Clinical Trials /

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

NCT03933761

Description:

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.

Related Conditions:
  • Ovarian Carcinoma
  • Ovarian Carcinosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official 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 PARPi With the Presence of an ABCB1 Fusion and the Absence of a BRCA1/2 Reversion

Clinical Trial IDs

  • ORG STUDY ID: ANZGOG 1721/2018
  • NCT ID: NCT03933761

Conditions

  • Ovarian Cancer
  • Carcinosarcoma

Interventions

DrugSynonymsArms
PamiparibBGB-290Pamiparib (BGB-290)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Pamiparib (BGB-290)ExperimentalDrug: Pamiparib Oral capsules 60mg twice daily continuously Although treatment is continuous, a cycle is defined as 4 weeks or 28 days.
  • Pamiparib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical benefit rate
Time Frame:Assessed at 16 weeks after commencing treatment.
Safety Issue:
Description:as assessed by RECIST v1.1 or by Gynaecological Cancer Intergroup (GCIG) Cancer antigen (CA)-125 criteria

Secondary Outcome Measures

Measure:Frequency of ABCB1 fusions and BRCA1/2 reversions
Time Frame:At Baseline
Safety Issue:
Description:in patients with germline or somatic BRCA1/2 high grade serous cancer or carcinosarcoma
Measure:Progression free survival
Time Frame:Through study completion, on average 6 months.
Safety Issue:
Description:in BRCA1/2 high grade serous cancer or carcinosarcoma patients with ABCB1 fusions in the absence of BRCA1/2 reversions treated with pamiparib.
Measure:Overall survival
Time Frame:Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Safety Issue:
Description:in BRCA1/2 high grade serous cancer or carcinosarcoma patients with ABCB1 fusions in the absence of BRCA1/2 reversions treated with pamiparib.
Measure:Duration of response
Time Frame:Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Safety Issue:
Description:Duration of response according to RECIST v1.1 in the subset of patients who achieved partial response or complete response.
Measure:Best overall response according to RECIST v1.1
Time Frame:Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Safety Issue:
Description:Best overall response is the best response from commencement of treatment according to RECIST v1.1
Measure:Best overall response according to CA-125
Time Frame:Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Safety Issue:
Description:defined as best response from commencement of treatment determined by GCIG CA-125 criteria
Measure:Patient reported symptom burden
Time Frame:At the time of consent to screening, at every cycle to 16 weeks, then every 4 cycles, and again at the time of progression. Assessed for up to 3 years after the last patient enrolled has commenced treatment.
Safety Issue:
Description:Using the Measure of Ovarian Cancer Symptoms and Treatment Concerns (MOST) v2 patient reported outcome measure (PROM) The scale measures disease or therapy related symptoms and symptom burden and well-being Scale ranges: Subscales are reported in five different categories with the subscale score ranges below Abdominal symptoms, higher values reflecting worst possible symptoms Disease or treatment-related symptoms, higher values reflecting worst possible symptoms Chemotherapy-related symptoms, higher values reflecting worst possible symptoms Psychological symptoms, higher values reflecting worst possible symptoms Well-being, higher values reflecting best possible symptoms Each of the 5 subscales can be scored and analysed separately (item by item) or by taking the average of the component items.
Measure:Patient reported results of the 40 item State-trait anxiety inventory for adults (STAI-ADTM)
Time Frame: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.
Safety Issue:
Description:The scale measures state level anxiety (S-Anxiety or current levels) and trait anxiety levels (T-anxiety or how someone generally feels) Scale ranges: STA Form Y-1 includes 20 items/questions, with a total score range of 20-80, and STA Form Y-2 includes 20 items/questions, with a total score range of 20-80. Each scored item/question is then given a weighted score of 1 to 4 with a rating of 4 indicative of a high level of anxiety for 10 x S-Anxiety items and 11 x T-Anxiety items. A high rating indicates the absences of anxiety for the remaining 10 S-Anxiety items and 9 T-Anxiety items. The scoring weights for the anxiety-present items are the same as the chosen numbers on the form and the scoring weight for the anxiety-absent items are reversed. For each form separately, weighted scores are then totalled and averaged. Groups of respondents will be identified (including most anxious, least anxious, and middle) based on top, bottom, and middle percentiles.
Measure:The type, grade and relationship to treatment of adverse events
Time Frame:During the treatment period, on average 3 years
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Australia New Zealand Gynaecological Oncology Group

Trial Keywords

  • High grade serous
  • ABCB1 fusion
  • BRCA 1/2 reversion

Last Updated