The purpose of this study is to investigate how effective the study drug IPI-549 is against types of cancers. IPI-549 is considered experimental because it is not approved by the US Food and Drug Administration (FDA) for the treatment of cancer.
Patients will be treated with 2 weeks of IPI-549, a specific PI3Kγ inhibitor. Tumor tissue for research purposes through core biopsies will be obtained prior to initiation of IPI-549 and at surgery.

Start Date06 Mar 2020

Sponsor / Collaborator

The V Foundation for Cancer Research

NCT03961698 / Active, not recruitingPhase 2

Ph 2, Multi-arm, Multicenter, Open-label Study to Evaluate Efficacy and Safety of IPI-549 Administered in Combo With Front-line Treatment Regimens in Pts With Locally Advanced and/or Metastatic Triple-Negative Breast Cancer or Renal Cell Carcinoma

MARIO-3 is a Phase 2 multi-arm combination cohort study designed to evaluate IPI-549, Infinity Pharmaceutical's first-in-class, oral immuno-oncology product candidate targeting immune-suppressive tumor-associated myeloid cells through selective inhibition of phosphoinositide-3-kinase (PI3K)-gamma, in combinations with Tecentriq and Abraxane (nab-paclitaxel) in front-line triple negative breast cancer (TNBC) and in combination with Tecentriq and Avastin (bevacizumab) in front-line renal cell cancer (RCC).

Start Date17 Dec 2019

Sponsor / Collaborator

Infinity Pharmaceuticals, Inc.

[+1]

NCT03980041 / CompletedPhase 2

A Phase 2, Multicenter, Randomized, Double-Blind, Active-Control Study to Evaluate the Efficacy and Safety of Nivolumab Administered in Combination With IPI-549 Compared to Nivolumab Monotherapy in the Treatment of Patients With Immune Therapy-Naïve, Advanced Urothelial Carcinoma

The purpose of this study is to measure the effect of IPI-549 in combination with nivolumab when compared to nivolumab monotherapy in advanced urothelial cancer patients.

Start Date25 Sep 2019

Sponsor / Collaborator

Infinity Pharmaceuticals, Inc.

[+1]

100 Clinical Results associated with Eganelisib

100 Translational Medicine associated with Eganelisib

100 Patents (Medical) associated with Eganelisib

Literatures (Medical) associated with Eganelisib

01 Nov 2023·Immunobiology

Evaluation of the anti-inflammatory effects of PI3Kδ/γ inhibitors for treating acute lung injury

Article

Author: Gao, Mingzhu ; Jia, Lei ; Zhu, Jingyu ; Xiong, Wendian ; Chen, Yun ; Jin, Jian ; Cai, Yanfei

Phosphatidylinositol 3-kinase delta (PI3Kδ) and gamma (PI3Kγ) are predominantly located in immune and hematopoietic cells. It is well-established that PI3Kδ/γ plays important roles in the immune system and participates in inflammation; hence, it could be a potential target for anti-inflammatory therapy. Currently, several PI3K inhibitors are used clinically to treat cancers with aberrant PI3K signaling; however, their role in treating acute respiratory inflammatory diseases has rarely been explored. Herein, we investigated the potential anti-inflammatory activities of several pharmacological PI3K inhibitors, including marketed drugs idelalisib (PI3Kδ), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K with preferential α/δ) and the clinical drug eganelisib (PI3Kγ), for treating acute lung injury (ALI). In the lipopolysaccharide-induced RAW264.7 macrophage inflammatory model, the four inhibitors significantly suppressed proinflammatory cytokine expression by inhibiting the PI3K signaling pathway. Oral administration of PI3K inhibitors markedly improved lung injury in a murine model of ALI. PI3K pathway inhibition decreased inflammatory cell infiltration and totalprotein levels, as well as reduced the expression of associated lung inflammatory factors. Collectively, all four representative PI3K inhibitors exerted prominent anti-inflammatory properties, indicating that PI3K δ and/or γ inhibition could be ideal targets to treat respiratory inflammatory diseases by reducing the inflammatory response. The findings of the current study provide a new basis for utilizing PI3K inhibitors to treat acute respiratory inflammatory diseases.

08 Aug 2023·ACS nano

Janus Silica Nanoparticle-Based Tumor Microenvironment Modulator for Restoring Tumor Sensitivity to Programmed Cell Death Ligand 1 Immune Checkpoint Blockade Therapy.

Article

Author: Liu, Xiaolong ; Li, Feida ; Yao, Cuiping ; Lin, Xinyi ; Guan, Jianhua ; Zeng, Yongyi ; Wang, Xiaoyan

An immunosuppressive tumor microenvironment (TME) with inadequate and exhausted tumor-infiltrating cytotoxic lymphocytes and abundant cellular immunosuppressors is the major obstacle responsible for the poor efficacy of PD-1/PD-L1 (programmed cell death 1 and its ligand 1) immune checkpoint blockade (ICB) therapy. Herein, a Janus silica nanoparticle (JSNP)-based immunomodulator is explored to reshape the TME for boosting the therapeutic outcomes of αPD-L1 therapy. The designed JSNP has two distinct domains, namely, an ultra pH-responsive side (UPS), which could encapsulate PI3Kγ inhibitor IPI549 in the pore structure, and a polycation-grafted intra-glutathione (GSH)-sensitive side (IGS), which could absorb CXCL9 cDNA on the surface. The final IPI549@UPS-IGS-PDMAEMA@CXCL9 cDNA (IUIPC) could release IPI549 in weak acid TME to target myeloid-derived suppressor cells (MDSCs) to reverse negative immunoregulation and then release CXCL9 cDNA in tumor cells with abundant GSH for sustained CXCL9 chemokine expression and secretion to improve cytotoxic lymphocyte recruitment signals, thereby jointly restoring tumor sensitivity to PD-1/PD-L1 ICB therapy. As expected, the IUIPC-mediated TME remodeling during αPD-L1 therapy significantly ameliorated TME immunosuppression, as well as induced potent systemic antitumor immune responses, which ultimately achieved a robustly boosted antitumor efficacy proven by remarkable suppression of primary tumor growth, obvious prevention of tumor recurrence, and significant regression of abscopal tumors. Hence, the IUIPC-mediated TME-regulating strategy provides an enormous perspective for the improvement of PD-1/PD-L1 ICB therapy.

13 Jun 2023·Clinical cancer research : an official journal of the American Association for Cancer Research

Eganelisib, a First-in-Class PI3Kγ Inhibitor, in Patients with Advanced Solid Tumors: Results of the Phase 1/1b MARIO-1 Trial.

Article

Author: O'Connell, Brenda ; Shapiro, Geoffrey ; Chmielowski, Bartosz ; Cohen, Ezra E W ; Peng, Guangbin ; Sullivan, Ryan ; Yeckes-Rodin, Heather ; Hong, David S ; Zizlsperger, Nora ; Tolcher, Anthony ; Patnaik, Amita ; Peng, Joanna ; Steuer, Conor ; Ilaria, Robert ; Wolchok, Jedd D ; Gutierrez, Martin ; Postow, Michael

PURPOSE:

Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.

PATIENTS AND METHODS:

Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE).

RESULTS:

The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors.

CONCLUSIONS:

On the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

News (Medical) associated with Eganelisib

08 May 2024

·www.sciencedaily.com

New target for potential leukemia therapy

Investigators discovered that a subset of myeloid and lymphoid leukemias depend on a molecular complex called PI3Kgamma for survival. The study provides both mechanistic and preclinical evidence supporting the rapid initiation of clinical trials for patients with acute myeloid leukemia (AML) to test an existing medicine that inhibits the complex, called eganelisib, both alone and in combination with the most used AML chemotherapy, cytarabine. Boston -- A team of Dana-Farber Cancer Institute investigators discovered that a subset of myeloid and lymphoid leukemias depend on a molecular complex called PI3Kgamma for survival. The study provides both mechanistic and preclinical evidence supporting the rapid initiation of clinical trials for patients with acute myeloid leukemia (AML) to test an existing medicine that inhibits the complex, called eganelisib, both alone and in combination with the most used AML chemotherapy, cytarabine. The study was published in Nature. "Given what we've observed, we can move very quickly to take these medicines, which appear to be safe and well tolerated, to patients with AML," says principal investigator Andrew Lane, MD, PhD, a clinician-scientist in the Adult Leukemia Program at Dana-Farber. "We are planning clinical trials to start hopefullywithin the next year." Treatment for AML has advanced in the last decade, but most patients ultimately relapse after treatment. Therapies that target AML-related mutations have provided options for subsets of patients, though the cancer eventually evolves to evade the therapy. The Dana-Farber team took a different approach to searching for therapeutic targets. Rather than focusing on mutations, first author Qingyu Luo, MD, PhD, a research fellow in Lane's lab, used genome wide CRISPR interference to search for genes that AML cells rely on to grow. He found a promising hit. A subset of leukemia cells relied on a gene called PI3KR5 to survive. That gene produces an important portion of the PI3Kgamma complex. This hit was attractive in part because the PI3Kgamma complex had been studied before, though not in AML. In addition, a medicine already existed to inhibit it. This drug, eganelisib, has been tested in trials for certain solid tumors to enhance cancer immunotherapy. What Luo and Lane had found, however, was a completely different mechanism of action in which the drug might work directly on leukemia cells to stop their growth. To validate this hypothesis, the team treated animal models harboring patient-derived leukemia xenografts with eganelisib. They found that the leukemia xenografts predicted to be highly dependent on PI3Kgamma shrank, and the animal models survived longer when treated with eganelisib. Looking at The Cancer Genome Atlas Data (TCGA), the team found that patients with AML predicted to be sensitive to eganelisib don't do as well in terms of survival on existing therapies compared to those with negative biomarkers. This finding suggests that this patient group, which can be identified by high levels of PI3KR5 expression, has a need for new medicines and could potentially benefit from treatment with eganelisib. "This is a drug that is ready to be tested in patients with AML," says Lane. "It's already been used in clinical trials for many patients with solid tumors." Luo, who initiated this research to improve existing therapies for AML, also treated animal models of leukemia with cytarabine alone and with eganelisib plus cytarabine. The team found that those treated with a combination of eganelisib and cytarabine survived longer than those treated with cytarabine alone, regardless of the leukemia's sensitivity to PI3Kgamma inhibition alone. The observations suggested that the two medicines worked synergistically. Luo investigated and found that PI3Kgamma, when inhibited, also results in the suppression of a leukemia cell metabolic process called oxidative phosphorylation (OXPHOS). Leukemia cells depend on OXPHOS for energy, and suppression of OXPHOS can result in their demise. Luo also discovered that leukemia cells that survive standard treatment with cytarabine tend to be more dependent on PI3Kgamma than they were prior to treatment. These surviving leukemia cells -- which are the cause of AML relapse -- could be vulnerable to combination therapy with eganelisib and cytarabine. "We want synergy, where two drugs mesh with each other," says Luo. "Through inhibition of PI3Kgamma, eganelisib has this downstream effect of suppressing an energy pathway important in AML relapse." The team is now focused on designing clinical trials for patients. "This study provides the scientific rationale for a clinical application and also helps us understand where the discoveries apply to the needs of our patients," says Lane. "Dana-Farber is one of the unique places where you can go from molecular biology in the lab to testing in models based on patient samples and then to rapidly initiating a clinical trial on the basis of this science."

ImmunotherapyClinical Result

12 Feb 2024

·www.fiercebiotech.com

Biotech bankruptcies hit 10-year peak in 2023

In terms of biotech bankruptcies, the new year is starting off bleak. In the first few days of 2024 alone, Humanigen and Athersys both filed for bankruptcy. More biotech companies filed for bankruptcy in 2023 than any year since 2010, underscoring a brutal year defined by layoffs, company closures and pipeline reprioritizations, according to data from S&P Global Market Intelligence. 2023 eclipsed all other years by far, with 18 companies filing for protection compared to eight in 2022, which had previously held the record as the highest bankruptcy year. https://public.flourish.studio/visualisation/16736139/ The year kicked off with Sorrento Therapeutics filing Chapter 11 amid a legal battle with billionaire Patrick Soon-Shiong and his immunotherapy biotech NantCell. The company had $235 million in debt and had run out of options. Sorrento had been developing a generic rival to Bristol Myers Squibb’s Abraxane, which was the subject of the dispute with Soon-Shiong. As of November 2023, Sorrento had laid off its chief financial officer in the final step in the closure process, according to a Securities and Exchange Commission document. For Infinity Pharmaceuticals, an unsuccessful merger with MEI Pharma was the straw that broke the camel’s back. The cancer-focused biotech filed for Chapter 11 bankruptcy on Sept. 29, a move that followed a 75% workforce reduction in July. Infinity had looked for a strategic transaction to keep running trials for eganelisib, a midstage asset being assessed in multiple indications, including urothelial cancer and solid tumors. MEI Pharma appeared to offer the saving Infinity sought until MEI shareholders’ sunk the deal, with 51% of voters opposed to the transaction. OncoSec Medical, which filed in June, was forced to wrap up after a pivotal trial of an interleukin 12-encoding plasmid in combination with Merck & Co.’s Keytruda failed to meet the bar for success in objective response rate. The phase 2b trial was testing the med, called TAVO-EP, in patients with unresectable or metastatic melanoma who had progressed after treatment with an anti-PD-1 checkpoint inhibitor. The company filed for bankruptcy after defaulting on a $2 million loan. https://public.flourish.studio/visualisation/16735813/ Back to court In terms of biotech bankruptcies, the new year is starting off bleak. In the first few days of 2024 alone, Humanigen and Athersys both filed for bankruptcy. The move comes as no surprise for Humanigen, a monoclonal-antibody-focused biotech that had been considering bankruptcy since last summer after talks of a potential reverse merger fell through. The company was on its last leg, with only $3.1 million in the bank last March after its anti-human GM-CSF mAb failed to improve outcomes in hospitalized COVID-19 patients in 2022. This is not the first time Humanigen has gone to the bankruptcy courts. The company, then named KaloBios Pharmaceuticals, also filed in 2015 but managed to reorganize and survive the struggle, according to the S&P data. The company emerged from bankruptcy the following year, thanks to a $14 million equity financing that helped recapitalize the business. Humanigen also picked up rights to a rare disease treatment called benznidazole. The biotech’s name changed to Humanigen in August 2017. But financial troubles again hit the newly named company, forcing the offloading of benznidazole in December 2017 as part of an agreement to exchange loan obligations for equity. Humanigen shifted from rare diseases to immunotherapy and oncology and moved lenzilumab to the center of its pipeline. Lenzilumab never quite found its footing in the clinic, with Humanigen testing it in cancer, COVID-19, graft-versus-host disease and others. A second therapy, the EphA-3-targeted monoclonal antibody ifabotuzumab, was also in development as recently as August 2023. That August pipeline update was the last from Humanigen, and, in January, bankruptcy papers (PDF) were filed. The company now plans to sell off its assets in a bidding process. But before filing the bankruptcy work, Humanigen sold off its biopharma business to Taran Therapeutics, meaning the therapies will go on via a stalking horse bid. Taran picked up a portfolio of monoclonal antibodies, including lenzilumab, ifabotuzumab and HGEN005, for $20 million. The writing was also on the wall for Athersys after the stem cell therapy company suffered a series of clinical setbacks. Ultimately, disappointing phase 3 data for an ischemic stroke cell therapy triggered the biotech to sell off all assets and file for bankruptcy Jan. 5. The healthcare sector as a whole has kicked off the year in third place among bankruptcy filings by sector, according to S&P, behind industrials and consumer discretionary. While the pace of bankruptcies across all sectors declined to start the year, S&P noted that companies are still facing relatively high interest rates and a challenging labor market. Editor's note: Chart data sourced from S&P Global Market Intelligence. Graphics by Gabrielle Masson.

Phase 2ImmunotherapyPhase 3AcquisitionCell Therapy

02 Oct 2023

·www.fiercebiotech.com

Infinity comes to an end with Chapter 11 bankruptcy filing

Infinity was developing eganelisib in several mid-stage studies, including urothelial cancer and in solid tumors. After a merger with MEI Pharma was unsuccessful, Infinity Pharma has filed for bankruptcy, just as executives had warned when the deal fell through. The Cambridge, Massachusetts-based biotech filed for Chapter 11 bankruptcy on Friday “after considering all strategic alternatives,” according to a regulatory filing dated Sept 28. The company will continue to operate at a reduced level while a restructuring transaction or asset sale is conducted. At the same time, board member Adelene Perkins resigned from her role as chair. Infinity cut three-quarters of its staff and three board members in July after a planned combination with MEI Pharma fell through. Infinity had warned in March that the merger may be the last chance to avoid bankruptcy for the cancer-focused company. Infinity was developing eganelisib in several mid-stage studies, including urothelial cancer and in solid tumors. As the financial troubles mounted, the company tried to look for a strategic transaction to keep the med going. Ultimately, those efforts did not secure a company-saving deal. Meanwhile, MEI has been trading barbs via press release with two shareholders Anson Funds and Cable Car Capital LLC, as the two firms try to remove board members. On Monday, MEI adopted a stockholder rights plan, also known as a poison pill defense, to try and deter the firms from taking control.

Executive ChangeClinical Trial FailureAcquisition

100 Deals associated with Eganelisib

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16296

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Head and Neck Neoplasms	Phase 2	US	-	26 Mar 2020
Advanced Head and Neck Carcinoma	Phase 2	US	-	06 Mar 2020
Human Papillomavirus-Related Squamous Cell Carcinoma	Phase 2	US	-	06 Mar 2020
Locally Advanced Head and Neck Squamous Cell Carcinoma	Phase 2	US	-	06 Mar 2020
Renal Cell Carcinoma	Phase 2	US	Infinity Pharmaceuticals, Inc.	17 Dec 2019
Triple Negative Breast Cancer	Phase 2	US	Infinity Pharmaceuticals, Inc.	17 Dec 2019
Advanced cancer	Phase 2	US	Infinity Pharmaceuticals, Inc.	25 Sep 2019
Advanced cancer	Phase 2	CZ	Infinity Pharmaceuticals, Inc.	25 Sep 2019
Advanced cancer	Phase 2	FR	Infinity Pharmaceuticals, Inc.	25 Sep 2019
Advanced cancer	Phase 2	IT	Infinity Pharmaceuticals, Inc.	25 Sep 2019

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03961698 (MARIO-3, Corporate Publications) Manual	Phase 2	Triple Negative Breast Cancer \| Transitional Cell Carcinoma First line Triple Negative	49	Atezolizumab+Albumin-Bound Paclitaxel+Eganelisib	tujumpsqoz(koqjaikipj) = ffgyrzmbve evwzhzepaf (qpewlmrshz ) View more	Positive	27 Jul 2021
NCT03980041 (MARIO-275, Corporate Publications) Manual	Phase 2	Triple Negative Breast Cancer \| Transitional Cell Carcinoma Triple Negative	49	Nivolumab+Placebo	cfpnmlmgys(mbxvgvoufj) = the most common ≥Grade 3 TEAEs across all doses, all causality, were disease progression (27.3%), anemia (12.1%), and hepatic AEs including hepatotoxicity (15.2%), increased ALT (12.1%) and increased AST (12.1%) with no Hy’s Law. ijgtrmhqoz (thzjuuyuxd ) View more	Positive	27 Jul 2021
				Nivolumab+eganelisib
NCT03980041 (MARIO-275, ASCO_GU2021) Manual	Phase 2	Advanced Urothelial Carcinoma	-	nivolumab+IPI 549	jvuqmshsez(xcutcrcyhb) = pjydavyzeg abmwpeliep (uqunuirxmj ) View more	Positive	20 Feb 2021
				placebo+nivolumab	jvuqmshsez(xcutcrcyhb) = svztyljvru abmwpeliep (uqunuirxmj, 1 - 91) View more
NCT03719326 (ARC-2, AACR2021) Manual	Phase 1	Ovarian Cancer \| Metastatic Triple-Negative Breast Carcinoma	29	AB928 150 mg + pegylated liposomal doxorubicin (Doublet)	yfgsmjemrh(wwhglbiiit) = Four pts reported 6 Gr ≥3 SAEs esyhevmcth (aysvjvyfio ) View more	Positive	15 Feb 2021
				IPI-549 40 mg + AB928 150 mg + pegylated liposomal doxorubicin (Triplet)
NCT02637531 (MARIO-1, Corporate Publications) Manual	Phase 1	Solid tumor	82	Opdivo+IPI-549	ndomxitbgx(labhcsdsvb) = ilibrlzhmu fwgamgziiu (qnodgxbiwx ) View more	Positive	10 Nov 2018
NCT02637531 (ASCO2018) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	31	Nivolumab+IPI-549 (dose-escalation)	zjdcrkakkf(snkoughqyy) = 2 DLTs each occurred at IPI-549 30 mg (Gr 3 rash) and 40 mg QD (Gr 3 rash; Gr 3 ALT/AST increase) hayvrjafch (vwokfzbwwa ) View more	Positive	04 Jun 2018

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