A Study Assessing Pamiparib With Radiation and/or Temozolomide (TMZ) in Participants With Newly Diagnosed or Recurrent 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.

• Pamiparib (Drug), also known as BGB-290: Administered as specified in the treatment arm
• TMZ (Drug): Administered as specified in the treatment arm
• Radiation (Radiation): Up to 60 Gy (total) over 6 - 7 weeks

Primary outcomes

• Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE [Arm A:Day 1 Pamiparib dose until 4 weeks after the last RT; Arm B: Day 1 of Pamiparib and Temozolomide until 4 weeks after the last RT; Arm C: 1st cycle of 28 days]: A DLT is defined as one of the following toxicities occurring during the DLT assessment window: Grade ≥3 non-hematologic, non-hepatic major organ adverse event (AE) Grade 4 neutropenia lasting >7 days Grade ≥3 febrile neutropenia Grade 3 thrombocytopenia with clinically significant bleeding Grade 4 thrombocytopenia lasting > 3 days and requiring transfusion, or any decreased platelet count <15,000/mm3/ <15.0 x 109/L Grade ≥4 anemia Grade ≥3 total bilirubin or hepatic transaminases (ALT or AST)
• Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE [From initiation of study treatment (for TEAE) or from the date informed consent has been signed (for SAE), until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months)]: A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first. An SAE is any untoward medical occurrence that, at any dose meets at least one of the following criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is considered a significant medical AE based on medical judgment.
• Phase 1b Escalation Phase Arm C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements [From the date of first dose up to end of study (EOS) visit (up to 3 years and 7.5 months)]
• Phase 2 Arm A: Modified Disease Control Rate (DCR) as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria [From the date of first dose up to first documentation of disease progression while participant is alive ( up to 3 years and 7.5 months)]: Modified DCR is defined as the percentage of participants with complete response (CR), partial response (PR) or stable disease (SD) per RANO criteria as the response assessment at the end-of-treatment (EOT) visit.
• Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria [From the date of first dose up to first documentation of disease progression while participant is alive (up to 3 years and 7.5 months)]: ORR (objective response rate) is defined as percentage of participants with best overall response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart).
• Phase 1b Arm C: Number of Cycles of Treatment Received by Participants [From the date of first dose up to EOS visit ( up to 3 years and 7.5 months)]: Data shows the number of participants who received treatment for the given number of cycles.
• Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant [From the date of first dose until EOS visit (up to 3 years and 7.5 months)]: The average dose intensity per participant = total dose (mg) per participant / duration of treatment (days).

Secondary outcomes

• Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib [Pre-dose, 2 hours post dose on Days 1 and 15 of radiation Therapy]
• Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria [From the date of first dose up to first documentation of disease progression while participant is alive (approximately 3 years and 7.5 months)]: Modified DCR is defined as the percentage of participants with complete response (CR), partial response (PR) or stable disease (SD) per RANO criteria as the response assessment at the end-of-treatment (EOT) visit.
• Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria [From the date of first dose up to first documentation of disease progression while participant is alive (up to 3 years and 7.5 months)]: DCR is defined as the percentage of participants with best overall response of CR, PR or SD per RANO criteria. CR or PR will be confirmed by a subsequent tumor assessment at least four weeks apart
• Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria [From the date of first dose up to first documentation of disease progression while participant is alive ( up to 3 years and 7.5 months)]: ORR is defined as percentage of participants with best overall response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart).
• Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria [From the date of first dose up to first documentation of disease progression while participant is alive (up to 3 years and 7.5 months)]: Clinical benefit rate (CBR) is defined as the percentage of participants with best overall response of CR, PR or SD ≥ 24 weeks per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks apart).
• Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria [From first documentation of CR or PR to first documentation of disease progression or death (up to 3 years and 7.5 months)]: DOR is defined as the time from the date of the earliest documented response to disease progression or death for any cause whichever occurs earlier (confirmed by a subsequent tumor assessment at least four weeks apart).
• Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria [From the date of first dose up to first documentation of disease progression or death (up to 3 years and 7.5 months)]: PFS is defined as the time from the first dose date to disease progression per RANO criteria or death, whichever occurs first.
• Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) [From the date of first dose up to the date of death (up to 3 years and 7.5 months)]: OS is defined as the time from the first dose date to date of death for any cause.
• Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From initiation of study treatment (for TEAE) or from the date informed consent has been signed (for SAE), until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months)]: A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or after first dose of study treatment or was worsening in severity from baseline (pretreatment) up to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer therapy, whichever occurs first. An SAE is any untoward medical occurrence that, at any dose meets at least one of the following criteria: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is considered a significant medical AE based on medical judgment.
• Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements [From the date of first dose up to EOS visit (up to 3 years and 7.5 months)]
• Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants [From date of first dose up to EOS Visit (up to 3 years and 7.5 months)]: Data shows the number of participants who received treatment for the given number of cycles.
• Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant [From date of first dose up to EOS Visit (up to 3 years and 7.5 months)]: The average dose intensity per participant = total dose (mg) per participant / duration of treatment (days).

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE (Primary), Number, participants: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 0; Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 0; Arm A: DE- Pamiparib 6Wks + RT 6 Wks 2; Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 1; Arm C: DE - Pamiparib + Temozolomide 20 mg 0; Arm C: DE - Pamiparib + Temozolomide 40 mg 3
• Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE (Primary), Number, participants: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 3; Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 8; Arm A: DE- Pamiparib 6Wks + RT 6 Wks 9; Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 9; Arm C: DE - Pamiparib + Temozolomide 20 mg 9; Arm C: DE - Pamiparib + Temozolomide 40 mg 8
• Phase 1b Escalation Phase Arm C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements (Primary), Number, Number of participants: Arm C: DE - Pamiparib + Temozolomide 20 mg 0; Arm C: DE - Pamiparib + Temozolomide 40 mg 0
• Phase 2 Arm A: Modified Disease Control Rate (DCR) as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria (Primary), Number, Percentage of participants: Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 65.6 (46.8 to 81.4)
• Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria (Primary), Number, Percentage of participants: Arm C: E- Pamiparib + Temozolomide 60 mg 10.7 (2.3 to 28.2)
• Phase 1b Arm C: Number of Cycles of Treatment Received by Participants (Primary), Number, participants: Arm C: DE - Pamiparib + Temozolomide 20 mg 2; Arm C: DE - Pamiparib + Temozolomide 40 mg 3
• Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant (Primary), Mean, milligrams/Day: Arm C: DE - Pamiparib + Temozolomide 20 mg 97.5 +/- 25.41; Arm C: DE - Pamiparib + Temozolomide 40 mg 107.6 +/- 14.65
• Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib (Secondary), Mean, ng/mL: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 891.3 +/- 444.51; Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 1817.0 +/- 1226.53; Arm A: DE- Pamiparib 6Wks + RT 6 Wks 1848.3 +/- 784.38; Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 2239.9 +/- 1011.07; Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 2134.3 +/- 953.06; Arm C: DE - Pamiparib + Temozolomide 20 mg 1893.3 +/- 718.46; Arm C: DE - Pamiparib + Temozolomide 40 mg 1550.8 +/- 1422.55; Arm C: E- Pamiparib + Temozolomide 60 mg 1500.2 +/- 943.35
• Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria (Secondary), Number, Percentage of participants: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 66.7 (9.4 to 99.2); Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 100.0 (54.1 to 100.0); Arm A: DE- Pamiparib 6Wks + RT 6 Wks 42.9 (9.9 to 81.6); Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 80.0 (28.4 to 99.5)
• Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria (Secondary), Number, Percentage of participants: Arm C: DE- Pamiparib + Temozolomide 20 mg 55.6 (21.2 to 86.3); Arm C: DE - Pamiparib + Temozolomide 40 mg 71.4 (29.0 to 96.3)
• Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria (Secondary), Number, Percentage of participants: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 0 (0.0 to 70.8); Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 16.7 (0.4 to 64.1); Arm A: DE- Pamiparib 6Wks + RT 6 Wks 0 (0.0 to 41.0); Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 3.1 (0.1 to 16.2); Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 0 (0.0 to 52.2)
• Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria (Secondary), Number, Percentage of participants: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 0 (0.0 to 70.8); Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 33.3 (4.3 to 77.7); Arm A: DE- Pamiparib 6Wks + RT 6 Wks 0 (0.0 to 41.0); Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 37.6 (21.1 to 56.3); Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 40.0 (5.3 to 85.3); Arm C: DE - Pamiparib + Temozolomide 20 mg 0 (0.0 to 33.6); Arm C: DE - Pamiparib + Temozolomide 40 mg 28.6 (3.7 to 71.0); Arm C: E- Pamiparib + Temozolomide 60 mg 17.9 (6.1 to 36.9)
• Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria (Secondary), Median, Months: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks ; Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 6.44 (NA to NA); Arm A: DE- Pamiparib 6Wks + RT 6 Wks ; Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 10.32 (NA to NA); Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide ; Arm C: DE - Pamiparib + Temozolomide 20 mg ; Arm C: DE - Pamiparib + Temozolomide 40 mg 11.7 (NA to NA); Arm C: E- Pamiparib + Temozolomide 60 mg NA (12.68 to NA)
• Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria (Secondary), Median, Months: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 3.12 (2.79 to 3.29); Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 8.94 (3.78 to 11.56); Arm A: DE- Pamiparib 6Wks + RT 6 Wks 2.56 (2.14 to NA); Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 4.44 (3.29 to 6.24); Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 5.75 (2.37 to 6.47); Arm C: DE - Pamiparib + Temozolomide 20 mg 1.81 (0.82 to 3.48); Arm C: DE - Pamiparib + Temozolomide 40 mg 2.66 (0.66 to 7.39); Arm C: E- Pamiparib + Temozolomide 60 mg 1.87 (1.48 to 1.91)
• Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) (Secondary), Median, Months: Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks 14.46 (13.93 to 14.98); Arm A: DE-Pamiparib 4 Wks + RT 6 Wks 13.44 (4.14 to 20.24); Arm A: DE- Pamiparib 6Wks + RT 6 Wks 10.25 (4.44 to 19.84); Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 12.71 (9.79 to 14.46); Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide 14.23 (7.98 to NA); Arm C: DE - Pamiparib + Temozolomide 20 mg 6.00 (2.60 to 9.79); Arm C: DE - Pamiparib + Temozolomide 40 mg 8.62 (2.96 to NA); Arm C: E- Pamiparib + Temozolomide 60 mg 7.79 (6.21 to 10.68)
• Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) (Secondary), Number, Number of participants: Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 40; Arm C: E- Pamiparib + Temozolomide 60 mg 29
• Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements (Secondary), Number, Number of participants: Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 0; Arm C: E- Pamiparib + Temozolomide 60 mg 0
• Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants (Secondary), Number, participants: Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 3; Arm C: E- Pamiparib + Temozolomide 60 mg 8
• Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant (Secondary), Mean, Milligrams/Day: Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks 109.0 +/- 22.07; Arm C: E- Pamiparib + Temozolomide 60 mg 109.5 +/- 15.22

Adverse events

Time frame: From initiation of study treatment (for TEAE) or from the date informed consent has been signed (for SAE), until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first (up to 3 years and 7.5 months)

Serious adverse events by term

Other adverse events by term

151 more terms not shown.

• Results publication: Xiong Y, Guo Y, Liu Y, Wang H, Gong W, Liu Y, Wang X, Gao Y, Yu F, Su D, Wang F, Zhu Y, Zhao Y, Wu Y, Qin Z, Sun X, Ren B, Jiang B, Jin W, Shen Z, Tang Z, Song X, Wang L, Liu X, Zhou C, Jiang B. Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor. Neoplasia. 2020 Sep;22(9):431-440. doi: 10.1016/j.neo.2020.06.009. Epub 2020 Jul 8. PMID 32652442

• Study Protocol (PDF, 2018-07-23)
• Statistical Analysis Plan (PDF, 2020-04-20)

• Study Director, Study director, BeiGene

NIH grants: 2017