Phase 2 trial of GS-9973, a selective syk inhibitor, and idelalisib (idela) in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).

Barr, Paul M.; Saylors, Gene; Spurgeon, Stephen E.; Cheson, Bruce D.; Greenwald, Daniel; O’Brien, Susan; Liem, André; McIntyre, Rosemary E.; Abella-Dominicis, Esteban; Hawkins, Michael; Reddy, Anita; Paolo, Julie Di; Wu, Ming-Shiou; Melchor-Khan, Flordeliza; Jin, Feng; Friedberg, Jonathan W.

doi:10.1200/jco.2014.32.15_suppl.7059

Cited by 15 publications

(9 citation statements)

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“…Estimating from reduction in serum levels of CCL3 and CCL4 (∼50% to 75%) as measures of BCR signaling, it appears that the BCR pathway was not completely suppressed since more potent inhibition of these markers has been reported (>90%) by the covalent BTK modifier ibrutinib . Combining GS9973 with idelalisib in patients with B‐cell malignancies was not tolerated, and the study was discontinued . It is unclear if the combination of these 2 agents was not tolerated due to the combined SYK/PI3Kδ mechanism or due to overlapping off‐target toxicities of these 2 distinct kinase inhibitors derived from separate chemistry scaffolds.…”

Section: Discussionmentioning

confidence: 99%

“…38 Combining GS9973 with idelalisib in patients with B-cell malignancies was not tolerated, and the study was discontinued. 39 It is unclear if the combination of these 2 agents was not tolerated due to the combined SYK/PI3Kδ mechanism or due to overlapping off-target toxicities of these 2 distinct kinase inhibitors derived from separate chemistry scaffolds.…”

Section: Discussionmentioning

confidence: 99%

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PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

Coffey

Rani

Betz

et al. 2016

The Journal of Clinical Pharmacology

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The spleen tyrosine kinase (SYK) regulates immune cell activation in response to engagement of a variety of receptors, making it an intriguing target for the treatment of inflammatory and autoimmune disorders as well as certain B‐cell malignancies. We have previously reported on the discovery and preclinical characterization of PRT062607, a potent and highly selective inhibitor of SYK that exhibits robust anti‐inflammatory activity in a variety of animal models. Here we present data from our first human studies aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of PRT062607 in healthy volunteers following single and multiple oral administrations. PRT062607 demonstrated a favorable PK profile and the ability to completely inhibit SYK activity in multiple whole‐blood assays. The PD half‐life in the more sensitive assays was approximately 24 hours and returned to predose levels by 72 hours. Selectivity for SYK was observed at all dose levels tested. Analysis of the PK/PD relationship indicated an IC50 of 324 nM for inhibition of B‐cell antigen receptor‐mediated B‐cell activation and 205 nM for inhibition of FcεRI‐mediated basophil degranulation. PRT062607 was safe and well tolerated across the entire range of doses. Clinical PK/PD was related to in vivo anti‐inflammatory activity of PRT062607 in the rat collagen‐induced arthritis model, which predicts that therapeutic concentrations may be safely achieved in humans for the treatment of autoimmune disease. PRT062607 has a desirable PK profile and is capable of safely, potently, and selectively suppressing SYK kinase function in humans following once‐daily oral dosing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

Coffey

Rani

Betz

et al. 2016

The Journal of Clinical Pharmacology

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“…A Phase II clinical trial of idelalisib in combination with the spleen tyrosine kinase inhibitor entospletinib in R/R CLL or NHL was discontinued due to frequent occurrence of pneumonitis (NCT01796470). 49 Two trials evaluating idelalisib + lenalidomide in recurrent FL (NCT01644799) and lenalidomide ± idelalisib in mantle cell lymphoma (NCT01838434) were suspended owing to tumor flares in treated patients. Moreover, the triplet of idelalisib + lenalidomide + rituximab has been associated with unexpected and serious toxicities, including rash, fevers, hypotension, and hepatotoxicity, which were thought to be related to high-level immune activation.…”

Section: Future Considerationsmentioning

confidence: 99%

Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential

Barrientos

2016

OTT

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Idelalisib is a first-in-class, oral, selective phosphatidylinositol 3-kinase δ inhibitor that offers a chemotherapy-free option for patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Clinical trials in iNHL have evaluated idelalisib as monotherapy and as combination therapy with rituximab, bendamustine, and rituximab + bendamustine. When administered to heavily pretreated patients with R/R iNHL, idelalisib monotherapy or combination therapy showed durable antitumor activity accompanied by sustained or improved quality-of-life outcomes. Idelalisib has an acceptable safety profile; however, serious or fatal diarrhea/colitis, hepatoxicity, pneumonitis, and intestinal perforation have occurred in treated patients. Selective inhibition of phosphatidylinositol 3-kinase δ with idelalisib is a valuable addition to available treatment options for patients with iNHL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. Two Phase III, randomized, placebo-controlled trials of idelalisib as combination therapy with rituximab or bendamustine + rituximab and a Phase I trial of idelalisib in combination with the Bruton’s tyrosine kinase inhibitor ONO/GS-4059 in R/R B-cell malignancies are currently ongoing. A Phase III monotherapy trial in previously treated follicular lymphoma or small lymphocytic lymphoma is planned. The development of other kinase inhibitors for the treatment of iNHL raises the potential for new treatment combinations. Additional research is needed to determine optimal therapy (monotherapy vs combination regimens), treatment sequencing, and long-term management.

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“…In addition to the phase I study summarized above of idelalisib in MCL [38], a few combination studies have opened but lack mature results or were stopped due to unexpected toxicity. These include the phase I study of lenalidomide with idelalisib for relapsed MCL mentioned above [45], and a phase II study of idelalisib plus the Syk inhibitor GS-9973 in patients with various B-NHL including MCL and DLBCL was stopped early due to an unexpectedly high rate of pneumonitis [56]. …”

Section: Clinical Efficacy Of Idelalisibmentioning

confidence: 99%

Idelalisib for the treatment of non-Hodgkin lymphoma

Graf

Gopal

2016

Expert Opinion on Pharmacotherapy

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Introduction B-cell Non-Hodgkin lymphomas (B-NHLs) include a number of disease subtypes, each defined by the tempo of disease progression and the identity of the cancerous cell. Idelalisib is a potent, selective inhibitor of the delta isoform of phosphatidylinositol-3-kinase (PI3K), a lipid kinase whose over-activity in B-NHL drives disease progression. Idelalisib has demonstrated activity in indolent B-NHL (iB-NHL) and is approved for use as monotherapy in patients with follicular lymphoma and small lymphocytic lymphoma and in combination with rituximab in patients with chronic lymphocytic leukemia. Areas Covered Herein we review the development and pharmacology of idelalisib, its safety and efficacy in clinical studies of iB-NHL, and its potential for inclusion in future applications in iB-NHL and in combination with other therapies. Expert Opinion Idelalisib adds to the growing arsenal of iB-NHL pharmacotherapeutics and to the progression of the field toward precision agents with good efficacy and reduced toxicities. Nevertheless, idelalisib carries important risks that require careful patient counseling and monitoring. The appropriate sequencing of idelalisib with other proven treatment options in addition to its potential for combination with established or novel drugs will be borne out in ongoing and planned investigations.

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Phase 2 trial of GS-9973, a selective syk inhibitor, and idelalisib (idela) in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).

Cited by 15 publications

References 0 publications

PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential

Idelalisib for the treatment of non-Hodgkin lymphoma

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