Delving into the Latest Updates on Samotolisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

Class I PI3K inhibitors(PI3-kinase class I inhibitors), mTOR inhibitors(Serine/threonine-protein kinase mTOR inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal Diseases

Active Indication

Metastatic Triple-Negative Breast CarcinomaMetastatic breast cancer

Inactive Indication

Advanced cancerColorectal CancerIndolent Non-Hodgkin Lymphoma+ [8]

Originator Organization

Eli Lilly & Co.

Active Organization

Eli Lilly & Co.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H26N4O3

InChIKeyACCFLVVUVBJNGT-AWEZNQCLSA-N

CAS Registry1386874-06-1

This research study is studying a combination of targeted therapies as a possible treatment for estrogen-receptor positive (ER+) endometrial cancer and low-grade serous ovarian cancer.
The drugs involved in this study are:
* Abemaciclib (also known as Verzenio™)
* Letrozole (also known as Femara®)
* Metformin (also known as Glucophage®)
* Zotatifin (also known as eFT226)

Start Date24 Dec 2018

Sponsor / Collaborator

Dana-Farber Cancer Institute, Inc.

[+2]

NCT03213678

/ Active, not recruitingPhase 2IIT

NCI-COG Pediatric MATCH (Molecular Analysis For Therapy Choice)- Phase 2 Subprotocol of LY3023414 in Patients With Solid Tumors

This phase II Pediatric MATCH trial studies how well samotolisib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with TSC or PI3K/MTOR mutations that have spread to other places in the body (metastatic) and have come back (recurrent) or do not respond to treatment (refractory). Samotolisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Start Date28 Nov 2017

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Samotolisib

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100 Translational Medicine associated with Samotolisib

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100 Patents (Medical) associated with Samotolisib

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33

Literatures (Medical) associated with Samotolisib

01 Jan 2025·Molecular Oncology

Assessments of prostate cancer cell functions highlight differences between a pan‐PI3K/mTOR inhibitor, gedatolisib, and single‐node inhibitors of the PI3K/AKT/mTOR pathway

Article

Author: Broege, Aaron ; Sen, Adrish ; Schulz, Stephen ; Iversrud, Charles ; Laing, Lance ; Kopher, Ross ; Seibel, Megan ; Molden, Jhomary ; MacNeil, Ian ; Rossetti, Stefano ; DeLaForest, Ann ; Davis, Laura ; Khan, Salmaan

Metastatic castration‐resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co‐targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi‐node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single‐node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti‐proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM‐controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN‐dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2− advanced breast cancer.

02 Oct 2024·Current Medical Research and Opinion

Efficacy and safety of interventions for metastatic castration resistant prostate cancer (mCRPC) patients progressing on androgen receptor-axis-targeted (ARAT) therapy: a systematic literature review

Review

Author: Gullapalli, Lakshmi ; Balijepalli, Chakrapani ; Joshy, Juhi ; Druyts, Eric ; Yan, Kevin ; Kotum, Sharon

BACKGROUNDTo review the literature to outline findings from clinical trials assessing interventions for metastatic castration-resistant prostate cancer (mCRPC) in patients who have progressed on androgen receptor-axis-targeted (ARAT) therapies.METHODSA systematic literature review was performed to identify trials that assessed the efficacy and safety of interventions used in patients that progressed on prior ARAT therapies. A literature search was conducted using the OVID platform that searched the EMBASE, MEDLINE, and CENTRAL bibliographic databases.RESULTSOf the 10,114 citations identified, a total of 36 studies representing 33 unique trials were included in the review. Of the 33 trials, 21 were randomized controlled trials and 12 were single-arm trials. A total of 11 were phase III trials, 13 were phase II trials, and 2 were phase I trials. The majority of included trials were open-label (n = 29) and the remaining were double-blind (n = 4). A total of 16 trials evaluated ARAT based therapies, 7 trials evaluated taxane-based treatments, 10 trials evaluated PARP inhibitors, 8 trials evaluated immunotherapies, and 8 trials evaluated other therapies (i.e. cabozantinib, mitoxantrone, radium-223,¹⁷⁷[Lu-177]-PNT2002,¹⁷⁷Lu-PSMA-617, samotolisib).CONCLUSIONSThis systematic review demonstrated there are limited effective treatment options in this patient population. Unlike other cancer types, immunotherapy agents appear to provide little to no benefit. Conversely, agents such as taxane-based chemotherapy (e.g. cabazitaxel) and radionuclide therapy provide the most value in this patient population. Further research is needed to explore new therapies in this disease area and to optimize existing treatment strategies with more effective combination therapies.

01 Sep 2024·JCO precision oncology

Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D.

Article

Author: Seibel, Nita L ; Ludwig, Kathleen ; Mhlanga, Joyce ; Weigel, Brenda J ; Coffey, Brent ; Piao, Jin ; Mooney, Margaret M ; Parsons, Donald Williams ; Hawkins, Douglas S ; Williams, P Mickey ; Fox, Elizabeth ; Berg, Stacey L ; Reid, Joel M ; Patton, David R ; Alonzo, Todd A ; Saguilig, Lauren ; Tricoli, James V ; Roy-Chowdhuri, Sinchita ; Laetsch, Theodore W ; Janeway, Katherine A ; Takebe, Naoko

PURPOSEPatients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.METHODSPatients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children.RESULTSA total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m²/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children.CONCLUSIONThis nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

100 Deals associated with Samotolisib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12167

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Triple-Negative Breast Carcinoma	Phase 2	US	Eli Lilly & Co.	05 Sep 2019
Recurrent Endometrial Cancer	Discovery	US	Eli Lilly & Co.	01 Sep 2015
metastatic non-small cell lung cancer	Discovery	US	Eli Lilly & Co.	01 Jul 2015
Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	Discovery	US	Eli Lilly & Co.	01 Jul 2015
squamous cell lung carcinoma	Discovery	US	Eli Lilly & Co.	01 Jul 2015
Metastatic castration-resistant prostate cancer	Discovery	US	Eli Lilly & Co.	29 Apr 2015
Metastatic Prostate Carcinoma	Discovery	US	Eli Lilly & Co.	29 Apr 2015
Squamous non-small cell lung cancer	Discovery	US	Eli Lilly & Co.	31 Jul 2012
Squamous non-small cell lung cancer	Discovery	PR	Eli Lilly & Co.	31 Jul 2012
Squamous non-small cell lung cancer	Discovery	IT	Eli Lilly & Co.	31 Jul 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03213678 (CTgov)	Phase 2	Refractory Central Nervous System Lymphoma \| Recurrent Medulloblastoma \| Ependymoma \| Relapsed Solid Neoplasm \| Non-Hodgkin's lymphoma refractory \| Advanced Malignant Solid Neoplasm \| Refractory Langerhans Cell Histiocytosis \| Wilms Tumor \| Malignant Histiocytic Disorders \| Refractory Malignant Germ Cell Tumor \| Rhabdomyosarcoma \| Refractory Malignant Solid Neoplasm \| Hepatoblastoma \| Rhabdoid Tumor \| Recurrent Glioma \| Neuroblastoma recurrent \| Osteosarcoma, Recurrent \| Recurrent Non-Hodgkin Lymphoma \| Recurrent Ewing Sarcoma \| Refractory Neuroblastoma	18	FDG-Positron Emission Tomography+Samotolisib	(fndbswmpxx) = okqtjcdqnz ehnspudafq (moyzkbjwti, txtapqxpgx - tazrsverjy) View more	-	04 Sep 2024
NCT02981342 (Pubmed \| Cancer Med)	Phase 2	Pancreatic adenocarcinoma metastatic PI3K \| mTOR	-	Abemaciclib	(nvrlptmfdi) = baqttvvbye ilvapdqckc (xfbstwlulq ) View more	Negative	01 Oct 2023
				Abemaciclib+LY3023414	(nvrlptmfdi) = axrcxakgbs ilvapdqckc (xfbstwlulq ) View more
NCT04032080 (CTgov)	Phase 2	Metastatic Triple-Negative Breast Carcinoma	10	Prexasertib+LY3023414	(eexqrimfia) = evddinzavv mozmczgqpi (stywcsqcrg, mzjqwmmzes - qsvsefpjpy) View more	-	11 Sep 2023
NCT02549989 (CTgov)	Phase 2	Recurrent Endometrial Cancer	28	LY3023414	(durfpraces) = ucbldeoevu pnwhswvysa (tlqfbnustp, obaxyxqqur - qltvhqvakt) View more	-	22 Feb 2023
NCT02407054 (Pubmed \| Clin Cancer Res)	Phase 1/2	Metastatic castration-resistant prostate cancer	142	Enzalutamide + Samotolisib	vmqznttljw(mxwzapztfi) = rgcsvkjhmc mmlsunzaux (nkqttwalnk ) View more	Positive	01 Apr 2022
				Placebo + Enzalutamide	vmqznttljw(mxwzapztfi) = crziexcevc mmlsunzaux (nkqttwalnk ) View more
NCT01655225 (Pubmed \| Invest New Drugs) Manual	Phase 1	Mesothelioma	42	LY3023414	(tnbqrdtkfr) = 200 mg twice daily（BID） wpekhmyjni (erimcwrqai ) View more	Positive	01 Aug 2021
NCT02407054 (CTgov)	Phase 2	Metastatic Prostate Carcinoma \| Metastatic castration-resistant prostate cancer	142	Enzalutamide+LY3023414 (Part B: 200 mg LY3023414 BID + 160 mg Enzalutamide QD)	txvgnwquom(uwkfugnrqk) = vkjqrxcrsn zbojgqbqia (xhlvyjzuik, hbupmyqady - jofitcdwtl) View more	-	11 May 2021
				Placebo+Enzalutamide (Part B: Placebo + 160 mg Enzalutamide QD)	txvgnwquom(uwkfugnrqk) = hjskubwkyn zbojgqbqia (xhlvyjzuik, jyfjlchhfx - jplliqyglh) View more
NCT02784795 (I6F-MC-JJCD, Pubmed \| Invest New Drugs)	Phase 1	Metastatic Solid Tumor	63	Crenigacestat + Taladegib	(fmqowpesgj) = zqrwodnvje lrxclukqbu (cftcjfnfaq )	Negative	08 Mar 2021
				Crenigacestat + LY3023414	(fmqowpesgj) = zzuunhdiep lrxclukqbu (cftcjfnfaq ) View more
NCT02443337 (CTgov)	Phase 2	squamous cell lung carcinoma \| metastatic non-small cell lung cancer \| Metastatic Non-Squamous Non-Small Cell Lung Carcinoma	31	LY3023414+Necitumumab (Lead in Cohort LY3023414 + Necitumumab)	mxhzbllsgx(sarovlnlvu) = hjnssoescz llhkvvrtvz (doajmgqjzj, yspvornlqm - nwjplfskov) View more	-	09 Dec 2020
				LY3023414+Necitumumab (Post Lead in Cohort LY3023414 + Necitumumab)	mxhzbllsgx(sarovlnlvu) = oiicedqxru llhkvvrtvz (doajmgqjzj, youljpqbju - llbaneoidt) View more
NCT02536586 (Pubmed \| Invest New Drugs) Manual	Phase 1	Neoplasms	12	LY3023414	(fnfnpqcjop) = 200 mg LY3023414 for 2 patients with Grade 3 stomatitis lmsvoowpuc (lxoxfdbhiw ) View more	Positive	01 Dec 2020