Locally Advanced or Metastatic Solid Tumors
Conditions
Keywords
Ovarian cancer, Triple negative breast cancer, Small cell lung cancer, Gastric cancer, temozolomide, BGB-290, antineoplastic agents, alkylating, alkylating agents,, Poly (ADP-ribose) polymerase inhibitors, enzyme inhibitors, Head and neck cancer, Esophageal cancer, Soft tissue sarcoma, Non small cell lung cancer, pamiparib
Brief summary
The primary objective of this study was to determine the safety and tolerability of pamiparib, the maximum tolerated dose (MTD) or maximum administered dose (MAD) for pamiparib combined with TMZ, to select the recommended Phase 2 dose (RP2D) and schedule of pamiparib in combination with TMZ, and to determine the antitumor activity of pamiparib in combination with TMZ.
Interventions
DRUGPamiparib
Administered by mouth as a capsule twice daily
DRUGTemozolomide
TMZ at various doses administered by mouth as a capsule once daily.
Sponsors
Myriad Genetics, Inc.
BeiGene
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Age ≥18 years old with advanced or metastatic stage solid tumors 2. Eastern Cooperative Oncology Group (ECOG) status ≤ 1 3. Have disease either evaluable (dose-escalation cohort) or measurable (dose-escalation and -expansion cohorts) per RECIST V1.1, except for prostate cancer participants 4. Agree to provide archival tumor tissue 5. Additional inclusion criteria for dose expansion cohorts: * Participants with homologous recombination deficiency (HRD+) or known BRCA mutant ovarian cancer Previously received at least one line of platinum-containing therapy in the advanced or metastatic setting and No progression or recurrent disease within 6 months from last platinum-containing regimen. * Participants with HRD+ or known BRCA mutant triple-negative breast cancer Up to one prior platinum-containing treatment in any treatment setting and up to 3 prior lines of therapy in the advanced or metastatic setting * Participants with HRD+ or known BRCA mutant prostate cancer Chemotherapy-naïve or previously received up to two taxane-based chemotherapy regimens, with documented prostate cancer progression * Participants with small cell lung cancer and gastric cancer, previously received ≤ 2 prior lines of therapy * Other HRD+ solid tumors of multiple indications Key
Exclusion criteria
All participants 1. Prior treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor. 2. Refractory to platinum-based therapy (dose-expansion cohort). NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | From first dose of study drug(s) to 28 days post-dose (up to approximately 1 year and 6 months) | 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) |
| Number of Participants Experiencing Adverse Events (AEs) | From the first dose of study drug(s) to 30 days after the last dose; up to approximately 5 years and 10 months | Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory values, vital signs, physical examination findings, and electrocardiogram results, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.03 |
| Objective Response Rate (ORR) | Up to approximately 5 years and 10 months | ORR is defined as the percentage of participants who have a best overall response (BOR) of complete response (CR) or partial response (PR) based on investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where BOR is defined as the best response recorded from the first postbaseline tumor assessment until data cutoff date, disease progression or start of new anticancer treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time 0 to 4 Hours (AUC0-4h) of Pamiparib | 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, and 4 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose. | — |
| Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Pamiparib | 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing | — |
| Terminal Elimination Half-life (t1/2) of Pamiparib | 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days) | — |
| Apparent Clearance (CL/F) of Pamiparib | 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days) | — |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of Pamiparib | 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days) | — |
| Maximum Observed Plasma Concentration (Cmax) of Pamiparib | 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose (each cycle is 28 days) | Pamiparib pharmakokinetic (PK) parameters were assessed in the first 20 participants enrolled in the dose escalation phase after a single dose on Day -2 and at steady state in combination with TMZ on Day 15. |
| Disease Control Rate (DCR) | Up to approximately 5 years and 10 months | DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD) based on investigator assessment using RECIST v1.1. |
| Duration of Response (DOR) | Up to approximately 5 years and 10 months | DOR is defined as the time from the date of the earliest documented CR or PR (that is subsequently confirmed) to disease progression or death due to any cause, whichever occurs earlier, based on investigator assessment using RECIST v1.1. Only responders will be included in the assessment. |
| Progression Free Survival (PFS) | Up to approximately 5 years and 10 months) | PFS is defined as the time (months) from the date of the first dose of combination treatment to disease progression or death due to any cause, whichever occurs first, based on investigator assessment using RECIST v1.1 |
| Overall Survival (OS) | Up to approximately 5 years and 10 months | OS is defined as the time from the date of the first dose of combination treatment to death due to any cause. |
| Plasma Concentration of Temozolomide (TMZ) | Predose (within 30 min prior to dose) and 1 hour post dose on Cycle 1 Day 1 and Cycle 1 Day 7 | — |
| Plasma Trough Concentrations of Pamiparib (Ctrough) | Cycle 1 Day 15 predose | — |
| Time to Reach Cmax (Tmax) of Pamiparib | 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose. | — |
Countries
Australia, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in multiple study centers in Australia, Europe, and North America.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 40 mg once daily on Days 1 to 7 within a 28-day cycle | 4 |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 60 mg once daily on Days 1 to 7 within a 28-day cycle | 13 |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 80 mg once daily on Days 1 to 7 within a 28-day cycle | 9 |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 100 mg once daily on Days 1 to 7 within a 28-day cycle | 3 |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 120 mg once daily on Days 1 to 7 within a 28-day cycle | 3 |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 40 mg once daily on Days 1 to 14 within a 28-day cycle | 14 |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) Pamiparib 60 mg twice daily in combination with TMZ 20 mg once daily administered continuously on Days 1 to 28 within a 28-day cycle | 14 |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) Pamiparib 60 mg twice daily in combination with TMZ 40 mg once daily administered continuously on Days 1 to 28 within a 28-day cycle | 6 |
| Dose Expansion: Gastric Cancer Participants with gastric or gastroesophageal junction cancer received TMZ 60 mg once daily administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle | 21 |
| Dose Expansion: Ovarian Cancer Participants with ovarian cancer, fallopian cancer, or primary peritoneal cancer received TMZ 60 mg once daily administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle | 4 |
| Dose Expansion: SCLC Participants with Small Cell Lung Cancer (SCLC) received TMZ 60 mg once daily administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle | 22 |
| Dose Expansion: TNBC Participants with triple negative breast cancer (TNBC) received TMZ 60 mg once daily administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle | 1 |
| Dose Expansion: Other HRD+ Cancers Participants with non-small cell lung cancer (NSCLC), esophageal cancer, squamous head and neck cancer, or soft tissue sarcomas whose tumors are homologous recombination deficiency (HRD)+ received TMZ 60 mg once daily administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle | 25 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 4 | 8 | 7 | 2 | 2 | 10 | 8 | 6 | 18 | 3 | 19 | 1 | 19 |
| Overall Study | Hospice | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Participant relocated abroad. | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Site withdrawal from study | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Sponsor Decision | 0 | 2 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 5 |
| Overall Study | Transferred care to oncologist | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 1 | 0 | 0 | 2 | 0 | 2 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Dose Expansion: Gastric Cancer | Dose Expansion: Ovarian Cancer | Dose Expansion: SCLC | Dose Expansion: TNBC | Dose Expansion: Other HRD+ Cancers | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.5 years STANDARD_DEVIATION 6.19 | 58.0 years STANDARD_DEVIATION 10.52 | 72.3 years STANDARD_DEVIATION 6.22 | 60.3 years STANDARD_DEVIATION 10.69 | 65.7 years STANDARD_DEVIATION 13.8 | 66.7 years STANDARD_DEVIATION 10.21 | 66.9 years STANDARD_DEVIATION 9.96 | 66.7 years STANDARD_DEVIATION 8.31 | 58.8 years STANDARD_DEVIATION 14.68 | 59.3 years STANDARD_DEVIATION 2.22 | 61.9 years STANDARD_DEVIATION 8.33 | 31.0 years | 58.1 years STANDARD_DEVIATION 8.28 | 62.0 years STANDARD_DEVIATION 10.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 11 Participants | 7 Participants | 2 Participants | 3 Participants | 11 Participants | 8 Participants | 4 Participants | 18 Participants | 3 Participants | 18 Participants | 1 Participants | 20 Participants | 110 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 4 Participants | 0 Participants | 5 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 5 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 5 Participants | 21 Participants |
| Race (NIH/OMB) White | 4 Participants | 10 Participants | 9 Participants | 2 Participants | 1 Participants | 7 Participants | 8 Participants | 5 Participants | 18 Participants | 2 Participants | 18 Participants | 1 Participants | 20 Participants | 105 Participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 5 Participants | 2 Participants | 1 Participants | 6 Participants | 7 Participants | 2 Participants | 8 Participants | 4 Participants | 8 Participants | 1 Participants | 10 Participants | 64 Participants |
| Sex: Female, Male Male | 1 Participants | 6 Participants | 4 Participants | 1 Participants | 2 Participants | 8 Participants | 7 Participants | 4 Participants | 13 Participants | 0 Participants | 14 Participants | 0 Participants | 15 Participants | 75 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 | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 8 / 13 | 7 / 9 | 2 / 3 | 2 / 3 | 10 / 14 | 8 / 14 | 6 / 6 | 18 / 21 | 3 / 4 | 19 / 22 | 1 / 1 | 19 / 25 |
| other Total, other adverse events | 4 / 4 | 13 / 13 | 9 / 9 | 3 / 3 | 3 / 3 | 14 / 14 | 14 / 14 | 6 / 6 | 20 / 21 | 4 / 4 | 22 / 22 | 1 / 1 | 24 / 25 |
| serious Total, serious adverse events | 1 / 4 | 4 / 13 | 1 / 9 | 2 / 3 | 2 / 3 | 5 / 14 | 5 / 14 | 0 / 6 | 9 / 21 | 3 / 4 | 9 / 22 | 0 / 1 | 9 / 25 |
Outcome results
Primary
Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs)
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: From first dose of study drug(s) to 28 days post-dose (up to approximately 1 year and 6 months)
Population: The dose-escalation safety analysis set comprised all dose-escalation phase participants who received pamiparib and/or TMZ.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
Number of Participants Experiencing Adverse Events (AEs)
Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including laboratory values, vital signs, physical examination findings, and electrocardiogram results, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.03
Time frame: From the first dose of study drug(s) to 30 days after the last dose; up to approximately 5 years and 10 months
Population: The Safety Analysis Set included all participants who received any dose of pamiparib and/or TMZ.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 4 Participants |
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 1 Participants |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 13 Participants |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 4 Participants |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 9 Participants |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 1 Participants |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 3 Participants |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 2 Participants |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 2 Participants |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 3 Participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 5 Participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 14 Participants |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 14 Participants |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 5 Participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 6 Participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 0 Participants |
| Dose Expansion: Gastric Cancer | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 20 Participants |
| Dose Expansion: Gastric Cancer | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 9 Participants |
| Dose Expansion: Ovarian Cancer | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 3 Participants |
| Dose Expansion: Ovarian Cancer | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 4 Participants |
| Dose Expansion: SCLC | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 9 Participants |
| Dose Expansion: SCLC | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 22 Participants |
| Dose Expansion: TNBC | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 1 Participants |
| Dose Expansion: TNBC | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 0 Participants |
| Dose Expansion: Other HRD+ Cancers | Number of Participants Experiencing Adverse Events (AEs) | Participants with Serious TEAEs | 9 Participants |
| Dose Expansion: Other HRD+ Cancers | Number of Participants Experiencing Adverse Events (AEs) | Participants With At Least 1 TEAE | 24 Participants |
Primary
Objective Response Rate (ORR)
ORR is defined as the percentage of participants who have a best overall response (BOR) of complete response (CR) or partial response (PR) based on investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where BOR is defined as the best response recorded from the first postbaseline tumor assessment until data cutoff date, disease progression or start of new anticancer treatment.
Time frame: Up to approximately 5 years and 10 months
Population: The Efficacy Analysis Set included all participants who were in the safety analysis set, had measurable disease at baseline and had at least one postbaseline tumor assessment unless discontinued treatment due to clinical progression or death prior to tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Objective Response Rate (ORR) | 0.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Objective Response Rate (ORR) | 16.7 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Objective Response Rate (ORR) | 25.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Objective Response Rate (ORR) | 0.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Objective Response Rate (ORR) | 0.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Objective Response Rate (ORR) | 21.4 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Objective Response Rate (ORR) | 0.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Objective Response Rate (ORR) | 25.0 percentage of participants |
| Dose Expansion: Gastric Cancer | Objective Response Rate (ORR) | 0.0 percentage of participants |
| Dose Expansion: Ovarian Cancer | Objective Response Rate (ORR) | 50.0 percentage of participants |
| Dose Expansion: SCLC | Objective Response Rate (ORR) | 15.0 percentage of participants |
| Dose Expansion: TNBC | Objective Response Rate (ORR) | 100.0 percentage of participants |
| Dose Expansion: Other HRD+ Cancers | Objective Response Rate (ORR) | 8.0 percentage of participants |
Secondary
Apparent Clearance (CL/F) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days)
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; Only 15 participants had data available to calculate CL/F.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Apparent Clearance (CL/F) of Pamiparib | 2.37 L/h | Geometric Coefficient of Variation 50 |
Secondary
Apparent Volume of Distribution During Terminal Phase (Vz/F) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days)
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; Only 15 participants had data available to calculate Vz/F.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Apparent Volume of Distribution During Terminal Phase (Vz/F) of Pamiparib | 38.14 liters | Geometric Coefficient of Variation 15 |
Secondary
Area Under the Curve From Time 0 to 4 Hours (AUC0-4h) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, and 4 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose.
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; per the prespecified analysis participants were analyzed in one group, regardless of dose of TMZ they received. Only 8 participants had available data to calculate AUC0-4 on Day 15.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Area Under the Curve From Time 0 to 4 Hours (AUC0-4h) of Pamiparib | Day -2 | 4646.4 h*ng/mL | Geometric Coefficient of Variation 45 |
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Area Under the Curve From Time 0 to 4 Hours (AUC0-4h) of Pamiparib | Cycle 1 Day 15 | 11119.5 h*ng/mL | Geometric Coefficient of Variation 41 |
Secondary
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; AUC0-inf could only be calculated for 15 participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Pamiparib | 25287.0 h*ng/mL | Geometric Coefficient of Variation 50 |
Secondary
Disease Control Rate (DCR)
DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD) based on investigator assessment using RECIST v1.1.
Time frame: Up to approximately 5 years and 10 months
Population: Efficacy Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Disease Control Rate (DCR) | 33.3 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Disease Control Rate (DCR) | 91.7 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Disease Control Rate (DCR) | 75.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Disease Control Rate (DCR) | 100.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Disease Control Rate (DCR) | 50.0 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Disease Control Rate (DCR) | 42.9 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Disease Control Rate (DCR) | 53.8 percentage of participants |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Disease Control Rate (DCR) | 75.0 percentage of participants |
| Dose Expansion: Gastric Cancer | Disease Control Rate (DCR) | 42.1 percentage of participants |
| Dose Expansion: Ovarian Cancer | Disease Control Rate (DCR) | 75.0 percentage of participants |
| Dose Expansion: SCLC | Disease Control Rate (DCR) | 75.0 percentage of participants |
| Dose Expansion: TNBC | Disease Control Rate (DCR) | 100.0 percentage of participants |
| Dose Expansion: Other HRD+ Cancers | Disease Control Rate (DCR) | 52.0 percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time from the date of the earliest documented CR or PR (that is subsequently confirmed) to disease progression or death due to any cause, whichever occurs earlier, based on investigator assessment using RECIST v1.1. Only responders will be included in the assessment.
Time frame: Up to approximately 5 years and 10 months
Population: Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Duration of Response (DOR) | 13.0 months |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Duration of Response (DOR) | 6.4 months |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Duration of Response (DOR) | 9.2 months |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Duration of Response (DOR) | 3.7 months |
| Dose Expansion: Ovarian Cancer | Duration of Response (DOR) | 5.4 months |
| Dose Expansion: SCLC | Duration of Response (DOR) | 3.8 months |
| Dose Expansion: TNBC | Duration of Response (DOR) | 11.0 months |
| Dose Expansion: Other HRD+ Cancers | Duration of Response (DOR) | NA months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Pamiparib
Pamiparib pharmakokinetic (PK) parameters were assessed in the first 20 participants enrolled in the dose escalation phase after a single dose on Day -2 and at steady state in combination with TMZ on Day 15.
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose (each cycle is 28 days)
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; per the prespecified analysis, participants were analyzed in one group, regardless of dose of TMZ they received. Only 13 participants had data available for calculation of Cmax on Day 15.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Maximum Observed Plasma Concentration (Cmax) of Pamiparib | Day -2 | 1945.31 ng/mL | Geometric Coefficient of Variation 25 |
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Maximum Observed Plasma Concentration (Cmax) of Pamiparib | Cycle 1 Day 15 | 3796.06 ng/mL | Geometric Coefficient of Variation 33 |
Secondary
Overall Survival (OS)
OS is defined as the time from the date of the first dose of combination treatment to death due to any cause.
Time frame: Up to approximately 5 years and 10 months
Population: The Safety Analysis Set included all participants who received any dose of pamiparib and/or TMZ.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Overall Survival (OS) | 7.6 months |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Overall Survival (OS) | 14.8 months |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Overall Survival (OS) | 12.7 months |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Overall Survival (OS) | 12.4 months |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Overall Survival (OS) | 12.3 months |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Overall Survival (OS) | 6.3 months |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Overall Survival (OS) | 13.9 months |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Overall Survival (OS) | 8.2 months |
| Dose Expansion: Gastric Cancer | Overall Survival (OS) | 6.6 months |
| Dose Expansion: Ovarian Cancer | Overall Survival (OS) | 21.2 months |
| Dose Expansion: SCLC | Overall Survival (OS) | 7.7 months |
| Dose Expansion: TNBC | Overall Survival (OS) | 19.4 months |
| Dose Expansion: Other HRD+ Cancers | Overall Survival (OS) | 9.8 months |
Secondary
Plasma Concentration of Temozolomide (TMZ)
Time frame: Predose (within 30 min prior to dose) and 1 hour post dose on Cycle 1 Day 1 and Cycle 1 Day 7
Population: PK Analysis Set: includes participants who received any dose of TMZ and contributed at least one plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Postdose 1H | 340.9 ng/mL | Geometric Coefficient of Variation 86 |
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Postdose 1H | 322.8 ng/mL | Geometric Coefficient of Variation 35 |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Postdose 1H | 636.7 ng/mL | Geometric Coefficient of Variation 57 |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Postdose 1H | 601.3 ng/mL | Geometric Coefficient of Variation 68 |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Postdose 1H | 822.3 ng/mL | Geometric Coefficient of Variation 74 |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Postdose 1H | 761.1 ng/mL | Geometric Coefficient of Variation 103 |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Postdose 1H | 1959.8 ng/mL | Geometric Coefficient of Variation 40 |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Postdose 1H | 1366.1 ng/mL | Geometric Coefficient of Variation 46 |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Postdose 1H | 1157.9 ng/mL | Geometric Coefficient of Variation 123 |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Postdose 1H | 1520.0 ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Postdose 1H | 1464.5 ng/mL | Geometric Coefficient of Variation 31 |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Plasma Concentration of Temozolomide (TMZ) | C1D1 Predose | NA ng/mL | — |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Postdose 1H | 1775.6 ng/mL | Geometric Coefficient of Variation 71 |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Plasma Concentration of Temozolomide (TMZ) | C1D7 Predose | NA ng/mL | — |
Secondary
Plasma Trough Concentrations of Pamiparib (Ctrough)
Time frame: Cycle 1 Day 15 predose
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; per the prespecified analysis, participants were analyzed in one group, regardless of dose of TMZ they received. Only 14 participants had data available for calculation of Ctrough on Day 15.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Plasma Trough Concentrations of Pamiparib (Ctrough) | 2335.6 ng/mL | Geometric Coefficient of Variation 76 |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time (months) from the date of the first dose of combination treatment to disease progression or death due to any cause, whichever occurs first, based on investigator assessment using RECIST v1.1
Time frame: Up to approximately 5 years and 10 months)
Population: Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Progression Free Survival (PFS) | 2.0 months |
| Dose Escalation: Pamiparib + TMZ 60 mg (Days 1-7) | Progression Free Survival (PFS) | 5.6 months |
| Dose Escalation: Pamiparib + TMZ 80 mg (Days 1-7) | Progression Free Survival (PFS) | 5.3 months |
| Dose Escalation: Pamiparib + TMZ 100 mg (Days 1-7) | Progression Free Survival (PFS) | NA months |
| Dose Escalation: Pamiparib + TMZ 120 mg (Days 1-7) | Progression Free Survival (PFS) | NA months |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-14) | Progression Free Survival (PFS) | 2.8 months |
| Dose Escalation: Pamiparib + TMZ 20 mg (Days 1-28) | Progression Free Survival (PFS) | 3.1 months |
| Dose Escalation: Pamiparib + TMZ 40 mg (Days 1-28) | Progression Free Survival (PFS) | 3.5 months |
| Dose Expansion: Gastric Cancer | Progression Free Survival (PFS) | 1.9 months |
| Dose Expansion: Ovarian Cancer | Progression Free Survival (PFS) | 6.4 months |
| Dose Expansion: SCLC | Progression Free Survival (PFS) | 3.5 months |
| Dose Expansion: TNBC | Progression Free Survival (PFS) | 14.8 months |
| Dose Expansion: Other HRD+ Cancers | Progression Free Survival (PFS) | 2.6 months |
Secondary
Terminal Elimination Half-life (t1/2) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing (each cycle is 28 days)
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; Only 17 participants had data available to calculate T1/2.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Terminal Elimination Half-life (t1/2) of Pamiparib | 11.82 hours |
Secondary
Time to Reach Cmax (Tmax) of Pamiparib
Time frame: 2 days before Cycle 1 Day 1 (Day -2) at predose, 30 min, 1, 2, 4, 6, 24, and 48 hours after dosing, and on Cycle 1 Day 15 at predose, 1, 2, and 4 hours postdose.
Population: The pamiparib pharmacokinetic analysis included the first 20 participants enrolled in the dose escalation phase; per the prespecified analysis, participants were analyzed in one group, regardless of dose of TMZ they received. Only 13 participants had data available for calculation of Tmax on Day 15.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Time to Reach Cmax (Tmax) of Pamiparib | Cycle 1 Day 15 | 1.83 hours |
| Dose Escalation: Pamiparib + Temozolomide (TMZ) 40 mg (Days 1-7) | Time to Reach Cmax (Tmax) of Pamiparib | Day -2 | 2.00 hours |