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A Study Assessing BGB-290 With Radiation and/or Temozolomide (TMZ) in Subjects With Newly Diagnosed or Recurrent Glioblastoma

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ClinicalTrials.gov Identifier: NCT03150862
Recruitment Status : Recruiting
First Posted : May 12, 2017
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
BeiGene ( BeiGene USA, Inc. )

Brief Summary:
This study is to evaluate the safety, efficacy and clinical activity of BGB-290 in combination with radiation therapy (RT) and/or temozolomide (TMZ) in subjects with newly diagnosed or recurrent/refractory glioblastoma.

Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: BGB-290 Drug: TMZ Radiation: Radiation Phase 1 Phase 2

Detailed Description:

An open‑label, multiple‑dose, dose-escalation study to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BGB-290 in combination with radiation therapy (RT) and/or TMZ with 2 arms and a potential third arm.

In dose escalation/Phase 1b, BGB-290 will be combined with RT (Arm A) or RT and TMZ (Arm B) in subjects with newly diagnosed unmethylated glioblastoma (GB), or BGB-290 will be combined with TMZ in subjects with methylated or unmethylated recurrent/refractory GB (Arm C).

The dose expansion/Phase 2 phase will enroll up to 4 cohorts: subjects with newly diagnosed unmethylated GB in Arm A and Arm B, and 2 potential cohorts of subjects with unmethylated and methylated recurrent/refractory GB in Arm C. Subjects in dose expansion may continue treatment in the absence of safety concerns and disease progression.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 30, 2017
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : October 31, 2021


Arm Intervention/treatment
Experimental: Arm A (Dose Escalation)
Approximately 18 subjects (newly diagnosed unmethylated GB) to receive BGB-290 and radiation therapy
Drug: BGB-290
BGB-290

Radiation: Radiation
Up to 60 Gy (total) over 6 - 7 weeks

Experimental: Arm B (Dose Escalation)
Approximately 24 subjects (newly diagnosed unmethylated GB) to receive BGB-290, radiation therapy (RT) and temozolomide (TMZ)
Drug: BGB-290
BGB-290

Drug: TMZ
TMZ

Radiation: Radiation
Up to 60 Gy (total) over 6 - 7 weeks

Experimental: Arm A (Dose Expansion)
Approximately 60 subjects (newly diagnosed unmethylated GB) to receive BGB-290 and radiation therapy
Drug: BGB-290
BGB-290

Radiation: Radiation
Up to 60 Gy (total) over 6 - 7 weeks

Experimental: Arm B (Dose Expansion)
Approximately 60 subjects (newly diagnosed unmethylated GB) to receive BGB-290, radiation therapy, and TMZ
Drug: BGB-290
BGB-290

Drug: TMZ
TMZ

Radiation: Radiation
Up to 60 Gy (total) over 6 - 7 weeks

Experimental: Arm C (Dose Escalation)
Approximately 24 subjects with recurrent/refractory methylated or unmethylated GB to receive BGB-290 and TMZ
Drug: BGB-290
BGB-290

Drug: TMZ
TMZ

Experimental: Arm C (Dose Expansion-Cohorts C1 and C2)
Approximately 120 subjects with recurrent/refractory GB (Cohort 1 - 60 subjects with unmethylated GB; Cohort 2 - 60 subjects with methylated GB) to receive BGB-290 and TMZ
Drug: BGB-290
BGB-290

Drug: TMZ
TMZ




Primary Outcome Measures :
  1. 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). ]
  2. Incidence, nature and severity of adverse events as assessed by CTCAE [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
  3. 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. ]
  4. 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

  5. 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


Secondary Outcome Measures :
  1. Pharmacokinetic (PK) parameters of BGB-290 of steady state Ctrough [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
  2. 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 ]
  3. 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 ]
  4. Objective response rate (ORR) [ Time Frame: From first dose BGB-290 to first documentation of disease progression assessed up to 5 years ]
  5. Clinical benefit rate (CBR). [ Time Frame: From first dose BGB-290 to first documentation of disease progression assessed up to 5 years ]
  6. Duration of response (DOR). [ Time Frame: From first dose BGB-290 to first documentation of disease progression assessed up to 5 years. ]
  7. 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 ]
  8. Overall survival (OS) [ Time Frame: From first dose BGB-290 until date of death, assessed up to 5 years ]
  9. 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)

  10. 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)

  11. 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)

  12. 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)

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 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)

  19. 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)

  20. 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)

  21. Overall survival (OS) [ Time Frame: From first dose BGB-290 until date of death, assessed up to 5 years ]
    Phase 2 (Arm C)

  22. 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)

  23. 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)

  24. 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)

  25. PK parameter of BGB-290 (Cmax) [ Time Frame: From first dose BGB-290 to 30 days post-dose. ]
    Phase 2 (Arm C)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: All subjects

  1. Age ≥ 18 years old.
  2. Confirmed diagnosis of glioblastoma (WHO Grade IV).
  3. Ability to undergo serial MRIs.
  4. ECOG status ≤ 1.
  5. Adequate bone marrow function.
  6. Adequate renal and hepatic 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 90 days after last dosing.
  8. Ability to swallow whole capsules.

    Subjects in Arms A and B (not Arm C) must also meet inclusion criteria 9 - 10:

  9. No previous treatment for GB 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.

    Subjects in Arm C must also meet inclusion criteria # 12 - 14:

  12. No prior systemic chemotherapy other than TMZ for GB.
  13. Progressive disease > 2 months after completion of first line therapy.
  14. At least one measurable lesion by mRANO.

    Subjects in Arm C Phase 2, Cohort C1 must also meet criteria # 15. This is not applicable to subjects enrolled in Arm C, Ph 1b.

  15. Documentation of unmethylated MGMT promoter status.

    Subjects in Arm C Phase 2, Cohort C2 must also meet Criteria #16. This is not applicable to subjects enrolled in Arm C Phase 1b.

  16. Documentation of methylated MGMT promoter status.

Exclusion Criteria: All subjects

  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. Uncontrolled seizure disorder.
  6. Active infection requiring systemic treatment.
  7. Known human immunodeficiency virus (HIV) or active viral hepatitis.
  8. Active, clinically significant cardiac disease or any Class 3 or 4 cardiac disease, ventricular arrhythmia or CVA ≤ 6 months prior to start of treatment.
  9. Active clinically significant gastrointestinal disease.
  10. Active bleeding disorder ≤ 6 months prior to start of treatment.
  11. Need for therapeutic anti-coagulation with heparin, warfarin or other anticoagulants.
  12. Use of any medications or food known to be strong or moderate cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong inducers.
  13. Pregnant or nursing females.
  14. Significant intercurrent illness that may result in subject's death prior to death from glioblastoma.
  15. Known hypersensitivity to any component of TMZ or decarbazine (DTIC). [Subjects in Arms B and C only.]

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03150862


Contacts
Contact: Katie Wood 1 (877) 828-5568 clinicaltrials@beigene.com
Contact: Rainer Brachmann, PhD 1 (877) 828-5568 clinicaltrials@beigene.com

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Sponsors and Collaborators
BeiGene USA, Inc.

Responsible Party: BeiGene USA, Inc.
ClinicalTrials.gov Identifier: NCT03150862     History of Changes
Other Study ID Numbers: BGB-290-104
First Posted: May 12, 2017    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by BeiGene ( BeiGene USA, Inc. ):
Adult glioblastoma, adult gian 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

Additional relevant MeSH terms:
Glioblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Temozolomide
Dacarbazine
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Antineoplastic Agents
Enzyme Inhibitors