Brain and Central Nervous System Tumors
Conditions
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
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.
Interventions
DRUGPamiparib
Administered as specified in the treatment arm
DRUGTMZ
Administered as specified in the treatment arm
RADIATIONRadiation
Up to 60 Gy (total) over 6 - 7 weeks
Sponsors
BeiGene USA, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
No Masking
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE | 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 | 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 | 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 | 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 | 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 | 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 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 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) | 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 and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | Pre-dose, 2 hours post dose on Days 1 and 15 of radiation Therapy | — |
| Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 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 | 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). |
| Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements | From the date of first dose up to EOS visit (up to 3 years and 7.5 months) | — |
| Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria | 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 | 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 | 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 | 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 | 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 | 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. |
Countries
Australia, France, Netherlands, Switzerland, United States
Participant flow
Recruitment details
This study consisted of a dose escalation phase and a dose expansion phase. A total of 116 participants were recruited in Netherlands, Switzerland and United States.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks Participants with newly diagnosed unmethylated glioblastoma (GBM) received 60 mg pamiparib orally BID for 2 weeks in combination with up to 60 Gy radiation for 6 weeks | 3 |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 4 weeks in combination with up to 60 Gy radiation for 6 weeks | 8 |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks | 9 |
| Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks | 40 |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide Participants with newly diagnosed unmethylated GBM received 60 mg pamiparib orally for 6 weeks in combination with up to 60 Gy radiation for 6 weeks and 60 mg temozolomide Wks 1 and 5 | 9 |
| Arm C: DE - Pamiparib + Temozolomide 20 mg Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 20 mg temozolomide once daily orally from Day 1 to Day 21 | 9 |
| Arm C: DE - Pamiparib + Temozolomide 40 mg Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 40 mg temozolomide once daily orally from Day 1 to Day 21 | 8 |
| Arm C: E- Pamiparib + Temozolomide 60 mg Participants with both methylated and unmethylated recurrent/refractory GBM received 60 mg pamiparib BID and 60 mg temozolomide once daily orally from Day 1 to Day 7 | 30 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Change in Methylation status | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 2 | 7 | 8 | 27 | 4 | 8 | 6 | 21 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Roll over in to Long Term Extension | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Sponsor's decision | 0 | 0 | 0 | 10 | 3 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 3 | 1 | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Arm A: Dose Expansion (E) - Pamiparib 6 Wks + RT 6 Wks | Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Arm C: DE - Pamiparib + Temozolomide 20 mg | Arm C: DE - Pamiparib + Temozolomide 40 mg | Arm C: E- Pamiparib + Temozolomide 60 mg | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 8.39 | 63.4 years STANDARD_DEVIATION 8.8 | 58.8 years STANDARD_DEVIATION 7.66 | 56.7 years STANDARD_DEVIATION 13.48 | 60.9 years STANDARD_DEVIATION 9.94 | 49.2 years STANDARD_DEVIATION 12.63 | 49.1 years STANDARD_DEVIATION 15.51 | 58.6 years STANDARD_DEVIATION 10.54 | 57.10 years STANDARD_DEVIATION 12.1 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown/Not Reported | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 7 Participants | 7 Participants | 38 Participants | 9 Participants | 7 Participants | 8 Participants | 27 Participants | 106 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 17 Participants | 4 Participants | 1 Participants | 4 Participants | 10 Participants | 39 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 7 Participants | 23 Participants | 5 Participants | 8 Participants | 4 Participants | 20 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 7 / 8 | 8 / 9 | 27 / 40 | 4 / 9 | 8 / 9 | 6 / 8 | 21 / 30 |
| other Total, other adverse events | 3 / 3 | 8 / 8 | 9 / 9 | 40 / 40 | 9 / 9 | 9 / 9 | 7 / 8 | 29 / 30 |
| serious Total, serious adverse events | 0 / 3 | 2 / 8 | 2 / 9 | 18 / 40 | 2 / 9 | 4 / 9 | 3 / 8 | 11 / 30 |
Outcome results
Primary
Phase 1b Arm C: 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 the date of first dose until EOS visit (up to 3 years and 7.5 months)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant | Pamiparib | 97.5 milligrams/Day | Standard Deviation 25.41 |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant | TMZ | 13.6 milligrams/Day | Standard Deviation 1.88 |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant | Pamiparib | 107.6 milligrams/Day | Standard Deviation 14.65 |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Average Dose Intensity of Pamiparib And TMZ Received Per Participant | TMZ | 28.2 milligrams/Day | Standard Deviation 10.8 |
Primary
Phase 1b Arm C: 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 the date of first dose up to EOS visit ( up to 3 years and 7.5 months)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 1 cycle | 4 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 4 cycles | 1 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | <1 cycle | 2 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 5 cycles | 1 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 2 cycles | 1 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 6 cycles | 0 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 7 cycles | 0 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | >7 cycles | 0 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 3 cycles | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | >7 cycles | 2 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | <1 cycle | 3 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 1 cycle | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 2 cycles | 2 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 3 cycles | 1 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 4 cycles | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 5 cycles | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 7 cycles | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm C: Number of Cycles of Treatment Received by Participants | 6 cycles | 0 participants |
Primary
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)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Escalation Phase Arm C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements | 0 Number of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Escalation Phase Arm C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements | 0 Number of participants |
Primary
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
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE | 0 participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE | 2 participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE | 1 participants |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE | 0 participants |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b Escalation Phase: Number of Participants With Dose-Limiting Toxicities (DLTs) as Assessed by CTCAE | 3 participants |
Primary
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)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Participants with At Least 1 TEAE | 3 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE with Grade 3 or Higher | 1 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Treatment Emergent SAEs | 0 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE Leading to Death | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Treatment Emergent SAEs | 2 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE with Grade 3 or Higher | 3 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Participants with At Least 1 TEAE | 8 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE Leading to Death | 0 participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE Leading to Death | 0 participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Treatment Emergent SAEs | 2 participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE with Grade 3 or Higher | 4 participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Participants with At Least 1 TEAE | 9 participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Participants with At Least 1 TEAE | 9 participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE Leading to Death | 0 participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE with Grade 3 or Higher | 4 participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Treatment Emergent SAEs | 2 participants |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Treatment Emergent SAEs | 4 participants |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE Leading to Death | 0 participants |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE with Grade 3 or Higher | 5 participants |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Participants with At Least 1 TEAE | 9 participants |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE with Grade 3 or Higher | 7 participants |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Treatment Emergent SAEs | 3 participants |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | TEAE Leading to Death | 0 participants |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b Escalation Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) as Assessed by CTCAE | Participants with At Least 1 TEAE | 8 participants |
Primary
Phase 2 Arm A: Modified Disease Control Rate (DCR) as Assessed by Response Assessment in Neuro-Oncology (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 ( up to 3 years and 7.5 months)
Population: The Efficacy Analysis Set (Arm A) includes participants in the Safety Analysis Set who had a tumor assessment at baseline and at End of Treatment unless discontinued treatment or study early due to disease progression or death prior to tumor assessment. Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arm A: Modified Disease Control Rate (DCR) as Assessed by Response Assessment in Neuro-Oncology (RANO) Criteria | 65.6 Percentage of participants |
Primary
Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria
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).
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)
Population: The Efficacy Analysis Set (Arm C) includes participants in the Safety Analysis Set who had measurable disease at baseline and at least one postbaseline tumor assessment unless discontinued treatment or study early due to disease progression or death prior to tumor assessment. Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arm C: Objective Response Rate (ORR) as Assessed Using RANO Criteria | 10.7 Percentage of participants |
Secondary
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)
Population: Efficacy Evaluable Analysis Set; Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria | 0 Percentage of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria | 16.7 Percentage of participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria | 0 Percentage of participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria | 3.1 Percentage of participants |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b and Phase 2 Arms A and B: ORR as Assessed Using RANO Criteria | 0 Percentage of participants |
Secondary
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)
Population: Efficacy Analysis Set; participants with available data were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 0 Percentage of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 33.3 Percentage of participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 0 Percentage of participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 37.6 Percentage of participants |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 40.0 Percentage of participants |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 0 Percentage of participants |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 28.6 Percentage of participants |
| Arm C: E- Pamiparib + Temozolomide 60 mg | Phase 1b and Phase 2 Arms A, B and C: Clinical Benefit Rate as Assessed Using RANO Criteria | 17.9 Percentage of participants |
Secondary
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)
Population: Efficacy Analysis Set; Only the participants with objective responses were included in DOR analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria | 6.44 Months |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria | 10.32 Months |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria | 11.7 Months |
| Arm C: E- Pamiparib + Temozolomide 60 mg | Phase 1b and Phase 2 Arms A, B and C: Duration of Response (DOR) as Assessed Using RANO Criteria | NA Months |
Secondary
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)
Population: Safety Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 14.46 Months |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 13.44 Months |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 10.25 Months |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 12.71 Months |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 14.23 Months |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 6.00 Months |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 8.62 Months |
| Arm C: E- Pamiparib + Temozolomide 60 mg | Phase 1b and Phase 2 Arms A, B and C: Overall Survival (OS) | 7.79 Months |
Secondary
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)
Population: Safety Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 3.12 Months |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 8.94 Months |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 2.56 Months |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 4.44 Months |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 5.75 Months |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 1.81 Months |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 2.66 Months |
| Arm C: E- Pamiparib + Temozolomide 60 mg | Phase 1b and Phase 2 Arms A, B and C: Progression Free Survival (PFS) as Assessed Using RANO Criteria | 1.87 Months |
Secondary
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
Population: The Pharmacokinetic (PK) Analysis Set includes all participants for whom valid pamiparib PK parameters can be estimated. Participants with available data were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 891.3 ng/mL | Standard Deviation 444.51 |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 1817.0 ng/mL | Standard Deviation 1226.53 |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 1848.3 ng/mL | Standard Deviation 784.38 |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 2239.9 ng/mL | Standard Deviation 1011.07 |
| Arm C: DE - Pamiparib + Temozolomide 20 mg | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 2134.3 ng/mL | Standard Deviation 953.06 |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 1893.3 ng/mL | Standard Deviation 718.46 |
| Arm C: DE - Pamiparib + Temozolomide 40 mg | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 1550.8 ng/mL | Standard Deviation 1422.55 |
| Arm C: E- Pamiparib + Temozolomide 60 mg | Phase 1B and Phase 2: Pharmacokinetics: Ctrough of Pamiparib | 1500.2 ng/mL | Standard Deviation 943.35 |
Secondary
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)
Population: Efficacy Analysis Set; Participants with available data were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria | 66.7 Percentage of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria | 100.0 Percentage of participants |
| Arm A: DE- Pamiparib 6Wks + RT 6 Wks | Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria | 42.9 Percentage of participants |
| Arm B: DE-Pamiparib 6 Wks + RT 6 Wks + Temozolomide | Phase 1b Arm A and Arm B Escalation Phase: Modified Disease Control Rate as Assessed by RANO Criteria | 80.0 Percentage of participants |
Secondary
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)
Population: Efficacy Analysis Set; Participants with available data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria | 55.6 Percentage of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 1b Escalation Phase Arm C: Disease Control Rate as Assessed by RANO Criteria | 71.4 Percentage of participants |
Secondary
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)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant | Pamiparib | 109.0 Milligrams/Day | Standard Deviation 22.07 |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant | TMZ | NA Milligrams/Day | — |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant | Pamiparib | 109.5 Milligrams/Day | Standard Deviation 15.22 |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Average Dose Intensity of Pamiparib and TMZ Received Per Participant | TMZ | 19.6 Milligrams/Day | Standard Deviation 11.6 |
Secondary
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)
Population: Safety Analysis Set; For Arm A Only participants who entered the maintenance phase were included in the analysis as per protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 1 cycle | 9 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 5 cycles | 3 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 3 cycles | 2 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 6 cycles | 3 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 2 cycles | 2 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 7 cycles | 0.0 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 4 cycles | 3 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | >7 cycles | 4 participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | <1 cycle | 3 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | >7 cycles | 5 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | <1 cycle | 8 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 1 cycle | 8 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 2 cycles | 7 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 3 cycles | 1 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 4 cycles | 1 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 5 cycles | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 6 cycles | 0 participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Cycles of Treatment Received by Participants | 7 cycles | 0 participants |
Secondary
Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with at Lease 1 TEAE | 40 Number of participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE with Grade 3 or Higher | 25 Number of participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment Emergent SAEs | 18 Number of participants |
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE Leading to Death | 3 Number of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE Leading to Death | 1 Number of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with at Lease 1 TEAE | 29 Number of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment Emergent SAEs | 11 Number of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Arms A and C Expansion Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE with Grade 3 or Higher | 19 Number of participants |
Secondary
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)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DE - Pamiparib 2 Wks + Radiation Therapy (RT) 6 Wks | Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements | 0 Number of participants |
| Arm A: DE-Pamiparib 4 Wks + RT 6 Wks | Phase 2 Expansion Phase Arm A and C: Number of Participants With Clinically Relevant Changes in Vital Signs and Clinical Laboratory Measurements | 0 Number of participants |