Clinical trial NCT03150862: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Brain and Central Nervous System Tumors
Keywords: Adult glioblastoma, adult giant 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
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2017-05-12
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE
timeFrame: 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
measure: Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE
timeFrame: 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)
measure: Phase 1b Escalation Phase Arm C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements
timeFrame: From the date of first dose up to end of study (EOS) visit (up to 3 years and 7.5 months)
measure: Phase 2 Arm A: Modified Disease Control Rate (DCR) as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria
timeFrame: 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)
measure: Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria
timeFrame: 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)
measure: Phase 1b Arm C: Number of Cycles of Treatment Received by Participants
timeFrame: From the date of first dose up to EOS visit ( up to 3 years and 7.5 months)
measure: Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant
timeFrame: From the date of first dose until EOS visit (up to 3 years and 7.5 months)
Secondary outcomes:
measure: Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib
timeFrame: Pre-dose, 2 hours post dose on Days 1 and 15 of radiation Therapy
measure: Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria
timeFrame: From the date of first dose up to first documentation of disease progression while participant is alive (approximately 3 years and 7.5 months)
measure: Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria
timeFrame: 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)
measure: Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria
timeFrame: 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)
measure: Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria
timeFrame: 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)
measure: Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria
timeFrame: From first documentation of CR or PR to first documentation of disease progression or death (up to 3 years and 7.5 months)
measure: Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria
timeFrame: From the date of first dose up to first documentation of disease progression or death (up to 3 years and 7.5 months)
measure: Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS)
timeFrame: From the date of first dose up to the date of death (up to 3 years and 7.5 months)
measure: Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: 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)
measure: Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements
timeFrame: From the date of first dose up to EOS visit (up to 3 years and 7.5 months)
measure: Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants
timeFrame: From date of first dose up to EOS Visit (up to 3 years and 7.5 months)
measure: Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant
timeFrame: From date of first dose up to EOS Visit (up to 3 years and 7.5 months)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Center For Neurosciences
state: Arizona
city: Los Angeles
country: United States
facility: UCLA
state: California
city: San Francisco
country: United States
facility: University of California At San Francisco
state: California
city: Denver
country: United States
facility: Sarah Cannon Research Institute (Scri) At Health One
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Kansas City
country: United States
facility: Midamerica Division, Inc
state: Missouri
city: Saint Louis
country: United States
facility: Washington University in St Louis
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center Mskcc
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Sarah Cannon Research Institute (Scri) Stephenson Cancer Center
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital Jefferson Health
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology, Pllc Nashville
state: Tennessee
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Zurich
country: Switzerland
facility: University of Zurich Medical School
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.