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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

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ClinicalTrials.gov Identifier: NCT02392611
Recruitment Status : Completed
First Posted : March 19, 2015
Results First Posted : December 29, 2020
Last Update Posted : December 29, 2020
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Solid Tumors and Lymphomas Drug: Alobresib Drug: Exemestane Drug: Fulvestrant Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 16, 2015
Actual Primary Completion Date : October 11, 2017
Actual Study Completion Date : October 11, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Monotherapy: Alobresib 0.6 mg
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
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Experimental: Monotherapy: Alobresib 1.4 mg
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
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Experimental: Monotherapy: Alobresib 2 mg
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
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Experimental: Monotherapy: Alobresib 3 mg
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
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Experimental: Monotherapy: Alobresib 4 mg
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
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Experimental: Monotherapy: Alobresib 6 mg
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
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Experimental: Combination Therapy: Alobresib 2 mg + 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.
Drug: Alobresib
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Drug: Exemestane
Tablets administered orally once daily on Cycle 1 Day 1 of 28 days cycle
Other Name: Aromasin®

Experimental: Combination Therapy: Alobresib 2 mg + 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.
Drug: Alobresib
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Drug: Fulvestrant
Administered intramuscularly on Cycle 1 Day 1 of 28 days cycle and every 28 days
Other Name: Faslodex®

Experimental: Combination Therapy: Alobresib 3 mg + 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.
Drug: Alobresib
Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle
Other Name: GS-5829

Drug: Fulvestrant
Administered intramuscularly on Cycle 1 Day 1 of 28 days cycle and every 28 days
Other Name: Faslodex®




Primary Outcome Measures :
  1. Number of Participants Experiencing Dose Limiting Toxicities (DLTs) [ Time Frame: 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 :
  1. 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) ]
    Cmax is defined as the maximum concentration of the drug.

  2. 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) ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

  3. 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) ]
    AUC0-24 is defined as the concentration of drug over time from time zero to time 24 hrs.

  4. 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) ]
    AUCtau is defined as the concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

  5. 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) ]
    Tmax is defined as the time (observed time point) of Cmax.

  6. 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) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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/Exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02392611


Locations
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United States, Arizona
Scottsdale, Arizona, United States
United States, Indiana
Fort Wayne, Indiana, United States
Goshen, Indiana, United States
United States, Texas
San Antonio, Texas, United States
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol  [PDF] June 20, 2016
Statistical Analysis Plan  [PDF] January 3, 2018

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02392611    
Other Study ID Numbers: GS-US-350-1599
2016-001912-39 ( EudraCT Number )
First Posted: March 19, 2015    Key Record Dates
Results First Posted: December 29, 2020
Last Update Posted: December 29, 2020
Last Verified: December 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gilead Sciences:
Estrogen Receptor Positive Breast Cancer
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Fulvestrant
Exemestane
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action