WithdrawnPhase 2ACTRN12619000583145

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

Sponsor

Australia New Zealand Gynaecological Oncology Group

Enrollment

40 participants

Start Date

Aug 15, 2019

Study Type

Interventional

Conditions

High Grade Serous Ovarian Cancer Carcinosarcoma

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.

Eligibility

Sex: FemalesMin Age: 18 Yearss

Inclusion Criteria33

Patient has provided written informed consent for pre-screening
Patient is able to comply with the study protocol and follow-up procedures, in the Investigator’s judgement
Patient is female aged a minimum of 18 years at time of consent
ECOG performance status 0-2
Patient has the ability to take oral medications without medical history of malabsorption or other chronic gastrointestinal disease, or other conditions that may harm compliance and/or absorption of the study agent
Patients with a histopathological diagnosis of HGSC 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 >80% of the primary tumour is a high grade serous ovarian carcinoma based on diagnostic pathology review and IHC profile
Patients with progressive disease defined by GCIG CA-125 and/or RECIST v1.1 criteria after 3 or more lines of chemotherapy or after progression on a P-gp substrate PARP inhibitor
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)
Disease that is amenable to a biopsy and/or ascitic drainage
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
Patient has a life expectancy > 12 weeks
Patient has consented to the collection and use of their fresh tumour biopsies and/or ascites samples
Patient has provided written informed consent for the main PRECISE study
Patient has an ABCB1 fusion(s) and the absence of BRCA1/2 reversions
Patient has platinum sensitive or platinum resistant HGSC
Patients who are refractory (progress during or within 4 weeks) to second or subsequent lines of platinum-based chemotherapy are eligible.
Patients who are primary platinum refractory (progress during or within 4 weeks of first line chemotherapy) are considered ineligible.
Recurrent disease that is measurable according to RECIST v1.1 or evaluable disease using CA-125 according to GCIG criteria
Adequate haematologic and end-organ function, as defined by the following laboratory results (obtained within 7 days prior to registration to the main study:
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 90 g/L (greater than or equal to 28 days after growth factor support or 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 (MDRD STUDY EQ; www.mdrd.com)
Total serum bilirubin less than or equal to 1.5 x upper limit of normal (ULN) or 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
Patients who are not pregnant
Females of childbearing potential require a negative serum pregnancy test within 7 days prior to registration into the main study
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.
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.
A formalin-fixed paraffin embedded FFPE tumour block, representative of the patient’s primary disease is available.
In cases where there is insufficient FFPE tumour, a discussion with the CPI must be had before registration into the main study.

Exclusion Criteria21

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 to the main study
Bisphosphonate and denosumab use are allowed on study, if administered at a stable dose > 28 days prior to registration to the main study
The use or anticipated need for food or drugs known to be 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 to the main study
Major surgical procedure, open biopsy, or significant traumatic injury less than or equal to 14 days prior to registration to the main study, or anticipation of need for major surgical procedure during the course of the study
Placement of vascular access device is not considered major surgery.
Prior radiation therapy less than or equal to 14 days prior to registration to the main study to non-target lesions. Patients who have received palliative radiotherapy of non-target lesions for local symptom control > 14 days prior to registration to the main study must have stabilisation of any AEs or a return to baseline prior to the registration to the main study
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:
Only supratentorial metastases
Brain imaging at screening without evidence of interim progression
No ongoing requirement for corticosteroids as therapy for brain metastases
o Anticonvulsants at a stable dose allowed (except for contraindicated medications carbamazepine and phenytoin)
No stereotactic radiation or whole-brain radiation prior to registration to the main study
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 to the main study
Symptomatic pulmonary embolism less than or equal to 28 days prior to registration to the main study
Any history of acute myocardial infarction less than or equal to 6 months prior to registration to the main study
Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV less than or equal to 6 months prior to registration to the main study
Any event of ventricular arrhythmia greater than or equal to Grade 2 in severity less than or equal to 6 months prior to registration to the main study. Any history of cerebrovascular accident (CVA) less than or equal to 6 months prior to registration to the main study
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.

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Interventions

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 regi

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.