Patient case: 64-year-old female with ovarian cancer; genetic feature: BRCA1

Clinical trial: Pamiparib in Fusion Positive, Reversion Negative High Grade Serous Ovarian Cancer or Carcinosarcoma With BRCA1/2 Gene Mutations If Progression on Substrate Poly ADP Ribose Polymerase Inhibitbor (PARPI) or Chemotherapy

Summary: This study is a phase II, multi-centre, open label study in patients with advanced ovarian cancer. The treatment being tested is Pamiparib, with daily dosing.
  All patients enrolled to the study will receive treatment with pamiparib. Patients will be selected for entry into the study based on the molecular signature of their cancer.

Detailed description: Ovarian cancer is the deadliest gynaecologic cancer in Western women. Although initially responsive to therapy, drug resistance commonly evolves.
  Novel mechanisms of drug resistance in ovarian cancer have been identified and include genetic mutations that result in the activation of a drug efflux pump and secondary mutations in BRCA1/2 genes that restore the cancer cell's ability to repair treatment related DNA damage. It is hypothesized that patients with BRCA1/2 mutant high grade serous ovarian cancer or carcinosarcoma who have progressed on recent therapy and have an activated efflux pump without a secondary BRCA1/1 mutation will be selectively sensitive to a new drug, Pamiparib, which does not get effluxed out of cancer cells.
  The primary objective of this trial is to assess the clinical benefit rate at > 4 months in 2 cohorts of patients (cohort 1: post substrate-PARP inhibitor and cohort 2: post chemotherapy) defined as response or absence of progression. Secondary objectives are to determine the median progression free and overall survival of patients treated with Pamiparib and the impact on symptom burden and benefit.

Eligibility: Inclusion Criteria - Pre-Screening
  -  Patient has provided written informed consent for the Pre-Screening part of the study
  -  Patient is able to comply with the study protocol and follow-up procedures, in the investigator's judgement
  -  Patient is female aged at least 18 years at screening
  -  ECOG performance status 0-2
  -  Ability to swallow whole capsules
  -  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:
  a. 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
  -  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
  1. 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.
  2. 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.
  -  Disease that is measurable according to RECIST v1.1 or evaluable disease using CA-125 according to GCIG criteria
  -  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)
  -  Patient has a life expectancy > 12 weeks
  Inclusion Criteria - Main Study
  -  Patient has provided written informed consent for main PRECISE study
  -  Patient continues to meet all pre-screening inclusion criteria
  -  Patient has an ABCB1 fusion(s) and the absence of a BRCA1/2 reversion
  -  Adequate haematologic and end-organ function, as defined by the following laboratory results (obtained ≤ 14 days before start of pamiparib on Day 1)
  -  Absolute neutrophil count (ANC) ≥1.5 x 109/L
  -  Platelet count ≥ 100 x 109/L
  -  Haemoglobin (Hb) ≥ 9 g/dL (≥ 28 days after transfusion)
  -  Estimated glomerular filtration rate ≥ 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 ≤1.5 x upper limit of normal (ULN)
  -  ≤ 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) ≤ 3 x upper limit of normal (ULN) or ≤ 5 x ULN for patients with liver metastases
  -  Females of childbearing potential must practice highly effective methods of birth control (Appendix 1) for the duration of the study and for at least 6 months after last study drug
  -  Patients must have recovered to ≤ grade 1 from their treatment-related adverse event (AE) with the exception of alopecia and peripheral neuropathy
  -  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.
  -  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.
  1. In cases where there is insufficient FFPE tumour, a discussion with the coordinating principal investigator (CPI) must be had before consent into the main study.
  Exclusion Criteria:
  -  Patients with a clear cell, mucinous, or other non-high grade serous histological subtype
  -  Prior treatment with non-substrate P-gp PARPi
  a. Prior treatment with substrate PARPi is allowed (Olaparib, Niraparib, Rucaparib, and Talazoparib)
  -  Leptomeningeal disease or uncontrolled, untreated brain metastases
  a. Patients with a history of treated and asymptomatic brain metastases are eligible, provided they meet all of the following: i. Only supratentorial metastases ii. Brain imaging at screening without evidence of interim progression iii. No ongoing requirement for corticosteroids as therapy for brain metastases [Anticonvulsants at a stable dose allowed (except for contraindicated medications carbamazepine and phenytoin)] iv. No stereotactic radiation or whole-brain radiation ≤ 14 days before Day 1
  -  Patients who are pregnant or nursing
  a. Females of childbearing potential require a negative serum pregnancy test ≤ 7 days before Day 1
  -  Patients who have received chemotherapy, biologic therapy, immunotherapy, investigational agent, anticancer Chinese medicine, or herbal remedies ≤ 5 half-lives if the half-life is known, ≤14 days if not known, prior to registration
  a. Bisphosphonate and denosumab use is allowed on study, if administered at a stable dose > 28 days prior to registration.
  -  The use or anticipated need for food or drugs known to be strong or moderate cytochrome P450 (CYP) 3A inhibitors or strong CYP3A inducers ≤ 5 half-lives if the half-life is known or ≤ 14 days if not known prior to registration
  -  Major surgical procedure, open biopsy, or significant traumatic injury ≤ 14 days prior to registration, or anticipation of need for major surgical procedure during the course of the study
  a. Placement of vascular access device is not considered major surgery
  -  Patient has a diagnosis of Myelodysplastic Syndrome (MDS)
  -  Patient has other diagnoses of malignancy
  a. 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 ≤ 2 years prior to registration
  -  Prior radiation therapy to target lesions
  -  Prior radiation therapy ≤ 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
  -  Patient has uncontrolled pleural effusion, pericardial effusion, or ascites requiring weekly recurrent drainage procedures
  -  Active infection requiring systemic treatment, acute/viral hepatitis or active chronic hepatitis B or C or active tuberculosis
  a. 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.
  -  Known history of intolerance to the excipients of the pamiparib capsule
  -  Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis, or melena ≤ 6 months prior to registration
  -  Previous complete gastric resection, chronic diarrhea, active inflammatory gastrointestinal disease, or any other disease-causing malabsorption syndrome
  a. Gastroesophageal reflux disease under treatment with proton-pump inhibitors is allowed.
  -  Any of the following cardiovascular criteria:
  1. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days prior to registration
  2. Symptomatic pulmonary embolism ≤ 28 days prior to registration
  3. Any history of acute myocardial infarction ≤ 6 months prior to registration
  4. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤ 6 months prior to registration
  5. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months prior to registration
  6. Any history of cerebrovascular accident (CVA) ≤ 6 months prior to registration

Relevance to patient case: definitely relevant