A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer

Patrick Schöffski, Sara Cresta, Ingrid A Mayer, Hans Wildiers, Silvia Damian, Steven Gendreau, Isabelle Rooney, Kari M Morrissey, Jill M Spoerke, Vivian W Ng, Stina M Singel, Eric Winer

Research output: Contribution to journalArticle

Abstract

BACKGROUND: This phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with letrozole, in patients with locally recurrent or metastatic breast cancer.

METHODS: This was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60-330 mg) plus paclitaxel (90 mg/m2) with and without bevacizumab (10 mg/kg) or trastuzumab (2-4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity.

RESULTS: Sixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5%), 21 (30.4%), and 2 (2.9%) patients, respectively. Six (8.7%) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib-paclitaxel drug-drug interaction. Two (3.4%) patients experienced complete responses, and 17 (29.3%) patients had partial responses.

CONCLUSIONS: Combining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT00960960 . Registered on August 13, 2009.

Original languageEnglish
Pages (from-to)109
JournalBreast Cancer Research
Volume20
Issue number1
DOIs
Publication statusPublished - Sep 5 2018

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letrozole
Paclitaxel
Breast Neoplasms
Maximum Tolerated Dose
Phosphatidylinositol 3-Kinase
Safety
Bevacizumab
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
Trastuzumab

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A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. / Schöffski, Patrick; Cresta, Sara; Mayer, Ingrid A; Wildiers, Hans; Damian, Silvia; Gendreau, Steven; Rooney, Isabelle; Morrissey, Kari M; Spoerke, Jill M; Ng, Vivian W; Singel, Stina M; Winer, Eric.

In: Breast Cancer Research, Vol. 20, No. 1, 05.09.2018, p. 109.

Research output: Contribution to journalArticle

Schöffski, Patrick ; Cresta, Sara ; Mayer, Ingrid A ; Wildiers, Hans ; Damian, Silvia ; Gendreau, Steven ; Rooney, Isabelle ; Morrissey, Kari M ; Spoerke, Jill M ; Ng, Vivian W ; Singel, Stina M ; Winer, Eric. / A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. In: Breast Cancer Research. 2018 ; Vol. 20, No. 1. pp. 109.
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abstract = "BACKGROUND: This phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with letrozole, in patients with locally recurrent or metastatic breast cancer.METHODS: This was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60-330 mg) plus paclitaxel (90 mg/m2) with and without bevacizumab (10 mg/kg) or trastuzumab (2-4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity.RESULTS: Sixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5{\%}), 21 (30.4{\%}), and 2 (2.9{\%}) patients, respectively. Six (8.7{\%}) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib-paclitaxel drug-drug interaction. Two (3.4{\%}) patients experienced complete responses, and 17 (29.3{\%}) patients had partial responses.CONCLUSIONS: Combining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study.TRIAL REGISTRATION: ClinicalTrials.gov, NCT00960960 . Registered on August 13, 2009.",
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T1 - A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer

AU - Schöffski, Patrick

AU - Cresta, Sara

AU - Mayer, Ingrid A

AU - Wildiers, Hans

AU - Damian, Silvia

AU - Gendreau, Steven

AU - Rooney, Isabelle

AU - Morrissey, Kari M

AU - Spoerke, Jill M

AU - Ng, Vivian W

AU - Singel, Stina M

AU - Winer, Eric

PY - 2018/9/5

Y1 - 2018/9/5

N2 - BACKGROUND: This phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with letrozole, in patients with locally recurrent or metastatic breast cancer.METHODS: This was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60-330 mg) plus paclitaxel (90 mg/m2) with and without bevacizumab (10 mg/kg) or trastuzumab (2-4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity.RESULTS: Sixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5%), 21 (30.4%), and 2 (2.9%) patients, respectively. Six (8.7%) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib-paclitaxel drug-drug interaction. Two (3.4%) patients experienced complete responses, and 17 (29.3%) patients had partial responses.CONCLUSIONS: Combining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study.TRIAL REGISTRATION: ClinicalTrials.gov, NCT00960960 . Registered on August 13, 2009.

AB - BACKGROUND: This phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with letrozole, in patients with locally recurrent or metastatic breast cancer.METHODS: This was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60-330 mg) plus paclitaxel (90 mg/m2) with and without bevacizumab (10 mg/kg) or trastuzumab (2-4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity.RESULTS: Sixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5%), 21 (30.4%), and 2 (2.9%) patients, respectively. Six (8.7%) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib-paclitaxel drug-drug interaction. Two (3.4%) patients experienced complete responses, and 17 (29.3%) patients had partial responses.CONCLUSIONS: Combining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study.TRIAL REGISTRATION: ClinicalTrials.gov, NCT00960960 . Registered on August 13, 2009.

U2 - 10.1186/s13058-018-1015-x

DO - 10.1186/s13058-018-1015-x

M3 - Article

C2 - 30185228

VL - 20

SP - 109

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

ER -