293 0
19/11/2020
Approval date [1] 307293 0
25/03/2021
Ethics approval number [1] 307293 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106718 0
Prof Steven Lane
Address 106718 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Brisbane QLD 4006
Country 106718 0
Australia
Phone 106718 0
+61 7 3845 3766
Fax 106718 0
Email 106718 0
steven.lane@qimrberghofer.edu.au
Contact person for public queries
Name 106719 0
Sarah Finlayson
Address 106719 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Level 6, 92-94 Parramatta Road
Camperdown NSW 2050
Country 106719 0
Australia
Phone 106719 0
+61 295625000
Fax 106719 0
Email 106719 0
most.study@sydney.edu.au
Contact person for scientific queries
Name 106720 0
Steven Lane
Address 106720 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Brisbane QLD 4006
Country 106720 0
Australia
Phone 106720 0
+61 7 3845 3766
Fax 106720 0
Email 106720 0
steven.lane@qimrberghofer.edu.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 is required for data sharing


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.