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

BeiGene

Status and phase: Completed; Phase 2; Phase 1

Conditions: Brain and Central Nervous System Tumors

Treatments: Drug: TMZ; Radiation: Radiation; Drug: Pamiparib

Study type: Interventional

Funder types: Industry

Identifiers

NCT03150862

2017-001554-33 (EudraCT Number)

BGB-290-104

Details and patient eligibility

About

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.

Full 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.

Enrollment: 116 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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116 participants in 5 patient groups

Arm A (Dose Escalation)

Experimental group

Description:

Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.

Treatment:

Drug: Pamiparib

Radiation: Radiation

Arm B (Dose Escalation)

Experimental group

Description:

Participants with newly diagnosed unmethylated GBM will receive Pamiparib, radiation therapy (RT) and temozolomide (TMZ).

Treatment:

Drug: Pamiparib

Radiation: Radiation

Drug: TMZ

Arm A (Dose Expansion)

Experimental group

Description:

Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy.

Treatment:

Drug: Pamiparib

Radiation: Radiation

Arm C (Dose Escalation)

Experimental group

Description:

Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.

Treatment:

Drug: Pamiparib

Drug: TMZ

Arm C (Dose Expansion-Cohorts C1 and C2)

Experimental group

Description:

Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.

Treatment:

Drug: Pamiparib

Drug: TMZ