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.
Completed
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| Alobresib | GS-5829 | Combination Therapy: Alobresib 2 mg + Exemestane |
| Exemestane | Aromasin® | Combination Therapy: Alobresib 2 mg + Exemestane |
| Fulvestrant | Faslodex® | Combination Therapy: Alobresib 2 mg + Fulvestrant |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Monotherapy: Alobresib 0.6 mg | Experimental | Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 0.6 mg to determine the MTD. |
|
| Monotherapy: Alobresib 1.4 mg | Experimental | Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 1.4 mg to determine the MTD. |
|
| Monotherapy: Alobresib 2 mg | Experimental | Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 2 mg to determine the MTD. |
|
| Monotherapy: Alobresib 3 mg | Experimental | Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 3 mg to determine the MTD. |
|
| Monotherapy: Alobresib 4 mg | Experimental | Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 4 mg to determine the MTD. |
|
| Monotherapy: Alobresib 6 mg | Experimental | Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 6 mg to determine the MTD. |
|
| Combination Therapy: Alobresib 2 mg + Exemestane | Experimental | Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with exemestane 25 mg. |
|
| Combination Therapy: Alobresib 2 mg + Fulvestrant | Experimental | Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with fulvestrant 500 mg. |
|
| Combination Therapy: Alobresib 3 mg + Fulvestrant | Experimental | Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 3 mg in combination with fulvestrant 500 mg. |
|
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/Exclusion criteria may apply.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) |
| Time Frame: | Baseline (Day 1) up to 28 days |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Pharmacokinetic (PK) Parameter: Cmax of Alobresib |
| 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) |
| Safety Issue: | |
| Description: | Cmax is defined as the maximum concentration of the drug. |
| Measure: | PK Parameter: Ctau of Alobresib |
| 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) |
| Safety Issue: | |
| Description: | Ctau is defined as the observed drug concentration at the end of the dosing interval. |
| Measure: | PK Parameter: AUC0-24 of Alobresib |
| 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) |
| Safety Issue: | |
| Description: | AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hrs. |
| Measure: | PK Parameter: AUCtau of Alobresib |
| 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) |
| Safety Issue: | |
| Description: | AUCtau is defined as the concentration of drug over time (the area under the concentration verses time curve over the dosing interval). |
| Measure: | PK Parameter: Tmax of Alobresib |
| 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) |
| Safety Issue: | |
| Description: | Tmax is defined as the time (observed time point) of Cmax. |
| Measure: | PK Parameter: t1/2 of Alobresib |
| 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) |
| Safety Issue: | |
| Description: | 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. |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Gilead Sciences |
December 29, 2020
