a study assessing pamiparib with radiation and/or temozolomide (tmz) in participants with newly diagnosed or recurrent glioblastoma

Conditions: Brain and Central Nervous System Tumors

Summary: the primary objective of this study is to evaluate the safety, efficacy and clinical activity of pamiparib in combination with radiation therapy (rt) and/or temozolomide (tmz) in participants with newly diagnosed or recurrent/refractory glioblastoma.

an open-label, multiple-dose, dose-escalation study to determine the safety, pharmacokinetics (pk) and pharmacodynamics (pd) of pamiparib in combination with radiation therapy (rt) and/or tmz. in dose escalation/phase 1b, pamiparib will be combined with rt (arm a) or rt and tmz (arm b) in participants with newly diagnosed unmethylated glioblastoma (gbm) and in arm c of the study pamiparib will be combined with tmz in participants with methylated or unmethylated recurrent/refractory gbm. the dose expansion/phase 2 phase will enroll up to 4 cohorts: participants with newly diagnosed unmethylated gbm in arms a and b, and 2 cohorts of participants with recurrent/refractory gbm grouped by o-6-methylguanine-dna methyltransferase (mgmt) status - unmethylated or methylated - in arm c. participants in arms a and b are treated until completion of rt and participants in arm c may continue treatment in the absence of safety concerns and disease progression.

Eligibility criteria:
key inclusion criteria: all participants 1. age ≥ 18 years old. 2. confirmed diagnosis of glioblastoma (who grade iv). 3. agreement to provide archival tumor tissue for exploratory biomarker analysis 4. ability to undergo serial mris. 5. eastern cooperative oncology group (ecog) status ≤ 1. 6. adequate hematologic and end-organ function 7. females of childbearing potential and non-sterile males must agree to use highly effective methods of birth control throughout the course of study and at least up to 6 months after last dosing. 8. ability to swallow whole capsules. participants in arms a and b (not arm c) must meet inclusion criteria # 9 - 11: 9. no previous treatment for gbm except surgery. 10. able to start radiation therapy ≤ 49 days after surgery but ≥ 14 days after a biopsy or ≥28 days after an open biopsy or craniotomy with adequate wound healing. 11. documented unmethylated mgmt promoter status. participants in arm c escalation (phase 1b) must meet inclusion criteria # 12 - 15: 12. documentation of mgmt promoter status 13. no prior systemic chemotherapy other than tmz for gbm. 14. histologically confirmed secondary glioblastoma 15. disease that is evaluable or measurable as defined by response assessment in neuro-oncology (rano) criteria participants in arm c expansion (phase 2), must meet criteria # 16 - 18: 16. histologically confirmed de novo (primary) glioblastoma with unequivocal first progressive disease (pd) after rt with concurrent/adjuvant tmz chemotherapy 17. disease that is measurable as defined by rano criteria 18. documentation of mgmt promoter status key exclusion criteria: all participants 1. prior chemotherapy, biologic therapy, immunotherapy or investigational agents ≤21 days prior to start of study treatment. 2. toxicity of ≥ grade 2 from prior therapy. 3. major surgery or significant other injury ≤ 4 weeks prior to start of study treatment. 4. history of other active malignancies within 2 years with exception of (i) adequately treated in situ cancer of the cervix, (ii) non-melanoma skin cancer, or (iii) localized adequately treated cancer with curative intent or malignancy diagnosed \> 2 years ago with no evidence of disease and no treatment ≤ 2 years prior to study treatment. 5. active infection requiring systemic treatment. 6. known human immunodeficiency virus (hiv) or active viral hepatitis. 7. active, clinically significant cardiac disease or any class 3 or 4 cardiac disease, ventricular arrhythmia or cerebrovascular accident (cva) ≤ 6 months prior to start of treatment. 8. active clinically significant gastrointestinal disease. 9. active bleeding disorder ≤ 6 months prior to start of treatment. 10. need for therapeutic anti-coagulation with heparin, warfarin or other anticoagulants. 11. use of any medications or food known to be strong or moderate cytochrome p450, family 3, subfamily a (cyp3a) inhibitors or strong inducers. 12. pregnant or nursing females. 13. significant intercurrent illness that may result in participant's death prior to death from glioblastoma. arms b and c only: 14. known hypersensitivity to any component of tmz or decarbazine (dtic). 15. have hereditary problems of galactose intolerance note: other protocol defined inclusion/exclusion criteria may apply.

Keywords: adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma, glioma neoplasms recurrent adult brain tumor neoplasms, central nervous system neoplasms, neoplasms by histologic type, neoplasms by site astrocytoma neuroepithelial neuroectodermal tumors germ cell and embryonal antineoplastic agents glandular and epithelial nerve tissue, nervous system diseases temozolomide bgb-290 alkylating, alkylating agents molecular mechanisms of pharmacological action poly(adp-ribose) polymerase inhibitors enzyme inhibitors