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

BeiGene USA, Inc.116 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

116

Conditions

Brain and Central Nervous System Tumors

Interventions

PamiparibDRUG

Administered as specified in the treatment arm

TMZDRUG

Administered as specified in the treatment arm

RadiationRADIATION

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (22)

Center For Neurosciences

Tucson, Arizona, United States

Outcomes

Primary Outcomes

Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE

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)

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

Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE

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.

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)

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

Data from ClinicalTrials.gov

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Secondary Outcomes

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

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.

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)

Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria

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

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)

Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria

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).

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)

Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria

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).

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)

Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria

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).

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)

Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria

PFS is defined as the time from the first dose date to disease progression per RANO criteria or death, whichever occurs first.

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)

Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS)

OS is defined as the time from the first dose date to date of death for any cause.

Time frame: From the date of first dose up to the date of death (up to 3 years and 7.5 months)

Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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

Data shows the number of participants who received treatment for the given number of cycles.

Time frame: From date of first dose up to EOS Visit (up to 3 years and 7.5 months)

Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant

The average dose intensity per participant = total dose (mg) per participant / duration of treatment (days).

Time frame: From date of first dose up to EOS Visit (up to 3 years and 7.5 months)