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Li Liu - One of the best experts on this subject based on the ideXlab platform.

  • phase i dose escalation study of Pilaralisib sar245408 xl147 in combination with paclitaxel and carboplatin in patients with solid tumors
    Oncologist, 2017
    Co-Authors: Jennifer J. Wheler, Joanne Lager, Christelle Castell, Jason Jiang, Li Liu, David G. Mutch, Anne M. Traynor
    Abstract:

    LESSONS LEARNED Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors. BACKGROUND Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors. METHODS A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included. RESULTS Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of Pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between Pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). CONCLUSION Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

  • Phase I Dose‐Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors
    The oncologist, 2017
    Co-Authors: Jennifer J. Wheler, Joanne Lager, Christelle Castell, Jason Jiang, Li Liu, David G. Mutch, Anne M. Traynor
    Abstract:

    LESSONS LEARNED Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors. BACKGROUND Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors. METHODS A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included. RESULTS Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of Pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between Pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). CONCLUSION Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

  • Phase I safety and pharmacokinetic dose-escalation study of Pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma
    Cancer Chemotherapy and Pharmacology, 2016
    Co-Authors: Oliver E. Bechter, Herlinde Dumez, Jo Costermans, Kevin Punie, Karl Hsu, Jean-françois Dedieu, Anne-frédérique Ghuysen, Elisa Francesconi, Jyoti Sharma, Li Liu
    Abstract:

    Purpose Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of Pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma. Methods A modified ‘3 + 3’ dose-escalation design was employed. Patients received Pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy. Results Eighteen patients were enrolled: Six patients received Pilaralisib 400 mg QD and 12 patients received Pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response. Conclusions With Pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of Pilaralisib.

  • Phase I safety and pharmacokinetic dose-escalation study of Pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma.
    Cancer chemotherapy and pharmacology, 2016
    Co-Authors: Oliver E. Bechter, Herlinde Dumez, Jo Costermans, Kevin Punie, Karl Hsu, Jean-françois Dedieu, Anne-frédérique Ghuysen, Elisa Francesconi, Jyoti Sharma, Li Liu
    Abstract:

    Purpose Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of Pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma.

  • Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147), a Pan-Class I PI3K Inhibitor, in Combination With Erlotinib in Patients With Solid Tumors
    The oncologist, 2015
    Co-Authors: Jean-charles Soria, Joanne Lager, Jason Jiang, Sandrine Mace, Li Liu, Patricia Lorusso, Ratislav Bahleda, Jean-francois Martini, Howard A Burris
    Abstract:

    Background.This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib (SAR245408), an oral panclass I phosphoinositide 3-kinase (PI3K) inhibitor, in combinationwitherlotinib,anepidermalgrowthfactorreceptor(EGFR) inhibitor. Methods. In a 3 1 3 dose-escalation study, patients with advanced solidtumors received Pilaralisib capsules once daily (21 days per 28-day cycle; 50–600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer whohadpreviouslyreceivedtreatmentwithanEGFRinhibitor was included. Results.Thirty-five patients were enrolled. Only one patient had anEGFRactivating mutation. One dose-limitingtoxicity wasreported(grade4drugreactionorrashwitheosinophilia and systemic symptoms). MTD was Pilaralisib 400 mg plus erlotinib 150 mg.The most commonly reported treatmentrelated adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect onPilaralisibpharmacokinetics.Pharmacodynamicanalyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity.

Jason Jiang - One of the best experts on this subject based on the ideXlab platform.

  • Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors.
    The oncologist, 2018
    Co-Authors: Gerald M. Edelman, Jordi Rodon, Joanne Lager, Christelle Castell, Jason Jiang, Eliezer M. Van Allen, Nikhil Wagle, Neal I. Lindeman, Lynette M. Sholl, Geoffrey I. Shapiro
    Abstract:

    LESSONS LEARNED A phase I study of the pan-class I phosphoinositide 3-kinase inhibitor Pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated Pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of Pilaralisib tablets was established as 400 mg once daily. BACKGROUND A phase I trial of Pilaralisib, an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated Pilaralisib in tablet formulation. MATERIALS AND METHODS Patients with advanced solid tumors received Pilaralisib tablets (100-600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy. RESULTS Twenty-two patients were enrolled. No dose-limiting toxicities (DLTs) were reported. The most common treatment-related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose-proportionally. Steady-state exposure was higher with Pilaralisib tablet formulation at 400 mg than with Pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC0-24] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR). CONCLUSION Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for Pilaralisib tablets, based on PK data, was 400 mg once daily.

  • phase i dose escalation study of Pilaralisib sar245408 xl147 in combination with paclitaxel and carboplatin in patients with solid tumors
    Oncologist, 2017
    Co-Authors: Jennifer J. Wheler, Joanne Lager, Christelle Castell, Jason Jiang, Li Liu, David G. Mutch, Anne M. Traynor
    Abstract:

    LESSONS LEARNED Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors. BACKGROUND Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors. METHODS A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included. RESULTS Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of Pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between Pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). CONCLUSION Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

  • Phase I Dose‐Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors
    The oncologist, 2017
    Co-Authors: Jennifer J. Wheler, Joanne Lager, Christelle Castell, Jason Jiang, Li Liu, David G. Mutch, Anne M. Traynor
    Abstract:

    LESSONS LEARNED Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors. BACKGROUND Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors. METHODS A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included. RESULTS Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of Pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between Pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). CONCLUSION Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

  • phase i ii dose escalation study of pi3k inhibitors Pilaralisib or voxtalisib in combination with letrozole in patients with hormone receptor positive and her2 negative metastatic breast cancer refractory to a non steroidal aromatase inhibitor
    Breast Cancer Research and Treatment, 2015
    Co-Authors: Kimberly L Blackwell, Jason Jiang, Howard A Burris, P Gomez, Lynn N Henry, Steven J Isakoff, Frank Campana, Sandrine Mace, Sara M Tolaney
    Abstract:

    This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of Pilaralisib (SAR245408), a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non-steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be Pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the Pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the Pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade ≥ 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the Pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, Pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer.

  • Phase I trial of the pan-PI3K inhibitor Pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed/refractory lymphoma
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
    Co-Authors: Jennifer R. Brown, Jordi Rodon, Joanne Lager, Jason Jiang, Matthew S. Davids, Pau Abrisqueta, Kasar, Coumaran Egile, Farrukh T. Awan
    Abstract:

    Purpose:This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the pan-PI3K inhibitor Pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. Experimental Design:Patients and Methods Patients were treated with the maximum tolerated dose of Pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AEs) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. Results:Twenty-five patients were included in the study; 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%) and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%) and anemia (16.0%). Pilaralisib exposure on cycle 1 Day 28 was similar to exposure in patients with solid tumors. In patients with CLL, Pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and three patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥ 50%. Overall, 14 patients (56.0%; seven patients with CLL and seven patients with lymphoma) had progression-free survival ≥ 6 months. Conclusions:Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent Pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development.

Joanne Lager - One of the best experts on this subject based on the ideXlab platform.

  • Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors.
    The oncologist, 2018
    Co-Authors: Gerald M. Edelman, Jordi Rodon, Joanne Lager, Christelle Castell, Jason Jiang, Eliezer M. Van Allen, Nikhil Wagle, Neal I. Lindeman, Lynette M. Sholl, Geoffrey I. Shapiro
    Abstract:

    LESSONS LEARNED A phase I study of the pan-class I phosphoinositide 3-kinase inhibitor Pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated Pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of Pilaralisib tablets was established as 400 mg once daily. BACKGROUND A phase I trial of Pilaralisib, an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated Pilaralisib in tablet formulation. MATERIALS AND METHODS Patients with advanced solid tumors received Pilaralisib tablets (100-600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy. RESULTS Twenty-two patients were enrolled. No dose-limiting toxicities (DLTs) were reported. The most common treatment-related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose-proportionally. Steady-state exposure was higher with Pilaralisib tablet formulation at 400 mg than with Pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC0-24] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR). CONCLUSION Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for Pilaralisib tablets, based on PK data, was 400 mg once daily.

  • phase i dose escalation study of Pilaralisib sar245408 xl147 in combination with paclitaxel and carboplatin in patients with solid tumors
    Oncologist, 2017
    Co-Authors: Jennifer J. Wheler, Joanne Lager, Christelle Castell, Jason Jiang, Li Liu, David G. Mutch, Anne M. Traynor
    Abstract:

    LESSONS LEARNED Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors. BACKGROUND Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors. METHODS A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included. RESULTS Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of Pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between Pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). CONCLUSION Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

  • Phase I Dose‐Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors
    The oncologist, 2017
    Co-Authors: Jennifer J. Wheler, Joanne Lager, Christelle Castell, Jason Jiang, Li Liu, David G. Mutch, Anne M. Traynor
    Abstract:

    LESSONS LEARNED Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors. BACKGROUND Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of Pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors. METHODS A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included. RESULTS Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of Pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between Pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%). CONCLUSION Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

  • Phase I trial of the pan-PI3K inhibitor Pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed/refractory lymphoma
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015
    Co-Authors: Jennifer R. Brown, Jordi Rodon, Joanne Lager, Jason Jiang, Matthew S. Davids, Pau Abrisqueta, Kasar, Coumaran Egile, Farrukh T. Awan
    Abstract:

    Purpose:This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the pan-PI3K inhibitor Pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. Experimental Design:Patients and Methods Patients were treated with the maximum tolerated dose of Pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AEs) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. Results:Twenty-five patients were included in the study; 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%) and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%) and anemia (16.0%). Pilaralisib exposure on cycle 1 Day 28 was similar to exposure in patients with solid tumors. In patients with CLL, Pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and three patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥ 50%. Overall, 14 patients (56.0%; seven patients with CLL and seven patients with lymphoma) had progression-free survival ≥ 6 months. Conclusions:Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent Pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development.

  • phase i trial of the pan pi3k inhibitor Pilaralisib sar245408 xl147 in patients with chronic lymphocytic leukemia cll or relapsed refractory lymphoma
    Clinical Cancer Research, 2015
    Co-Authors: Jennifer R. Brown, Jordi Rodon, Joanne Lager, Jason Jiang, Matthew S. Davids, Pau Abrisqueta, Coumaran Egile, Siddha Kasar, Farrukh T. Awan
    Abstract:

    Purpose:This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the pan-PI3K inhibitor Pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. Experimental Design:Patients and Methods Patients were treated with the maximum tolerated dose of Pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AEs) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. Results:Twenty-five patients were included in the study; 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%) and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%) and anemia (16.0%). Pilaralisib exposure on cycle 1 Day 28 was similar to exposure in patients with solid tumors. In patients with CLL, Pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and three patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥ 50%. Overall, 14 patients (56.0%; seven patients with CLL and seven patients with lymphoma) had progression-free survival ≥ 6 months. Conclusions:Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent Pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development.

Oliver E. Bechter - One of the best experts on this subject based on the ideXlab platform.

  • Phase I safety and pharmacokinetic dose-escalation study of Pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma
    Cancer Chemotherapy and Pharmacology, 2016
    Co-Authors: Oliver E. Bechter, Herlinde Dumez, Jo Costermans, Kevin Punie, Karl Hsu, Jean-françois Dedieu, Anne-frédérique Ghuysen, Elisa Francesconi, Jyoti Sharma, Li Liu
    Abstract:

    Purpose Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of Pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma. Methods A modified ‘3 + 3’ dose-escalation design was employed. Patients received Pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy. Results Eighteen patients were enrolled: Six patients received Pilaralisib 400 mg QD and 12 patients received Pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response. Conclusions With Pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of Pilaralisib.

  • Phase I safety and pharmacokinetic dose-escalation study of Pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma.
    Cancer chemotherapy and pharmacology, 2016
    Co-Authors: Oliver E. Bechter, Herlinde Dumez, Jo Costermans, Kevin Punie, Karl Hsu, Jean-françois Dedieu, Anne-frédérique Ghuysen, Elisa Francesconi, Jyoti Sharma, Li Liu
    Abstract:

    Purpose Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of Pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma.

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  • phase i ii dose escalation study of pi3k inhibitors Pilaralisib or voxtalisib in combination with letrozole in patients with hormone receptor positive and her2 negative metastatic breast cancer refractory to a non steroidal aromatase inhibitor
    Breast Cancer Research and Treatment, 2015
    Co-Authors: Kimberly L Blackwell, Jason Jiang, Howard A Burris, P Gomez, Lynn N Henry, Steven J Isakoff, Frank Campana, Sandrine Mace, Sara M Tolaney
    Abstract:

    This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of Pilaralisib (SAR245408), a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non-steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be Pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the Pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the Pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade ≥ 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the Pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, Pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer.

  • Phase I/II study of Pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer
    Breast Cancer Research and Treatment, 2015
    Co-Authors: Sara Tolaney, Frank Campana, Howard Burris, Elaina Gartner, Ingrid A. Mayer, Cristina Saura, Matthew Maurer, Eva Ciruelos, Agustin A. Garcia, Jason Jiang
    Abstract:

    This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor Pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of Pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of Pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady-state Pilaralisib exposure was similar to previous studies with Pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.

  • Phase II study of the PI3K inhibitor Pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma
    Gynecologic oncology, 2014
    Co-Authors: Ursula A. Matulonis, Frank Campana, Coumaran Egile, Ignace Vergote, Floor J. Backes, Lainie P. Martin, Scott Mcmeekin, Michael J. Birrer, Sharad A. Ghamande
    Abstract:

    Abstract Objective Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor Pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma. Methods This Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received Pilaralisib 600mg capsules or 400mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free survival (PFS) >6months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to Pilaralisib. Results 67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS>6months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (40.3%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade ≥3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%). Conclusions Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma.