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

Phase 1

Completed

• Conditions: Solid Tumors and Lymphomas
• Interventions: Drug: Alobresib; Drug: Exemestane; Drug: Fulvestrant

• Registration Number: NCT02392611
• Lead Sponsor: Gilead Sciences

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-03-13
• Study First Submitted QC: 2015-03-13
• Study Start: 2015-03-16
• Study First Posted: 2015-03-19
• Primary Completion: 2017-10-11
• Study Completion: 2017-10-11
• Status Verified: 2020-12
• Results First Submitted: 2020-12-02
• Results First Submitted QC: 2020-12-02
• Last Update Submitted: 2020-12-02
• Results First Posted: 2020-12-29
• Last Update Posted: 2020-12-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 33

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Monotherapy: Alobresib 0.6 mg	Alobresib	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.
Combination Therapy: Alobresib 2 mg + Exemestane	Exemestane	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	Fulvestrant	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	Fulvestrant	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.
Monotherapy: Alobresib 1.4 mg	Alobresib	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	Alobresib	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	Alobresib	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	Alobresib	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.
Combination Therapy: Alobresib 2 mg + Exemestane	Alobresib	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.
Monotherapy: Alobresib 6 mg	Alobresib	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 + Fulvestrant	Alobresib	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	Alobresib	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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: 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: 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).
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: 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.
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.