Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alobresib (Formerly GS-5829) in Adults With Advanced Solid Tumors and Lymphomas and in Combination With Exemestane or Fulvestrant in Adults With Estrogen Receptor Positive Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alobresib (Formerly GS-5829) as a Monotherapy in Subjects With Advanced Solid Tumors and Lymphomas and in Combination With Exemestane or Fulvestrant in Subjects With Estrogen Receptor Positive Breast Cancer

Conditions
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Solid Tumors and Lymphomas

Intervention / Treatment
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* Drug: Alobresib
* Drug: Exemestane
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy: Alobresib 0.6 mg<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;|
| Experimental: Monotherapy: Alobresib 1.4 mg<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;|
| Experimental: Monotherapy: Alobresib 2 mg<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;|
| Experimental: Monotherapy: Alobresib 3 mg<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;|
| Experimental: Monotherapy: Alobresib 4 mg<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;|
| Experimental: Monotherapy: Alobresib 6 mg<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;|
| Experimental: Combination Therapy: Alobresib 2 mg + Exemestane<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;Drug: Exemestane<br>* Tablets administered orally once daily on Cycle 1 Day 1 of 28 days cycle<br>* Other names: Aromasin®;|
| Experimental: Combination Therapy: Alobresib 2 mg + Fulvestrant<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;Drug: Fulvestrant<br>* Administered intramuscularly on Cycle 1 Day 1 of 28 days cycle and every 28 days<br>* Other names: Faslodex®;|
| Experimental: Combination Therapy: Alobresib 3 mg + Fulvestrant<br>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. | Drug: Alobresib<br>* Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle<br>* Other names: GS-5829;Drug: Fulvestrant<br>* Administered intramuscularly on Cycle 1 Day 1 of 28 days cycle and every 28 days<br>* Other names: Faslodex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Day 1) up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: Cmax of Alobresib | Cmax is defined as the maximum concentration of the drug. | 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) | 
| PK Parameter: Ctau of Alobresib | Ctau is defined as the observed drug concentration at the end of the dosing interval. | 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) | 
| PK Parameter: AUC0-24 of Alobresib | AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hrs. | 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) | 
| 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). | 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) | 
| PK Parameter: Tmax of Alobresib | Tmax is defined as the time (observed time point) of Cmax. | 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) | 
| 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. | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estrogen Receptor Positive Breast Cancer