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Pictilisib (GDC-0941, RG7321)

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Pictilisib (GDC-0941, RG7321) is a small molecule Class I phosphatidylinositol-3-kinase (PI3K)-α/δ specific inhibitor with an IC50 of 3 nM for both isoforms.1  Discovered by Piramed Ltd, which was acquired by F. Hoffmann-La Roche, pictilisib is currently being investigated by Genentech for use in breast, lung, and solid cancers, as well as non-Hodgkin lymphoma.

A Phase I, open-label, dose-escalation study using a 3 + 3 design to assess the safety, tolerability, and pharmacokinetics of daily orally administered pictilisib has recently been completed for non-Hodgkin lymphoma (NHL),2 and Genentech is currently preparing to progress into Phase II trials.

In vitro studies suggest pictilisib is significantly more active compared with idelalisib against mantle cell lymphoma (MCL) cell lines and primary samples.3  It has also been shown to arrest a panel of six peripheral and cutaneous T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them.4

Lymphoma/CLL clinical trials

NCT00876122: An Open-Label, Phase I, Dose-Escalation Study of PI3-Kinase Inhibitor (GDC-0941) in Patients With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma for Which Standard Therapy Either Does Not Exist or Has Proven Ineffective or Intolerable – COMPLETED

Study Design
Phase: I
Allocation: Non-randomized
Enrollment: 60
Intervention Model: Single group assignment
Masking: Open label
Primary Purpose: Treatment
Condition: Non-Hodgkin lymphoma
Intervention: Drug (GDC-0941), escalating oral dose

Results
Full data are not yet available

Lymphoma/CLL literature

Tabe Y, et al. Class IA PI3K inhibition inhibits cell growth and proliferation in mantle cell lymphoma. Acta Haematol. 2014;131:59–69. View

Iyengar S, et al. P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood. 2013;121:2274–84. View

Bressanin D, et al. Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels. Oncotarget. 2012;3:811–23. View

Martín-Sánchez E, et al. Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas. Haematologica. 2013;98:57–64. View

Wullschleger S, et al. Quantitative MRI establishes the efficacy of PI3K inhibitor (GDC-0941) multi-treatments in PTEN-deficient mice lymphoma. Anticancer Res. 2012;32:415–20. View

García-Martínez JM, et al. Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice. Br J Cancer. 2011;104:1116–25. View

Congress lymphoma/CLL abstracts

ASH 2013
Quayle SN, et al. Inhibition Of HDAC6 In Combination With Targeted Agents Results In Broad Synergistic Decreases In Viability In Non-Hodgkin’s Lymphoma (NHL) Cells. 55th ASH Annual Meeting and Exposition. December 7–10, 2013. Poster #3071. View

EHA 2013
No data presented

ASCO 2013
No data presented

ICML 2013
Iyengar S, et al. A high PIK3CA/PIK3CD mRNA ratio in mantle cell lymphoma can predict resistance to PI3KD inhibition and is more common with multiple relapse. 12th International Conference on Malignant Lymphoma. June 19–22, 2013. Oral presentation #110.

Authors: Prof. Anton Hagenbeek, Prof. Ulrich Jäger, Secretariat

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