Solid Tumors and Lymphomas
Conditions
Keywords
Estrogen Receptor Positive Breast Cancer
Brief summary
The primary objectives of this study are to characterize the safety and tolerability and determine the maximum tolerated dose (MTD) or recommended dose for phase 2 study (RDP2) of alobresib as a monotherapy in participants with advanced solid tumors and lymphomas, and in combination with exemestane or fulvestrant in participants with advanced estrogen receptor positive breast cancer.
Interventions
DRUGAlobresib
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
DRUGExemestane
Tablets administered orally once daily on Cycle 1 Day 1 of 28 days cycle
DRUGFulvestrant
Administered intramuscularly on Cycle 1 Day 1 of 28 days cycle and every 28 days
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Group 1: Histologically or cytologically confirmed advanced malignant solid tumor or lymphoma (any subtype) that is refractory to or intolerant of standard therapy or for which no standard therapy is available * Group 2: Post-menopausal women with advanced stage estrogen receptor positive breast cancer who are candidates for exemestane or fulvestrant * Group 3: Individuals with lymphoma are limited to diffuse large B-cell lymphoma and peripheral T-cell lymphoma that are refractory to or intolerant of standard therapy or for which no standard therapy is available * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 * Adequate organ function defined as follows: * Hematologic: Platelets ≥ 100 x 10\^9/L; Hemoglobin ≥ 9.0 g/ dL; Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (without platelet transfusion or any growth factors within previous 7 days of the hematologic laboratory values obtained at screening visit). Participants in the Group 3 lymphoma expansion may be enrolled with an ANC of ≥ 1.0 x 10\^9 /L; Platelets ≥ 75 x 10\^9 /L. * Hepatic: Aspartate transaminase (AST) / Alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN); Total or conjugated bilirubin ≤ 1.5 x ULN * Renal: Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 ml/min as calculated by the cockcroft-gault method * Coagulation: International Normalized Ratio (INR) ≤ 1.2 Key
Exclusion criteria
* Known brain metastasis or leptomeningeal disease * Myocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification \> Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of study Day 1 * Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (ie, larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days of first dose of study drug * History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (\> 450 ms for males and \> 470 ms for females). Individuals who screen-fail due to this criterion are not eligible to be re-screened * Clinically significant bleeding within 28 days of study Day 1 * Known human immunodeficiency virus (HIV) infection * Hepatitis B surface antigen positive * Hepatitis C virus (HCV) antibody positive * No active anticoagulation within 7 days of study Day 1; including acetylsalicylic acid, low molecular weight heparin, or warfarin. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | Baseline (Day 1) up to 28 days | A DLT was a toxicity, considered possibly related to alobresib, and which occurred during DLT assessment window (Day 1 through Cycle 1 Day 28) in each cohort: Grade ≥ 4 neutropenia (absolute neutrophil count \[ANC\] \< 500/mm\^3); Grade ≥3 neutropenia (ANC\< 1000/mm\^3) with fever (a single temperature of \> 38.3°C or a sustained temperature of ≥ 38°C for more than 1 hour \[hr\]); Grade ≥ 3 thrombocytopenia; Grade ≥ 2 bleeding; Grade ≥ 3 non hematologic toxicity, except Grade 3 nausea or emesis with maximum duration of 48 hrs on adequate medical therapy and Grade 3 diarrhea which persists for \< 72 hrs in absence of maximal medical therapy; Grade ≥ 2 non hematologic treatment-emergent adverse event (TEAE) of potential clinical significance; treatment interruption ≥ 7 days due to unresolved toxicity; and any Grade 3 or 4 elevation in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) associated with a Grade 2 elevation in bilirubin that is at least possibly related to alobresib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: Ctau of Alobresib | Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Day 8 (1 Cycle = 28 days) | Ctau is defined as the observed drug concentration at the end of the dosing interval. |
| PK Parameter: AUC0-24 of Alobresib | Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days) | AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hrs. |
| Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days) | Cmax is defined as the maximum concentration of the drug. |
| PK Parameter: Tmax of Alobresib | Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days) | Tmax is defined as the time (observed time point) of Cmax. |
| PK Parameter: t1/2 of Alobresib | Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days) | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Due to short sampling period of the terminal elimination phase in these cohorts t1/2 values should be interpreted with caution. |
| PK Parameter: AUCtau of Alobresib | Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Day 8 (1 Cycle = 28 days) | AUCtau is defined as the concentration of drug over time (the area under the concentration verses time curve over the dosing interval). |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United states. The first participant was screened on 16 March 2015. The last study visit occurred on 11 October 2017.
Pre-assignment details
37 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Monotherapy: Alobresib 0.6 mg Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 0.6 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD. | 2 |
| Monotherapy: Alobresib 1.4 mg Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 1.4 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD. | 1 |
| Monotherapy: Alobresib 2 mg Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 2 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD. | 1 |
| Monotherapy: Alobresib 3 mg Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 3 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD. | 7 |
| Monotherapy: Alobresib 4 mg Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 4 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD. | 6 |
| Monotherapy: Alobresib 6 mg Participants with advanced solid tumors and lymphomas who had failed or were intolerant to standard therapy, or for whom no standard therapy existed received alobresib tablets at a dose of 6 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle to determine the MTD. | 4 |
| Combination Therapy: Alobresib 2 mg + Exemestane Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy existed, received alobresib tablets at a dose of 2 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle in combination with exemestane 25 mg tablets administered orally once daily on C1D1 of 28 days cycle. | 4 |
| Combination Therapy: Alobresib 2 mg + Fulvestrant Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy existed, received alobresib tablets at a dose of 2 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle in combination with fulvestrant 500 mg administered intramuscularly on C1D1 of 28 days cycle and every 28 days (± 3 days). | 3 |
| Combination Therapy: Alobresib 3 mg + Fulvestrant Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy existed, received alobresib tablets at a dose of 3 mg orally once daily on Study Day 1 through C1D28 of 28 days cycle in combination with fulvestrant 500 mg administered intramuscularly on C1D1 of 28 days cycle and every 28 days (± 3 days). | 3 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Enrolled, not treated | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Progressive disease | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Monotherapy: Alobresib 0.6 mg | Monotherapy: Alobresib 1.4 mg | Monotherapy: Alobresib 2 mg | Monotherapy: Alobresib 3 mg | Monotherapy: Alobresib 4 mg | Monotherapy: Alobresib 6 mg | Combination Therapy: Alobresib 2 mg + Exemestane | Combination Therapy: Alobresib 2 mg + Fulvestrant | Combination Therapy: Alobresib 3 mg + Fulvestrant | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 1 Participants | 5 Participants | 4 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 2 Participants | 12 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 6 Participants | 6 Participants | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 26 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 2 Participants | 1 Participants | 1 Participants | 7 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 29 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 22 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 9 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 |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 0 / 1 | 0 / 1 | 1 / 7 | 0 / 6 | 1 / 4 | 1 / 4 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 2 / 2 | 1 / 1 | 1 / 1 | 7 / 7 | 5 / 6 | 4 / 4 | 3 / 4 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 2 | 1 / 1 | 0 / 1 | 3 / 7 | 2 / 6 | 1 / 4 | 0 / 4 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
A DLT was a toxicity, considered possibly related to alobresib, and which occurred during DLT assessment window (Day 1 through Cycle 1 Day 28) in each cohort: Grade ≥ 4 neutropenia (absolute neutrophil count \[ANC\] \< 500/mm\^3); Grade ≥3 neutropenia (ANC\< 1000/mm\^3) with fever (a single temperature of \> 38.3°C or a sustained temperature of ≥ 38°C for more than 1 hour \[hr\]); Grade ≥ 3 thrombocytopenia; Grade ≥ 2 bleeding; Grade ≥ 3 non hematologic toxicity, except Grade 3 nausea or emesis with maximum duration of 48 hrs on adequate medical therapy and Grade 3 diarrhea which persists for \< 72 hrs in absence of maximal medical therapy; Grade ≥ 2 non hematologic treatment-emergent adverse event (TEAE) of potential clinical significance; treatment interruption ≥ 7 days due to unresolved toxicity; and any Grade 3 or 4 elevation in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) associated with a Grade 2 elevation in bilirubin that is at least possibly related to alobresib.
Time frame: Baseline (Day 1) up to 28 days
Population: The Full Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Monotherapy: Alobresib 0.6 mg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
| Monotherapy: Alobresib 1.4 mg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
| Monotherapy: Alobresib 2 mg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
| Monotherapy: Alobresib 3 mg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 1 Participants |
| Monotherapy: Alobresib 4 mg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 1 Participants |
| Monotherapy: Alobresib 6 mg | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 2 Participants |
| Combination Therapy: Alobresib 2 mg + Exemestane | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 Participants |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) | 1 Participants |
Secondary
Pharmacokinetic (PK) Parameter: Cmax of Alobresib
Cmax is defined as the maximum concentration of the drug.
Time frame: Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days)
Population: Participants in the PK Analysis Set (included all enrolled participants who took at least 1 dose of study drug and had at least 1 nonmissing postdose value reported by the PK laboratory) with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monotherapy: Alobresib 0.6 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 35.2 ng/mL | Standard Deviation 7.21 |
| Monotherapy: Alobresib 0.6 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 64.0 ng/mL | Standard Deviation 26.8 |
| Monotherapy: Alobresib 1.4 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 59.1 ng/mL | — |
| Monotherapy: Alobresib 1.4 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 117.0 ng/mL | — |
| Monotherapy: Alobresib 2 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 141.0 ng/mL | — |
| Monotherapy: Alobresib 2 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 174.0 ng/mL | — |
| Monotherapy: Alobresib 3 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 197.5 ng/mL | Standard Deviation 109.97 |
| Monotherapy: Alobresib 3 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 296.5 ng/mL | Standard Deviation 199.49 |
| Monotherapy: Alobresib 4 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 281.7 ng/mL | Standard Deviation 98.78 |
| Monotherapy: Alobresib 4 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 407.2 ng/mL | Standard Deviation 154.29 |
| Monotherapy: Alobresib 6 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 711.5 ng/mL | Standard Deviation 350.84 |
| Monotherapy: Alobresib 6 mg | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 376.2 ng/mL | Standard Deviation 257.22 |
| Combination Therapy: Alobresib 2 mg + Exemestane | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 193.0 ng/mL | Standard Deviation 68.56 |
| Combination Therapy: Alobresib 2 mg + Exemestane | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 160.8 ng/mL | Standard Deviation 7.93 |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 149.7 ng/mL | Standard Deviation 27.47 |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 278.0 ng/mL | Standard Deviation 95.69 |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 1 | 234.3 ng/mL | Standard Deviation 70.49 |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cycle 1 Day 8 | 458.7 ng/mL | Standard Deviation 29.48 |
Secondary
PK Parameter: AUC0-24 of Alobresib
AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hrs.
Time frame: Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days)
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monotherapy: Alobresib 0.6 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 640.0 h*ng/mL | Standard Deviation 101.99 |
| Monotherapy: Alobresib 0.6 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 699.5 h*ng/mL | Standard Deviation 392.28 |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 1838.5 h*ng/mL | — |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 1896.1 h*ng/mL | — |
| Monotherapy: Alobresib 2 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 1413.2 h*ng/mL | — |
| Monotherapy: Alobresib 2 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 1603.3 h*ng/mL | — |
| Monotherapy: Alobresib 3 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 2336.1 h*ng/mL | Standard Deviation 1125.8 |
| Monotherapy: Alobresib 3 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 4430.5 h*ng/mL | Standard Deviation 3776.16 |
| Monotherapy: Alobresib 4 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 2692.1 h*ng/mL | Standard Deviation 834.79 |
| Monotherapy: Alobresib 4 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 5584.5 h*ng/mL | Standard Deviation 3121.02 |
| Monotherapy: Alobresib 6 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 9432.2 h*ng/mL | Standard Deviation 6278.61 |
| Monotherapy: Alobresib 6 mg | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 6347.4 h*ng/mL | Standard Deviation 4602.91 |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 1752.6 h*ng/mL | Standard Deviation 485.84 |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 1549.0 h*ng/mL | Standard Deviation 498.72 |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 1900.9 h*ng/mL | Standard Deviation 363.22 |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 2525.7 h*ng/mL | Standard Deviation 1091.23 |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 8 | 5665.1 h*ng/mL | Standard Deviation 596 |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: AUC0-24 of Alobresib | Cycle 1 Day 1 | 3038.5 h*ng/mL | Standard Deviation 263.15 |
Secondary
PK Parameter: AUCtau of Alobresib
AUCtau is defined as the concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Time frame: Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Day 8 (1 Cycle = 28 days)
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Monotherapy: Alobresib 0.6 mg | PK Parameter: AUCtau of Alobresib | 643.3 h*ng/mL | Standard Deviation 109.4 |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: AUCtau of Alobresib | 1838.5 h*ng/mL | — |
| Monotherapy: Alobresib 2 mg | PK Parameter: AUCtau of Alobresib | 1591.8 h*ng/mL | — |
| Monotherapy: Alobresib 3 mg | PK Parameter: AUCtau of Alobresib | 4391.7 h*ng/mL | Standard Deviation 3716.47 |
| Monotherapy: Alobresib 4 mg | PK Parameter: AUCtau of Alobresib | 4128.5 h*ng/mL | Standard Deviation 333.78 |
| Monotherapy: Alobresib 6 mg | PK Parameter: AUCtau of Alobresib | 9373.8 h*ng/mL | Standard Deviation 6220.97 |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: AUCtau of Alobresib | 1750.8 h*ng/mL | Standard Deviation 478.46 |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: AUCtau of Alobresib | 2514.3 h*ng/mL | Standard Deviation 1097.14 |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: AUCtau of Alobresib | 5644.0 h*ng/mL | Standard Deviation 603.8 |
Secondary
PK Parameter: Ctau of Alobresib
Ctau is defined as the observed drug concentration at the end of the dosing interval.
Time frame: Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Day 8 (1 Cycle = 28 days)
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Monotherapy: Alobresib 0.6 mg | PK Parameter: Ctau of Alobresib | 14.7 ng/mL | Standard Deviation 0.28 |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: Ctau of Alobresib | 60.7 ng/mL | — |
| Monotherapy: Alobresib 2 mg | PK Parameter: Ctau of Alobresib | 34.4 ng/mL | — |
| Monotherapy: Alobresib 3 mg | PK Parameter: Ctau of Alobresib | 131.0 ng/mL | Standard Deviation 149.21 |
| Monotherapy: Alobresib 4 mg | PK Parameter: Ctau of Alobresib | 168.4 ng/mL | Standard Deviation 165.71 |
| Monotherapy: Alobresib 6 mg | PK Parameter: Ctau of Alobresib | 237.1 ng/mL | Standard Deviation 167.31 |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: Ctau of Alobresib | 44.2 ng/mL | Standard Deviation 21.62 |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: Ctau of Alobresib | 59.4 ng/mL | Standard Deviation 36.8 |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: Ctau of Alobresib | 170.0 ng/mL | Standard Deviation 39 |
Secondary
PK Parameter: t1/2 of Alobresib
t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Due to short sampling period of the terminal elimination phase in these cohorts t1/2 values should be interpreted with caution.
Time frame: Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days)
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Monotherapy: Alobresib 0.6 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 16.6 hour |
| Monotherapy: Alobresib 0.6 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 13.7 hour |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 35.3 hour |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 28.7 hour |
| Monotherapy: Alobresib 2 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 15.8 hour |
| Monotherapy: Alobresib 2 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 15.9 hour |
| Monotherapy: Alobresib 3 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 20.2 hour |
| Monotherapy: Alobresib 3 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 16.8 hour |
| Monotherapy: Alobresib 4 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 19.2 hour |
| Monotherapy: Alobresib 4 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 16.1 hour |
| Monotherapy: Alobresib 6 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 17.8 hour |
| Monotherapy: Alobresib 6 mg | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 21.1 hour |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 14.0 hour |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 13.5 hour |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 23.4 hour |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 22.0 hour |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 1 | 15.2 hour |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: t1/2 of Alobresib | Cycle 1 Day 8 | 22.3 hour |
Secondary
PK Parameter: Tmax of Alobresib
Tmax is defined as the time (observed time point) of Cmax.
Time frame: Cycle 1: Predose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hrs postdose on Days 1 and 8 (1 Cycle = 28 days)
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Monotherapy: Alobresib 0.6 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 1.3 hour |
| Monotherapy: Alobresib 0.6 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 2.1 hour |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 4.0 hour |
| Monotherapy: Alobresib 1.4 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 0.6 hour |
| Monotherapy: Alobresib 2 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 0.5 hour |
| Monotherapy: Alobresib 2 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 0.5 hour |
| Monotherapy: Alobresib 3 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 1.0 hour |
| Monotherapy: Alobresib 3 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 2.0 hour |
| Monotherapy: Alobresib 4 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 0.9 hour |
| Monotherapy: Alobresib 4 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 0.5 hour |
| Monotherapy: Alobresib 6 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 4.1 hour |
| Monotherapy: Alobresib 6 mg | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 0.8 hour |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 0.5 hour |
| Combination Therapy: Alobresib 2 mg + Exemestane | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 0.5 hour |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 6.1 hour |
| Combination Therapy: Alobresib 2 mg + Fulvestrant | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 0.5 hour |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: Tmax of Alobresib | Cycle 1 Day 8 | 0.5 hour |
| Combination Therapy: Alobresib 3 mg + Fulvestrant | PK Parameter: Tmax of Alobresib | Cycle 1 Day 1 | 1.1 hour |