A Phase 1b/2 Study of GS-5829 in Combination With Fulvestrant or Exemestane in Subjects With Advanced Estrogen Receptor Positive, HER2 Negative-Breast Cancer

The primary objectives of the Phase 1b Dose Escalation part of this study are to characterize the safety and tolerability of GS-5829 in combination with exemestane or fulvestrant and to determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose of GS-5829 in combination with fulvestrant in women with advanced estrogen receptor positive, HER2-negative (ER+/HER2-) breast cancer.
The primary objective of the Randomized Phase 2 Dose Expansion portion of this study is to evaluate the efficacy of GS-5829 in combination with fulvestrant compared to fulvestrant alone in women with advanced ER+/HER2- breast cancer.
This study was terminated early and the Phase 2 portion of the study was not conducted.

Start Date10 Jan 2017

Sponsor / Collaborator

Gilead Sciences, Inc.

NCT02607228 / TerminatedPhase 1/2

A Phase 1b/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Subjects With Metastatic Castrate-Resistant Prostate Cancer

This study consists of two phases: Dose Escalation (Phase 1b) and Dose Expansion (Phase 2)
The Dose Escalation phase will characterize the safety, tolerability, and determine the maximum tolerated dose (MTD) of alobresib as a single agent and in combination with enzalutamide, in participants with metastatic castrate-resistant prostate cancer (mCRPC).
The Dose Expansion phase will evaluate the following:
In group 1, the efficacy of alobresib as a single agent in participants with mCRPC who have progressed while receiving enzalutamide (may have also received abiraterone)
In group 2, the efficacy of alobresib combined with enzalutamide in participants with mCRPC who have progressed while receiving treatment with abiraterone (may not have previously received enzalutamide)
In group 3, the efficacy of alobresib combined with enzalutamide in participants with mCRPC who have had prostate specific antigen (PSA) progression, but not radiographic progression, while receiving treatment with enzalutamide (participants may have also previously received abiraterone)

Start Date08 Dec 2015

Sponsor / Collaborator

Gilead Sciences, Inc.

NCT02392611 / CompletedPhase 1

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

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.

Start Date16 Mar 2015

Sponsor / Collaborator

Gilead Sciences, Inc.

100 Clinical Results associated with Alobresib

100 Translational Medicine associated with Alobresib

100 Patents (Medical) associated with Alobresib

Literatures (Medical) associated with Alobresib

15 Sep 2022·Clinical Cancer Research

Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

Article

Author: Aggarwal, Rahul ; Starodub, Alexander N. ; Koh, Brian D. ; Xing, Guan ; Armstrong, Andrew J. ; Carducci, Michael A.

AbstractPurpose:A phase Ib study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extraterminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A phase I study (1599) in solid tumors/lymphoma was also conducted.Patients and Methods:Men with confirmed mCRPC and disease progression despite abiraterone and/or enzalutamide treatment were enrolled in a 3 + 3 dose escalation paradigm starting at 2 mg daily with GS-5829 alone and in combination with 160 mg daily enzalutamide. The primary efficacy endpoint was nonprogression rate at week 24; secondary endpoints included prostate-specific antigen reduction from baseline, progression-free survival, and GS-5829 pharmacokinetics (PK). PK and safety were also evaluated in Study 1599.Results:Thirty-one men, with a median of five prior regimens, received at least 1 dose of study drug in Study 1604. Treatment-emergent adverse events (TEAE) were reported in 94% of patients; 16% discontinued for TEAEs. There were no dose-dependent increases in the AUCtau or Cmax after once-daily administration of GS-5829 2 to 9 mg, and biomarkers CCR2 inhibition and HEXIM1 induction were increased only at higher doses of monotherapy. A high degree of interpatient variability existed across all doses in PK and pharmacodynamic parameters. The proportion with nonprogression at week 24, estimated by Kaplan–Meier model, was 25% (95% confidence interval, 10–42) for all treated patients.Conclusions:GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose proportional increases in plasma concentrations in patients with mCRPC.

01 Jun 2020·LeukemiaQ1 · MEDICINE

The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment

Q1 · MEDICINE

Article

Author: Estrov, Zeev ; Keating, Michael J ; Thompson, Philip A ; Sivina, Mariela ; Clarke, Astrid ; Burger, Jan A ; Ferrajoli, Alessandra ; Kim, Ekaterina ; Jain, Nitin ; Wierda, William G ; Bhalla, Kapil N ; Ten Hacken, Elisa

Despite major improvements in treatment outcome with novel targeted therapies, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, chronic lymphocytic leukemia (CLL) remains incurable in the majority of patients. Activation of PI3K, NF-κB, and/or MYC has been linked to residual disease and/or resistance in ibrutinib-treated patients. These pathways can be targeted by inhibitors of bromodomain and extra-terminal (BET) proteins. Here we report about the preclinical activity of GS-5829, a novel BET inhibitor, in CLL. GS-5829 inhibited CLL cell proliferation and induced leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. IκBα modulation indicates that GS-5829 also inhibited NF-κB signaling. GS-5829-induced apoptosis resulted from an imbalance between positive (BIM) and negative regulators (BCL-X_L) of the intrinsic apoptosis pathway. The antileukemia activity of GS-5829 increased synergistically in combinations with B-cell receptor signaling inhibitors, the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, and the SYK inhibitor entospletinib. In cocultures that mimic the lymph node microenvironment, GS-5829 inhibited signaling pathways within nurselike cells and their growth, indicating that BET inhibitors also can target the supportive CLL microenvironment. Collectively, these data provide a rationale for the clinical evaluation of BET inhibitors in CLL.

01 Oct 2018·Clinical Cancer ResearchQ1 · MEDICINE

Inhibition of BET Bromodomain Proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a Biologically Aggressive Variant of Endometrial Cancer

Q1 · MEDICINE

Article

Author: Azodi, Masoud ; Manzano, Aranzazu ; Riccio, Francesco ; Altwerger, Gary ; Schwartz, Peter E. ; Han, Chanhee ; Schlessinger, Joseph ; Zammataro, Luca ; Menderes, Gulden ; Bellone, Stefania ; Ratner, Elena ; Yadav, Ghanshyam ; Silasi, Dan-Arin ; Wong, Serena ; Pettinella, Francesca ; Cocco, Emiliano ; Santin, Alessandro D. ; Bianchi, Anna ; Litkouhi, Babak ; Lopez, Salvatore ; Bonazzoli, Elena ; Huang, Gloria S. ; Predolini, Federica ; Hui, Pei ; Buza, Natalia ; Manara, Paola

AbstractPurpose: Uterine serous carcinoma (USC) is a rare and aggressive variant of endometrial cancer. Whole-exome sequencing (WES) studies have recently reported c-Myc gene amplification in a large number of USCs, suggesting c-Myc as a potential therapeutic target. We investigated the activity of novel BET bromodomain inhibitors (GS-5829 and GS-626510, Gilead Sciences Inc.) and JQ1 against primary USC cultures and USC xenografts.Experimental Design: We evaluated c-Myc expression by qRT-PCR in a total of 45 USCs including fresh-frozen tumor tissues and primary USC cell lines. We also performed IHC and Western blot experiments in 8 USC tumors. USC cultures were evaluated for sensitivity to GS-5829, GS-626510, and JQ1 in vitro using proliferation, viability, and apoptosis assays. Finally, the in vivo activity of GS-5829, GS-626510, and JQ1 was studied in USC-ARK1 and USC-ARK2 mouse xenografts.Results: Fresh-frozen USC and primary USC cell lines overexpressed c-Myc when compared with normal tissues (P = 0.0009 and 0.0083, respectively). High c-Myc expression was found in 7 of 8 of primary USC cell lines tested by qRT-PCR and 5 of 8 tested by IHC. In vitro experiments demonstrated high sensitivity of USC cell lines to the exposure to GS-5829, GS-626510, and JQ1 with BET inhibitors causing a dose-dependent decrease in the phosphorylated levels of c-Myc and a dose-dependent increase in caspase activation (apoptosis). In comparative in vivo experiments, GS-5829 and/or GS-626510 were found more effective than JQ1 at the concentrations/doses used in decreasing tumor growth in both USC-ARK1 and USC-ARK2 mouse xenograft models.Conclusions: GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy-resistant USC-overexpressing c-Myc. Clinical studies with GS-5829 in patients with USC harboring chemotherapy-resistant disease are warranted. Clin Cancer Res; 24(19); 4845–53. ©2018 AACR.

News (Medical) associated with Alobresib

01 Aug 2022

·www.prnewswire.com

BridGene Biosciences names David Sperandio, Ph.D., as Head of Chemistry

SAN JOSE, Calif., Aug. 1, 2022 /PRNewswire/ -- BridGene Biosciences, Inc., a biotechnology company using a proprietary chemoproteomics technology to discover and develop small molecules for high value, traditionally undruggable targets, today announced that David Sperandio, Ph.D., a medicinal chemist with more than 20 years' experience, has joined the company as the Head of Chemistry. Dr. Sperandio, an inventor on 23 patents and author of 25 peer-reviewed publications, has extensive experience leading cross-functional teams from molecule discovery through IND filing. Dr. Sperandio will lead the BridGene chemistry team and supervise research into covalent chemistry, chemical proteomics and quantitative mass spectrometry as methods for identifying undruggable targets. Additionally, Dr. Sperandio will be responsible for advancing BridGene's internal pipeline of first-in-class drugs for hard-to-drug targets in oncology. BridGene co-founder and CEO Ping Cao, Ph.D., commented, "David's addition to our leadership team and the recent Series B financing deepen BridGene's capabilities for using IMTAC™ to discover new drugs for novel and traditionally undruggable targets. David's leadership and experience will help expand BridGene's library of molecules to identify as potential drug candidates as we aim to advance a pipeline of first-in-class drugs for these new targets." Dr. Sperandio most recently served as an Executive Director at Biomea Fusion, where he led the team that identified BMF-500, a potential best-in-class targeted covalent FLT-3 inhibitor for the treatment of acute myeloid leukemia. Prior to joining Biomea Fusion, Sperandio led a collaboration of R2M Pharma Inc. with Tenaya Therapeutics Inc., which discovered novel HDAC6 inhibitors for cardiovascular diseases and was key for the clinical development of TN-301, an experimental treatment for heart failure. Dr. Sperandio started his career at Celera Corp. and focused on the structure-guided discovery of covalent reversible serine-protease inhibitors. He later moved to Gilead Sciences Inc., where he led the chemistry team that discovered Alobresib (GS-5829), a novel BRD4 inhibitor for prostate cancer, and Presatorvir (GS-5806), the first small molecule RSV fusion inhibitor that reached the clinic and showed proof of concept in men. Dr. Sperandio commented, "I am excited to join BridGene at such a dynamic time for the company. 2022 has been a remarkable year so far, and I look forward to working closely with the management team to continue to drive the success of IMTAC™." Dr. Sperandio obtained his doctoral degree in Organic Chemistry from the University of Zurich and completed his postdoctoral research at Stanford University. About BridGene Biosciences BridGene is a biotechnology company focused on discovering and developing innovative small molecules that drug traditionally undruggable targets, providing new paths to treat diseases. By using its proprietary chemoproteomics platform, IMTAC™, BridGene can screen small molecules against proteins in live cells to discover drug candidates for high value and traditionally undruggable targets. For this purpose, BridGene takes advantage of its proprietary, diverse library of tagged, drug-like small molecules. The ultimate goal is to enable breakthrough small molecule drug discovery with expanded mechanisms to treat diseases with targets previously inaccessible to small molecules. The uniqueness of BridGene's technology allows it to perform IMTAC™ screening for both covalent and non-covalent molecules, target different amino acids and discover new targets for disease treatments by deconvoluting phenotypic screening hits. The company is advancing a diversified pipeline of first-in-class drugs for targets in multiple disease areas. For more information, visit . Contact Tiberend Strategic Advisors, Inc. Investors Jonathan Nugent +1-205-566-3026 [email protected] Media Bill Borden +1-732-910-1620 [email protected] Dave Schemelia +1-609-468-9325 [email protected] SOURCE BridGene Biosciences

CollaborateFirst in ClassSmall molecular drug

29 Jul 2021

·www.globenewswire.com

Kura Oncology Appoints Helen Collins, MD to Board of

SAN DIEGO, July 29, 2021 (GLOBE NEWSWIRE) -- Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, today announced the appointment of industry veteran Helen Collins, M.D., to its board of directors. Dr. Collins served as Chief Medical Officer at Five Prime Therapeutics, where she oversaw the development of bemarituzumab, a first-in-class anti-FGFR2b antibody for the treatment of patients with gastric cancer. “With a deep background in medical oncology/hematology and significant experience leading clinical development programs targeting cancers of high unmet need, Helen brings a valuable perspective to the board as we continue to advance our pipeline of precision medicines,” said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. “On behalf of Kura Oncology and our board of directors, we want to welcome her to the board and look forward to drawing upon her strategic and clinical acumen as we work to fulfill our mission of bringing new treatment options to patients.” Dr. Collins joins the Kura board of directors with more than 25 years of medical experience. Most recently, she served as Executive Vice President and Chief Medical Officer at Five Prime Therapeutics, where she was responsible for the strategy and execution of the company’s clinical development plans until its acquisition by Amgen in April 2021. Previously, Dr. Collins held positions of increasing responsibility at Gilead Sciences, most recently as Program and Clinical Lead for Gilead’s GS-5829 (BET inhibitor) and GS-4059 (BTK inhibitor) programs, and Amgen, most recently as Global Lead of Oncology Biosimilars. Prior to her career in the biopharma industry, Dr. Collins practiced as a medical oncologist/hematologist for 12 years. She earned her M.D. from Johns Hopkins University School of Medicine, completing her residency at Johns Hopkins Hospital and oncology fellowship at Stanford University School of Medicine, and her B.A. from Bryn Mawr College. “I’m pleased to join the Kura board of directors as the company continues to build on the strong foundation of its clinical and preclinical pipeline,” said Dr. Collins. “I am impressed by the preliminary data from the menin inhibitor program, KO-539, in acute myeloid leukemia, as well as the broad therapeutic potential of the tipifarnib program, and I look forward to contributing to their continued progress and success.” About Kura Oncology Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer. The Company’s pipeline consists of small molecule drug candidates that target cancer signaling pathways. KO-539, a potent and selective menin inhibitor, is currently in a Phase 1/2 clinical trial (KOMET-001) and targeting patients with relapsed/refractory acute myeloid leukemia, including patients with NPM1 mutations. Tipifarnib, a potent, selective and orally bioavailable farnesyl transferase inhibitor, has received Breakthrough Therapy Designation for the treatment of patients with HRAS mutant head and neck squamous cell carcinoma (HNSCC) and is currently in a registration-directed study (AIM-HN) in patients with this devastating disease. In addition, Kura is pursuing the use of tipifarnib in combination with other oncology therapeutics to address larger genetic subsets, including patients who have HRAS and/or PIK3CA-dependent HNSCC. The Company is also developing a next-generation farnesyl transferase inhibitor, which is intended to target innovative biology and larger oncology indications through rational combinations. For additional information about Kura, please visit the Company’s website at . Forward-Looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and therapeutic potential of Kura’s drug candidates, tipifarnib and KO-539, progress and expected timing of Kura’s drug development programs and clinical trials and submission of regulatory filings, the presentation of data from clinical trials, plans regarding regulatory filings and future clinical trials, the regulatory approval path for tipifarnib, the strength of Kura’s balance sheet and the adequacy of cash on hand. Factors that may cause actual results to differ materially include the risk that compounds that appeared promising in early research or clinical trials do not demonstrate safety and/or efficacy in later preclinical studies or clinical trials, the risk that Kura may not obtain approval to market its drug candidates, uncertainties associated with performing clinical trials, regulatory filings, applications and other interactions with regulatory bodies, the risks associated with reliance on third parties to successfully conduct clinical trials, the risks associated with reliance on outside financing to meet capital requirements, the risks associated with the COVID-19 global pandemic, and other risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "believes," "estimates," "projects," "promise," "potential," "expects," "plans," "anticipates," "intends," "continues," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to the Company's periodic and other filings with the Securities and Exchange Commission, which are available at . Such forward-looking statements are current only as of the date they are made, and Kura assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts Company:Pete De SpainVice President, Investor Relations &Corporate Communications(858) 500-8803pete@kuraoncology.com Investors:Robert H. UhlManaging DirectorWestwicke ICR(858) 356-5932robert.uhl@westwicke.com Media:Jason SparkManaging DirectorCanale Communications(619) 849-6005jason@canalecomm.com

AntibodyBreakthrough TherapyBiosimilarFirst in ClassSmall molecular drug

100 Deals associated with Alobresib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 3	US	Gilead Sciences, Inc.	10 Jan 2017
ER-positive/HER2-negative Breast Cancer	Phase 3	US	Gilead Sciences, Inc.	10 Jan 2017
ER-positive/HER2-positive Breast Cancer	Phase 3	US	Gilead Sciences, Inc.	10 Jan 2017
Castration-Resistant Prostatic Cancer	Phase 3	US	Gilead Sciences, Inc.	08 Dec 2015
Advanced Malignant Solid Neoplasm	Phase 2	US	Gilead Sciences, Inc.	16 Mar 2015
Prostatic Cancer	Phase 2	-	Gilead Sciences, Inc.	-
Diffuse Large B-Cell Lymphoma	Phase 1	-	Gilead Sciences, Inc.	-
Estrogen receptor positive breast cancer	Discovery	US	Gilead Sciences, Inc.	16 Mar 2015
Lymphoma	Discovery	US	Gilead Sciences, Inc.	16 Mar 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02607228 (Pubmed) Manual	Phase 1	Metastatic castration-resistant prostate cancer	31	GS-5829	(udpwftoprb) = nfvrjlmlau eemipfgaiz (fhakhlnroe, 10 - 42) View more	Negative	11 Jul 2022
NCT02392611 (CTgov)	Phase 1	Advanced Malignant Solid Neoplasm \| Estrogen receptor positive breast cancer \| Lymphoma	33	Alobresib (Monotherapy: Alobresib 0.6 mg)	rledqdhmic(bjeekhmnwo) = npewowezki rockpwkksb (dglpvaviuh, ufpswtwjlj - wwekmlgort) View more	-	29 Dec 2020
				Alobresib (Monotherapy: Alobresib 1.4 mg)	rledqdhmic(bjeekhmnwo) = cyuowcllke rockpwkksb (dglpvaviuh, bdyvajrpaq - bflslgvakv) View more
NCT02607228 (CTgov)	Phase 1/2	Castration-Resistant Prostatic Cancer	31	Alobresib (Monotherapy: Alobresib 2 mg)	xixgspzviz(pgzumswvmf) = klrjtrzeke mhnzygyoug (kasrfcpnfk, xzirmrshyh - nbofwxrgrz) View more	-	08 Dec 2020
				Alobresib (Monotherapy: Alobresib 3 mg)	xixgspzviz(pgzumswvmf) = xpajmfoyxm mhnzygyoug (kasrfcpnfk, ryedyzccvf - khrjcnlski) View more
NCT02983604 (CTgov)	Phase 1/2	ER-positive/HER2-positive Breast Cancer \| ER-positive/HER2-negative Breast Cancer	14	Exemestane+GS-5829 (GS-5829 4 mg + Exemestane)	ddiawwliwc(zghosvyvhl) = zoatrsxgtn owedewplae (psmewfgfyb, onengqhsbm - phsanhftaf) View more	-	07 Aug 2019
				Fulvestrant+GS-5829 (GS-5829 4 mg + Fulvestrant)	ddiawwliwc(zghosvyvhl) = nxfjafwibf owedewplae (psmewfgfyb, mnbinlohse - rlgsnsvtek) View more

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