NCT02392611

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

Completed Phase 1 Results posted Last updated 29 December 2020

What this trial tests

Phase 1 trial testing Alobresib in Solid Tumors and Lymphomas in 33 participants. Completed in 11 October 2017.

Timeline

16 March 2015

Primary endpoint
11 October 2017

11 October 2017

Quick facts

Lead sponsor	Gilead Sciences
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	33
Start date	16 March 2015
Primary completion	11 October 2017
Estimated completion	11 October 2017
Sites	4 locations across United States

Drugs / interventions tested

• Alobresib — full drug profile →
• Exemestane (exemestane) — full drug profile →
• Fulvestrant (fulvestrant) — full drug profile →

Conditions studied

• Solid Tumors and Lymphomas — all drugs for Solid Tumors and Lymphomas →

Sponsor

Gilead Sciences — full company profile →

Who can join

18 and older, any sex, with Solid Tumors and Lymphomas. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants Experiencing Dose Limiting Toxicities (DLTs) Primary · 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

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	0
Monotherapy: Alobresib 1.4 mg	0
Monotherapy: Alobresib 2 mg	0
Monotherapy: Alobresib 3 mg	1
Monotherapy: Alobresib 4 mg	1
Monotherapy: Alobresib 6 mg	2
Combination Therapy: Alobresib 2 mg + Exemestane	0
Combination Therapy: Alobresib 2 mg + Fulvestrant	0
Combination Therapy: Alobresib 3 mg + Fulvestrant	1

Pharmacokinetic (PK) Parameter: Cmax of Alobresib Secondary · 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.

Cycle 1 Day 1

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	35.2	± 7.21
Monotherapy: Alobresib 1.4 mg	59.1
Monotherapy: Alobresib 2 mg	141.0
Monotherapy: Alobresib 3 mg	197.5	± 109.97
Monotherapy: Alobresib 4 mg	281.7	± 98.78
Monotherapy: Alobresib 6 mg	376.2	± 257.22
Combination Therapy: Alobresib 2 mg + Exemestane	160.8	± 7.93
Combination Therapy: Alobresib 2 mg + Fulvestrant	149.7	± 27.47
Combination Therapy: Alobresib 3 mg + Fulvestrant	234.3	± 70.49

Cycle 1 Day 8

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	64.0	± 26.80
Monotherapy: Alobresib 1.4 mg	117.0
Monotherapy: Alobresib 2 mg	174.0
Monotherapy: Alobresib 3 mg	296.5	± 199.49
Monotherapy: Alobresib 4 mg	407.2	± 154.29
Monotherapy: Alobresib 6 mg	711.5	± 350.84
Combination Therapy: Alobresib 2 mg + Exemestane	193.0	± 68.56
Combination Therapy: Alobresib 2 mg + Fulvestrant	278.0	± 95.69
Combination Therapy: Alobresib 3 mg + Fulvestrant	458.7	± 29.48

PK Parameter: Ctau of Alobresib Secondary · 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.

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	14.7	± 0.28
Monotherapy: Alobresib 1.4 mg	60.7
Monotherapy: Alobresib 2 mg	34.4
Monotherapy: Alobresib 3 mg	131.0	± 149.21
Monotherapy: Alobresib 4 mg	168.4	± 165.71
Monotherapy: Alobresib 6 mg	237.1	± 167.31
Combination Therapy: Alobresib 2 mg + Exemestane	44.2	± 21.62
Combination Therapy: Alobresib 2 mg + Fulvestrant	59.4	± 36.80
Combination Therapy: Alobresib 3 mg + Fulvestrant	170.0	± 39.00

PK Parameter: AUC0-24 of Alobresib Secondary · 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.

Cycle 1 Day 1

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	699.5	± 392.28
Monotherapy: Alobresib 1.4 mg	1896.1
Monotherapy: Alobresib 2 mg	1413.2
Monotherapy: Alobresib 3 mg	2336.1	± 1125.80
Monotherapy: Alobresib 4 mg	2692.1	± 834.79
Monotherapy: Alobresib 6 mg	6347.4	± 4602.91
Combination Therapy: Alobresib 2 mg + Exemestane	1549.0	± 498.72
Combination Therapy: Alobresib 2 mg + Fulvestrant	1900.9	± 363.22
Combination Therapy: Alobresib 3 mg + Fulvestrant	3038.5	± 263.15

Cycle 1 Day 8

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	640.0	± 101.99
Monotherapy: Alobresib 1.4 mg	1838.5
Monotherapy: Alobresib 2 mg	1603.3
Monotherapy: Alobresib 3 mg	4430.5	± 3776.16
Monotherapy: Alobresib 4 mg	5584.5	± 3121.02
Monotherapy: Alobresib 6 mg	9432.2	± 6278.61
Combination Therapy: Alobresib 2 mg + Exemestane	1752.6	± 485.84
Combination Therapy: Alobresib 2 mg + Fulvestrant	2525.7	± 1091.23
Combination Therapy: Alobresib 3 mg + Fulvestrant	5665.1	± 596.00

PK Parameter: AUCtau of Alobresib Secondary · 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).

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	643.3	± 109.40
Monotherapy: Alobresib 1.4 mg	1838.5
Monotherapy: Alobresib 2 mg	1591.8
Monotherapy: Alobresib 3 mg	4391.7	± 3716.47
Monotherapy: Alobresib 4 mg	4128.5	± 333.78
Monotherapy: Alobresib 6 mg	9373.8	± 6220.97
Combination Therapy: Alobresib 2 mg + Exemestane	1750.8	± 478.46
Combination Therapy: Alobresib 2 mg + Fulvestrant	2514.3	± 1097.14
Combination Therapy: Alobresib 3 mg + Fulvestrant	5644.0	± 603.80

PK Parameter: Tmax of Alobresib Secondary · 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.

Cycle 1 Day 1

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	2.1	2.0 – 2.1
Monotherapy: Alobresib 1.4 mg	4.0	4.0 – 4.0
Monotherapy: Alobresib 2 mg	0.5	0.5 – 0.5
Monotherapy: Alobresib 3 mg	2.0	0.6 – 4.1
Monotherapy: Alobresib 4 mg	0.5	0.4 – 1.0
Monotherapy: Alobresib 6 mg	4.1	1.1 – 4.2
Combination Therapy: Alobresib 2 mg + Exemestane	0.5	0.5 – 6.1
Combination Therapy: Alobresib 2 mg + Fulvestrant	6.1	0.6 – 24.1
Combination Therapy: Alobresib 3 mg + Fulvestrant	1.1	0.5 – 5.9

Cycle 1 Day 8

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	1.3	0.6 – 2.1
Monotherapy: Alobresib 1.4 mg	0.6	0.6 – 0.6
Monotherapy: Alobresib 2 mg	0.5	0.5 – 0.5
Monotherapy: Alobresib 3 mg	1.0	0.4 – 4.0
Monotherapy: Alobresib 4 mg	0.9	0.5 – 2.1
Monotherapy: Alobresib 6 mg	0.8	0.5 – 2.0
Combination Therapy: Alobresib 2 mg + Exemestane	0.5	0.5 – 0.6
Combination Therapy: Alobresib 2 mg + Fulvestrant	0.5	0.5 – 0.6
Combination Therapy: Alobresib 3 mg + Fulvestrant	0.5	0.4 – 1.0

PK Parameter: t1/2 of Alobresib Secondary · 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.

Cycle 1 Day 1

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	16.6	11.1 – 22.0
Monotherapy: Alobresib 1.4 mg	35.3	35.3 – 35.3
Monotherapy: Alobresib 2 mg	15.8	15.8 – 15.8
Monotherapy: Alobresib 3 mg	20.2	9.9 – 35.1
Monotherapy: Alobresib 4 mg	19.2	7.2 – 26.6
Monotherapy: Alobresib 6 mg	21.1	7.4 – 34.9
Combination Therapy: Alobresib 2 mg + Exemestane	13.5	10.1 – 14.2
Combination Therapy: Alobresib 2 mg + Fulvestrant	23.4	16.1 – 30.7
Combination Therapy: Alobresib 3 mg + Fulvestrant	15.2	14.7 – 15.8

Cycle 1 Day 8

Group	Value	95% CI
Monotherapy: Alobresib 0.6 mg	13.7	13.1 – 14.4
Monotherapy: Alobresib 1.4 mg	28.7	28.7 – 28.7
Monotherapy: Alobresib 2 mg	15.9	15.9 – 15.9
Monotherapy: Alobresib 3 mg	16.8	10.6 – 27.8
Monotherapy: Alobresib 4 mg	16.1	10.5 – 22.8
Monotherapy: Alobresib 6 mg	17.8	8.4 – 18.8
Combination Therapy: Alobresib 2 mg + Exemestane	14.0	11.4 – 23.8
Combination Therapy: Alobresib 2 mg + Fulvestrant	22.0	11.4 – 33.9
Combination Therapy: Alobresib 3 mg + Fulvestrant	22.3	20.0 – 24.5

Adverse events — posted to ClinicalTrials.gov

Time frame: First dose date up to 30 days after last dose of study drug (up to approximately 60.3 weeks for monotherapy groups and 42 weeks for combination therapy groups). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Monotherapy: Alobresib 0.6 mg

Serious: 1/2 (50%)

Deaths: 1/2

Monotherapy: Alobresib 1.4 mg

Serious: 1/1 (100%)

Deaths: 0/1

Monotherapy: Alobresib 2 mg

Serious: 0/1 (0%)

Deaths: 0/1

Monotherapy: Alobresib 3 mg

Serious: 3/7 (43%)

Deaths: 1/7

Monotherapy: Alobresib 4 mg

Serious: 2/6 (33%)

Deaths: 0/6

Monotherapy: Alobresib 6 mg

Serious: 1/4 (25%)

Deaths: 1/4

Combination Therapy: Alobresib 2 mg + Exemestane

Serious: 0/4 (0%)

Deaths: 1/4

Combination Therapy: Alobresib 2 mg + Fulvestrant

Serious: 0/3 (0%)

Deaths: 0/3

Combination Therapy: Alobresib 3 mg + Fulvestrant

Serious: 0/3 (0%)

Deaths: 0/3

Serious adverse events (10 terms)

Reaction	System	Monotherapy: Alobresib 0.6…	Monotherapy: Alobresib 1.4…	Monotherapy: Alobresib 2 mg	Monotherapy: Alobresib 3 mg	Monotherapy: Alobresib 4 mg	Monotherapy: Alobresib 6 mg	Combination Therapy: Alobr…	Combination Therapy: Alobr…	Combination Therapy: Alobr…
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Atrioventricular block complete	Cardiac disorders	—	—	—	—	—	—	—	—	—
Adrenal haemorrhage	Endocrine disorders	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Pain	General disorders	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—
Cholangitis	Hepatobiliary disorders	—	—	—	—	—	—	—	—	—
Pyelonephritis acute	Infections and infestations	—	—	—	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—	—	—	—
Deep vein thrombosis	Vascular disorders	—	—	—	—	—	—	—	—	—

Other adverse events (93 terms — click to expand)

Reaction	System	Monotherapy: Alobresib 0.6…	Monotherapy: Alobresib 1.4…	Monotherapy: Alobresib 2 mg	Monotherapy: Alobresib 3 mg	Monotherapy: Alobresib 4 mg	Monotherapy: Alobresib 6 mg	Combination Therapy: Alobr…	Combination Therapy: Alobr…	Combination Therapy: Alobr…
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—	—	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Splenomegaly	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—	—	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—	—	—	—	—	—
Cataract	Eye disorders	—	—	—	—	—	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Ascites	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Flatulence	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Gastrointestinal sounds abnormal	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Gingival pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—
Catheter site pain	General disorders	—	—	—	—	—	—	—	—	—
Chest pain	General disorders	—	—	—	—	—	—	—	—	—
Generalised oedema	General disorders	—	—	—	—	—	—	—	—	—
Ill-defined disorder	General disorders	—	—	—	—	—	—	—	—	—
Injection site reaction	General disorders	—	—	—	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—
Hyperbilirubinaemia	Hepatobiliary disorders	—	—	—	—	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—	—	—	—	—
Localised infection	Infections and infestations	—	—	—	—	—	—	—	—	—
Oral candidiasis	Infections and infestations	—	—	—	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—	—	—	—

Most-reported serious reactions: Thrombocytopenia, Atrioventricular block complete, Adrenal haemorrhage, Constipation, Pain, Pyrexia, Cholangitis, Pyelonephritis acute.

Data from ClinicalTrials.gov NCT02392611 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy.
   Lu Y, Chan YT, Tan HY, Li S, et al · · 2020 · cited 318× · PMID 32340605 · DOI 10.1186/s12943-020-01197-3
2. Drug Discovery Targeting Bromodomain-Containing Protein 4.
   Liu Z, Wang P, Chen H, Wold EA, et al · · 2017 · cited 234× · PMID 28195723 · DOI 10.1021/acs.jmedchem.6b01761
3. Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy.
   Alqahtani A, Choucair K, Ashraf M, Hammouda DM, et al · · 2019 · cited 198× · PMID 30906568 · DOI 10.4155/fsoa-2018-0115
4. Bromodomain inhibitors and cancer therapy: From structures to applications.
   Pérez-Salvia M, Esteller M. · · 2017 · cited 197× · PMID 27911230 · DOI 10.1080/15592294.2016.1265710
5. Epigenetics-targeted drugs: current paradigms and future challenges.
   Dai W, Qiao X, Fang Y, Guo R, et al · · 2024 · cited 131× · PMID 39592582 · DOI 10.1038/s41392-024-02039-0
6. Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.
   Tang P, Zhang J, Liu J, Chiang CM, et al · · 2021 · cited 109× · PMID 33616410 · DOI 10.1021/acs.jmedchem.0c01487
7. Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg.
   Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, et al · · 2020 · cited 83× · PMID 33134907 · DOI 10.1016/j.jhepr.2020.100167
8. Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy.
   Manzotti G, Ciarrocchi A, Sancisi V. · · 2019 · cited 60× · PMID 30841549 · DOI 10.3390/cancers11030304