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Trial registered on ANZCTR


Registration number
ACTRN12619000583145
Ethics application status
Approved
Date submitted
2/04/2019
Date registered
15/04/2019
Date last updated
14/08/2019
Date data sharing statement initially provided
15/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase II, Signal-Seeking Trial of the Clinical Benefit Rate Associated with Pamiparib in Subjects with Germline or Somatic BRCA1/2 High Grade Serous Ovarian Cancer or carcinosarcoma who have progressed on P-gp substrate chemotherapy or PARP inhibitors with the Presence of an ABCB1 Fusion and the Absence of a BRCA1/2 Reversion
Scientific title
A Phase II, Signal-Seeking Trial of the Clinical Benefit Rate Associated with Pamiparib in Subjects with Germline or Somatic BRCA1/2 High Grade Serous Ovarian Cancer or carcinosarcoma who have progressed on P-gp substrate chemotherapy or PARP inhibitors with the Presence of an ABCB1 Fusion and the Absence of a BRCA1/2 Reversion
Secondary ID [1] 296229 0
ANZGOG 1721/2018
Universal Trial Number (UTN)
Trial acronym
PRECISE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High Grade Serous Ovarian Cancer 309869 0
Carcinosarcoma 309870 0
Condition category
Condition code
Cancer 308661 308661 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A phase 2 study, single group assignment.
Participants have been categorised into two cohorts upon registration into the study. Each cohort is defined as the following:
- Cohort 1: Participants registered to the study who have had most recent treatment with substrate-PARPi. Patients n=20
- Cohort 2: Participants registered to the study who have had most recent treatment with chemotherapy. Patients n=20

Experimental drug is Pamiparib (BGB-290)
60 mg of Pamiparib (3 capsules of 20mg) will be administered orally twice a day, once in the morning and once in the evening continuously in 28 day cycles.

Patients will remain on treatment until progressive disease, unacceptable toxicity, patient discontinuation/withdrawal or at the discretion of the investigator. Patients who discontinue treatment due to progressive disease will be followed for survival only and patients who discontinue treatment for other reasons will be followed for progression and survival.

Patients can be on treatment continuously until 3 years after the last patient has commenced treatment. This equates to an average of 3 to 5 years for the purpose of this study

A patient diary will be used to monitor adherence to the study drug Pamiparib.

Intervention code [1] 314154 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307623 0
Number of patients with clinical benefit as defined as response at any stage or absence of progression for greater than or equal to 16 weeks by RECIST v1.1 for patients with RECIST measurable disease and by GCIG CA-125 criteria for patients without RECIST v1.1 measurable disease.
Timepoint [1] 307623 0
16 weeks after treatment commencement.
Secondary outcome [1] 352504 0
Frequency of ABCB1 fusions and BRCA1/2 reversions as a single composite outcome in patients with germline or somatic BRCA1/2 high grade serous cancer or carcinosarcoma.

This outcome will be assessed descriptively as a count of the number of screening events required to achieve the planned sample of 20 (per cohort) will be provided. Multiple screening attempts for the same patient count as separate screening events.
Timepoint [1] 352504 0
Since this is assessed as the number of patients needing to be pre-screened in order to achieve the sample size of 20, this is assessed at the conclusion of patient recruitment to the main study, once 20 patients have been accrued.
Secondary outcome [2] 368964 0
Progression free survival in BRCA1/2 high grade serous cancer or carcinosarcoma patients with ABCB1 fusions in the absence of BRCA1/2 reversions treated with pamiparib. Progression will be determined by first occurrence of disease progression as determined using RECIST v1.1.
Timepoint [2] 368964 0
From Cycle 1 Day 1 to the first occurrence of disease progression. The frequency of assessment is 12 weekly, starting at week 16.
Secondary outcome [3] 368965 0
Overall survival in BRCA1/2 high grade serous cancer or carcinosarcoma patients with ABCB1 fusions in the absence of BRCA1/2 reversions treated with pamiparib,
Timepoint [3] 368965 0
From Cycle 1 Day 1 to the date of death from any cause. Death will always be assessed symptomatically as absence of all vital signs such as respiration and cardiac activity. Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Secondary outcome [4] 368966 0
Duration of response according to RECIST v1.1 in the subset of patients who achieved partial response, or complete response defined as the time from the first documented disease response to the date of disease progression. Deceased patients without progressive disease will be censored at the date of last disease assessment.
Timepoint [4] 368966 0
From the first documented disease response to the date of disease progression. The frequency of assessment is 12 weekly, starting at week 16. Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Secondary outcome [5] 368967 0
Best overall response is the best response from commencement of treatment according to RECIST v1.1.
Timepoint [5] 368967 0
From commencement of treatment through to disease progression. The frequency of assessment is 12 weekly, starting at week 16. Assessed for up to 3 years after the last patient enrolled has commenced treatment. Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Secondary outcome [6] 368968 0
Best overall response (BOR) according to CA-125 defined as best response from commencement of treatment determined by GCIG CA-125 criteria.
Timepoint [6] 368968 0
From commencement of treatment through to disease progression. Frequency of assessment is every 4 weeks for the first 32 weeks, and then 12 weekly thereafter. Assessed for up to 3 years after the last patient enrolled has commenced treatment
Secondary outcome [7] 368969 0
Patient reported symptom burden using the MOST v2 PROM at the time of consent to screening and patient reported symptom benefit and adverse effects at every cycle for the first 4 cycles, then every 4 cycles, and again at the time of progression.
Timepoint [7] 368969 0
From consent to screening through to disease progression and end of treatment. Frequency of assessment is every 4 weeks for the first 16 weeks, then at 32 weeks and then 12 weekly thereafter, Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Secondary outcome [8] 368970 0
Patient reported 40 item scale STAI-AD (TM) results at the time of pre-screening consent, immediately prior to clinician consult with notification of pre-screening results, and immediately following notification of pre-screening results.
Timepoint [8] 368970 0
This will be assessed 3 times - at the time of pre-screening consent, immediately prior to clinician consult with notification of pre-screening results, and immediately following notification of pre-screening results
Secondary outcome [9] 368971 0
The type, grade and relationship to treatment of adverse events, assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Timepoint [9] 368971 0
During the treatment period.

Eligibility
Key inclusion criteria
Inclusion Criteria - Pre Screening
1. Patient has provided written informed consent for the Pre-Screening part of the study
2. Patient is able to comply with the study protocol and follow-up procedures, in the investigator’s judgement
3. Patient is female aged a minimum of 18 years at screening
4. ECOG performance status 0-2
5. Ability to swallow whole capsules
6. Patients with a histopathological diagnosis of High Grade Serous Ovarian Carcinoma or carcinosarcoma of the ovary (including primary peritoneal cancers and Fallopian tube cancers) as defined by histological diagnosis and immunohistochemistry (IHC) and with a germline or somatic BRCA1/2 mutation:
- Mixed histologies are allowed provided that greater than or equal to 80% of the primary tumour is a high grade serous ovarian carcinoma based on diagnostic pathology review and IHC profile
7. Progressive symptomatic or asymptomatic recurrent disease defined by GCIG CA-125 and/or RECIST v1.1 criteria after > 1 line of chemotherapy and/or after P-gp substrate PARPi provided that the patient must not have progressed nor had recurrent disease within 6 months of the completion of the last platinum-containing regimen
- Patients may continue on treatment as per standard of care by their usual clinician while awaiting the results of pre-screening with no impact on usual care
- Patients who have been treated with both substrate PARPi and substrate chemotherapy will be considered eligible for either cohort 1 or cohort 2 based on the therapy they have most recently progressed on (Cohort 1 is progression on PARPi and cohort 2 is progression on chemotherapy) provided that the patient must not have progressed nor had recurrent disease within 6 months of the completion of the last platinum-containing regimen via RECIST v1.1 criteria
8. Disease that is measurable according to RECIST v1.1 or evaluable disease using CA-125 according to GCIG criteria
9. Disease that is amenable to a biopsy and/or ascitic drainage (note that lesions intended to be biopsied should not be target lesions with the preference of the biopsy site having progressed on most recent imaging where clinically safe and feasible)
10. Patient has a life expectancy > 12 weeks

Inclusion Criteria - Main Study
1. Patient has provided written informed consent for main PRECISE study
2. Patient continues to meet all pre-screening inclusion criteria
3. Patient has an ABCB1 fusion(s) and the absence of a BRCA1/2 reversion
4. Adequate haematologic and end-organ function, as defined by the following
laboratory results (obtained less than or equal to 14 days before start of pamiparib on Day 1):
- Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L
- Platelet count greater than or equal to 100 x 109/L
- Haemoglobin (Hb) greater than or equal to 9 g/dL (greater than or equal to 28 days after transfusion)
- Estimated glomerular filtration rate greater than or equal to 30 mL/min/1.73 m2 by the Modification of Diet in Renal Disease study equation
- Total serum bilirubin less than or equal to 1.5 x upper limit of normal (ULN)
- Less than or equal to 4 x ULN, if Gilbert’s syndrome or if indirect bilirubin concentrations suggestive of extrahepatic source of elevation
- Aspartate and alanine aminotransferase (AST and ALT) less than or equal to 3 x upper limit of normal (ULN) or less than or equal to 5 x ULN for patients with liver metastases
5. Females of childbearing potential must practice highly effective methods of birth control for the duration of the study and for at least 6 months after last study drug.
6. Patients must have recovered to less than or equal to grade 1 from their treatment-related adverse event (AE) with the exception of alopecia and peripheral neuropathy
7. Patient has consented to the use of their collected fresh tumour biopsies, archival FFPE specimen, ascites and peripheral blood samples as detailed in the protocol for
translational research, including but not limited to DNA, RNA and protein-based biomarker detection
8. Able to provide a formalin-fixed paraffin embedded (FFPE) tumour block, representative of the participant’s primary disease, which must be forwarded to the Central Laboratory within 20 working days post registration
- In cases where there is insufficient FFPE tumour, a discussion with the CPI must be had before consent into the main study
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with a clear cell, mucinous, or other non-high grade serous histological
subtype
2. Prior treatment with non-substrate P-gp PARPi
- Prior treatment with substrate PARPi is allowed (olaparib, niraparib, rucaparib, and talazoparib)
3. Leptomeningeal disease or uncontrolled, untreated brain metastases
- Patients with a history of treated and asymptomatic brain metastases are eligible, provided they meet all of the following:
o Only supratentorial metastases
o Brain imaging at screening without evidence of interim progression
o No ongoing requirement for corticosteroids as therapy for brain metastases
(Anticonvulsants at a stable dose allowed (except for contraindicated medications) carbamazepine and phenytoin)
o No stereotactic radiation or whole-brain radiation less than or equal to 14 days before Day 1
4. Patients who are pregnant or nursing
- Females of childbearing potential require a negative serum pregnancy test less than or equal to 7 days before Day 1.
5. Patients who have received chemotherapy, biologic therapy, immunotherapy, investigational agent, anticancer Chinese medicine, or herbal remedies less than or equal to 5 half-lives if the half-life is known, less than or equal to 14 days if not known, prior to registration.
- Bisphosphonate and denosumab use is allowed on study, if administered at a stable dose > 28 days prior to registration.
6. The use or anticipated need for food or drugs known to be strong or moderate cytochrome P450 (CYP) 3A inhibitors or strong CYP3A inducers less than or equal to 5 half-lives if the half-life is known or less than or equal to 14 days if not known prior to registration
7. Major surgical procedure, open biopsy, or significant traumatic injury less than or equal to 14 days prior to registration, or anticipation of need for major surgical procedure during the course of the study
- Placement of vascular access device is not considered major surgery.
8. Patient has a diagnosis of Myelodysplastic Syndrome (MDS)
9. Patient has other diagnoses of malignancy
- Except for surgically excised non-melanoma skin cancer, adequately treated carcinoma in situ of the cervix, adequately treated non-invasive bladder cancer, ductal carcinoma in situ treated surgically with curative intent, or a malignancy diagnosed > 2 years ago with no current evidence of disease and no therapy less than or equal to 2 years prior to registration
10. Prior radiation therapy to target lesions
11. Prior radiation therapy less than or equal to 14 days before start of pamiparib on Day 1 to non-target lesions. Patients who have received palliative radiotherapy of non-target lesions for local symptom control > 14 days before start of pamiparib must have stabilisation of any AEs or a return to baseline prior to the start of pamiparib
12. Patient has uncontrolled pleural effusion, pericardial effusion, or ascites requiring weekly recurrent drainage procedures
13. Active infection requiring systemic treatment, acute/viral hepatitis or active chronic hepatitis B or C or active tuberculosis
- Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose HBV DNA is > 500 IU/mL or patients with active hepatitis C should be excluded. Note: Inactive hepatitis B surface antigen carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C patients can be enrolled.
14. Known history of intolerance to the excipients of the pamiparib capsule
15. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis, or melena less than or equal to 6 months prior to registration
16. Previous complete gastric resection, chronic diarrhea, active inflammatory gastrointestinal disease, or any other disease-causing malabsorption syndrome
- Gastroesophageal reflux disease under treatment with proton-pump inhibitors is allowed.
17. Any of the following cardiovascular criteria:
- Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, less than or equal to 28 days prior to registration
- Symptomatic pulmonary embolism less than or equal to 28 days prior to registration
- Any history of acute myocardial infarction less than or equal to 6 months prior to registration
- Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV 6 months prior to registration
- Any event of ventricular arrhythmia greater than or equal to Grade 2 in severity less than or equal to 6 months prior to registration
- Any history of cerebrovascular accident (CVA) less than or equal to 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)
Allocation is not concealed.
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
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

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,QLD,WA,VIC
Recruitment hospital [1] 12061 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 12062 0
Royal Hospital for Women - Randwick
Recruitment hospital [3] 12064 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [4] 14540 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [5] 14541 0
Macarthur Cancer Therapy Centre - Campbelltown
Recruitment hospital [6] 14542 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [7] 14543 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 24219 0
2031 - Randwick
Recruitment postcode(s) [2] 27552 0
2298 - Waratah
Recruitment postcode(s) [3] 27553 0
2560 - Campbelltown
Recruitment postcode(s) [4] 24218 0
3000 - Melbourne
Recruitment postcode(s) [5] 27555 0
3168 - Clayton
Recruitment postcode(s) [6] 27554 0
4101 - South Brisbane
Recruitment postcode(s) [7] 24221 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 300829 0
Other Collaborative groups
Name [1] 300829 0
Australia New Zealand Gynaecological Oncology Group
Address [1] 300829 0
Australia New Zealand Gynaecological Oncology Group
Level 6, Chris O’Brien Lifehouse
119-143 Missenden Road, CAMPERDOWN NSW 2050
Country [1] 300829 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australia New Zealand Gynaecological Oncology Group
Address
Australia New Zealand Gynaecological Oncology Group
Level 6, Chris O’Brien Lifehouse
119-143 Missenden Road, CAMPERDOWN NSW 2050
Country
Australia
Secondary sponsor category [1] 300374 0
None
Name [1] 300374 0
Address [1] 300374 0
Country [1] 300374 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301599 0
Peter MacCallum Cancer Centre
Ethics committee address [1] 301599 0
C/O HREC Secretariat
Victorian Comprehensive Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Ethics committee country [1] 301599 0
Australia
Date submitted for ethics approval [1] 301599 0
08/10/2018
Approval date [1] 301599 0
07/03/2019
Ethics approval number [1] 301599 0
HREC/43987/PMCC-2018

Summary
Brief summary
Ovarian cancer is the deadliest gynaecologic cancer in Western women.

The purpose of this study is to test the effect of a new drug called Pamiparib in patients with high grade serous ovarian cancer with BRCA1/2 mutations who have progressed on PARPi or chemotherapy.

Who is it for?
You may be eligible for this study if you are aged 18 or over and have a diagnosis of high grade serous ovarian cancer or carcinosarcoma of the ovary (including primary peritoneal cancers and Fallopian tube cancers).

Study details
All participants in this study will take three capsules (60mg) of the medication Pamiparib every morning and evening continuously and will have hospital visits for assessments every 28 days for the first 8 months, then every 3 months thereafter, 28 days is defined as 1 treatment cycle. Participants will be asked to provide blood samples, biopsy tissue for analysis and allow access to medical records. Treatment with pamiparib will continue until disease progression, unacceptable toxicity for the participant, or participant discontinuation/withdrawal from the study.

It is hoped this research will demonstrate the sensitivity of high-grade serous ovarian cancer and carcinosarcoma of the ovary to this new medication, expanding treatment options for patients with these cancer types.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87506 0
Dr Alison Freimund
Address 87506 0
Peter MacCallum Cancer Centre
Victorian Comprehensive Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 87506 0
Australia
Phone 87506 0
+61 3 8559 7903
Fax 87506 0
Email 87506 0
ali.freimund@petermac.org
Contact person for public queries
Name 87507 0
Dr Alison Freimund
Address 87507 0
Peter MacCallum Cancer Centre
Victorian Comprehensive Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 87507 0
Australia
Phone 87507 0
+61 3 8559 7903
Fax 87507 0
Email 87507 0
ali.freimund@petermac.org
Contact person for scientific queries
Name 87508 0
Dr Alison Freimund
Address 87508 0
Peter MacCallum Cancer Centre
Victorian Comprehensive Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 87508 0
Australia
Phone 87508 0
+61 3 8559 7903
Fax 87508 0
Email 87508 0
ali.freimund@petermac.org

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 other documents available
Summary results
No Results