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

• ClinicalTrials.gov Identifier: NCT03150862
• Recruitment Status: Completed
• First Posted: May 12, 2017
• Results First Posted: May 31, 2022
• Last Update Posted: May 31, 2022
• Sponsor: BeiGene USA, Inc.
• Information provided by (Responsible Party): BeiGene ( BeiGene USA, Inc. )

Tracking Information

• First Submitted Date: May 8, 2017
• First Posted Date: May 12, 2017
• Results First Submitted Date: March 3, 2022
• Results First Posted Date: May 31, 2022
• Last Update Posted Date: May 31, 2022
• Actual Study Start Date: July 24, 2017
• Actual Primary Completion Date: March 17, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2022)

• Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE [ Time Frame: 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 [ 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) ]
  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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).

Original Primary Outcome Measures (submitted: May 10, 2017)

• Incidence and nature of dose limiting toxicities (DLTs) as assessed by CTCAE [ Time Frame: From first dose BGB-290 to 10 weeks post-dose (Arms A and B). From first dose BGB-290 to 28 days post-dose (Arm C). ]
• Incidence, nature and severity of adverse events as assessed by CTCAE [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
• Number of treatment cycles, dose intensity of components of each treatment regimen, and changes in vital signs and clinical laboratory tests during and following treatment [ Time Frame: From first dose BGB-290 to 30 days post dose. ]
• Phase 2: Arm A [BGB-290 + RT] and Arm B [BGB-290 + RT + TMZ] [ Time Frame: From first dose BGB-290 to first documentation of progression while subject is alive assessed up to 5 years. ]
  Modified disease control rate (DCR) using mRANO
• Phase 2 Arm C [BGB-290 + TMZ] [ Time Frame: From first dose of BGB-290 to first documentation of progression assessed up to 5 years. ]
  Objective response rate (ORR) using mRANO

Current Secondary Outcome Measures (submitted: May 11, 2022)

• Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ 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) ]
  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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: May 10, 2017)

• Pharmacokinetic (PK) parameters of BGB-290 of steady state Ctrough [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
• Modified disease control rate (DCR). (Arms A and B) [ Time Frame: From first dose BGB-290 to first documentation of disease progression while subject is alive assessed up to 5 years ]
• Disease control rate (Arm C) [ Time Frame: From first dose BGB-290 to first documentation of disease progression while subject is alive assessed up to 5 years ]
• Objective response rate (ORR) [ Time Frame: From first dose BGB-290 to first documentation of disease progression assessed up to 5 years ]
• Clinical benefit rate (CBR). [ Time Frame: From first dose BGB-290 to first documentation of disease progression assessed up to 5 years ]
• Duration of response (DOR). [ Time Frame: From first dose BGB-290 to first documentation of disease progression assessed up to 5 years. ]
• Progression free survival (PFS). [ Time Frame: From first dose BGB-290 until first documentation of disease progression or death, whichever is first, assessed up to 5 years ]
• Overall survival (OS) [ Time Frame: From first dose BGB-290 until date of death, assessed up to 5 years ]
• Objective response rate (ORR). [ Time Frame: From the first dose BGB-290 to first documentation of disease progression, assessed up to 5 years ]
  Phase 2 (Arm A and Arm B)
• Clinical benefit rate (CBR) [ Time Frame: From first dose BGB-290 to first documentation of disease progression, assessed up to 5 years ]
  Phase 2 (Arm A and Arm B)
• Duration of response (DOR) [ Time Frame: From first dose BGB-290 to first documentation of disease progression, assessed up to 5 years ]
  Phase 2 (Arm A and Arm B)
• Progression free survival (PFS) [ Time Frame: From first dose BGB-290 until first documentation of disease progression or death, whichever is first, assessed up to 5 years ]
  Phase 2 (Arm A and Arm B)
• Overall survival (OS) [ Time Frame: From first dose BGB-290 until date of death, assessed up to 5 years ]
  Phase 2 (Arm A and Arm B)
• Incidence, nature and severity of adverse events as assessed by CTCAE [ Time Frame: From first dose BGB-290 to 30 days post dose. ]
  Phase 2 (Arm A and Arm B)
• Number of treatment cycles, dose intensity of components of each treatment regimen, and changes in vital signs and clinical laboratory tests during and following treatment [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
  Phase 2 (Arm A and Arm B)
• PK parameter of BGB-290 of steady state Ctrough [ Time Frame: From first dose BGB-290 to 30 days post dose. ]
  Phase 2 (Arm A and Arm B)
• PK parameter of BGB-290 (Cmax) [ Time Frame: From first dose BGB-290 to 30 days post dose. ]
  Phase 2 (Arm A and Arm B)
• Disease control rate (DCR). [ Time Frame: From first dose BGB-290 to first documentation of disease progression while subject is alive, assessed up to 5 years ]
  Phase 2 (Arm C)
• Duration of response (DOR). [ Time Frame: From first dose BGB-290 to first documentation of disease progression, assessed up to 5 years ]
  Phase 2 (Arm C)
• Progression free survival (PFS) [ Time Frame: From first dose BGB-290 until first documentation of disease progression or death, whichever is first, assessed up to 5 years ]
  Phase 2 (Arm C)
• Overall survival (OS) [ Time Frame: From first dose BGB-290 until date of death, assessed up to 5 years ]
  Phase 2 (Arm C)
• Incidence, nature and severity of adverse events as assessed by CTCAE [ Time Frame: From first dose BGB-290 to 30 days post dose. ]
  Phase 2 (Arm C)
• Number of treatment cycles, dose intensity of components of each treatment regimen, and changes in vital signs and clinical laboratory tests during and following treatment [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
  Phase 2 (Arm C)
• PK parameter of BGB-290 of steady state Ctrough [ Time Frame: From first dose BGB-290 to 30 days post dose. ]
  Phase 2 (Arm C)
• PK parameter of BGB-290 (Cmax) [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
  Phase 2 (Arm C)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Assessing Pamiparib With Radiation and/or Temozolomide (TMZ) in Participants With Newly Diagnosed or Recurrent Glioblastoma
• Official Title: A Phase 1b/2 Study to Assess the Safety, Tolerability and Efficacy of BGB-290 in Combination With Radiation Therapy (RT) and/or Temozolomide (TMZ) in Subjects With First-line or Recurrent/Refractory Glioblastoma
• Brief 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

No Masking

Primary Purpose: Treatment

• Condition: Brain and Central Nervous System Tumors

Intervention

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

Study Arms

• Experimental: Arm A (Dose Escalation)
  Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.
  Interventions:

  • Drug: Pamiparib
  • Radiation: Radiation
• Experimental: Arm B (Dose Escalation)
  Participants with newly diagnosed unmethylated GBM will receive Pamiparib, radiation therapy (RT) and temozolomide (TMZ).
  Interventions:

  • Drug: Pamiparib
  • Drug: TMZ
  • Radiation: Radiation
• Experimental: Arm A (Dose Expansion)
  Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.
  Interventions:

  • Drug: Pamiparib
  • Radiation: Radiation
• Experimental: Arm C (Dose Escalation)
  Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.
  Interventions:

  • Drug: Pamiparib
  • Drug: TMZ
• Experimental: Arm C (Dose Expansion-Cohorts C1 and C2)
  Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.
  Interventions:

  • Drug: Pamiparib
  • Drug: TMZ

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 12, 2019): 116
• Original Estimated Enrollment (submitted: May 10, 2017): 300
• Actual Study Completion Date: March 17, 2021
• Actual Primary Completion Date: March 17, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands, Switzerland, United States
• Removed Location Countries: Australia, France

Administrative Information

• NCT Number: NCT03150862
• Other Study ID Numbers: BGB-290-104; 2017-001554-33 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: BeiGene ( BeiGene USA, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: BeiGene USA, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; BeiGene

• PRS Account: BeiGene
• Verification Date: May 2022