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Clinical Trial
. 2018 Sep 5;20(1):109.
doi: 10.1186/s13058-018-1015-x.

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  1   2 , Sara Cresta  3 , Ingrid A Mayer  4 , Hans Wildiers  5 , Silvia Damian  3 , Steven Gendreau  6 , Isabelle Rooney  7 , Kari M Morrissey  8 , Jill M Spoerke  6 , Vivian W Ng  9 , Stina M Singel  7 , Eric Winer  10
Affiliations
Clinical Trial

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 et al. Breast Cancer Res. .

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.

Keywords: GDC-0941; PI3K; Pictilisib.

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Conflict of interest statement

Ethics approval and consent to participate

This study was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki. Approval of the protocol and any accompanying material provided to the patients was obtained from independent ethics committees at participating institutions (Table 4). All patients provided written informed consent.

Consent for publication

Not applicable.

Competing interests

PS has received travel support from Roche for presentation of parts of this work at the 37th San Antonio Breast Cancer Symposium in 2014, institutional research support from Genentech for exploring pictilisib in patient-derived xenograft models of sarcoma, and institutional technical support from Roche (donation of a LightCycler). In addition, and outside the submitted work, PS has received honoraria (institutional support) from Daiichi Sankyo, Eisai, Eli Lilly, Medpace, Novartis, and Swedish Orphan Biovitrium; consulting or advisory role institutional support from Sixth Element Capital, Adaptimmune, Amcure, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Cristal Therapeutics, Daiichi Sankyo, Eisai, Eli Lilly, Epizyme, Genzyme, Ipsen, Loxo Oncology, Medpace, Nektar, Novartis, Philogen, PIQUR Therapeutics, and Plexxikon; speaker’s bureau institutional support from Bayer, Eisai, Eli Lilly, GSK, Novartis, PharmaMar, and Swedish Orphan Biovitrium; research funding (institutional support) from Bayer, Blueprint Medicines, CoBioRes NV, Exelixis, GSK, Novartis, and Plexxikon; and institutional support for travel, accommodation, and expenses from Sixth Element Capital, Adaptimmune, Amcure, AstraZeneca, Bayer, Blueprint Medicines, BMS, Boehringer Ingelheim, Cristal Therapeutics, Daiichi Sankyo, Eisai, Eli Lilly, Epizyme, Genzyme, GSK, Ipsen, Loxo Oncology, Medpace, Nektar, Novartis, PharmaMar, Philogen, PIQUR Therapeutics, Plexxikon, and Swedish Orphan Biovitrium. IAM has received research support from Novartis and Pfizer and advisory board honoraria from Novartis. HW has received advisory board honoraria, speaker‘s fees, and travel support from Roche. SG, IR, KMM, JMS, VWN, and SMS are employees of Genentech/Roche. EW has received research support from Genentech, an advisory board honorarium from Genentech, and scientific advisory board support from Leap Pharmaceuticals. SC and SD declare that they have no potential conflicts of interest.

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Figures

Fig. 1
Fig. 1
Participant flow diagram. AE Adverse event, PD Progressive disease
Fig. 2
Fig. 2
Plasma 6α-OH-paclitaxel/paclitaxel AUC ratio as a function of pictilisib dose. Patients with evaluable 6α-OH-paclitaxel and paclitaxel PK after multiple doses of paclitaxel and pictilisib were pooled across all paclitaxel treatment arms (parts 1 and 2, n = 49). Black lines represent the median ratio for each dose level, and dots represent individual subject ratios. PK Pharmacokinetics
Fig. 3
Fig. 3
Waterfall plot of maximum percentage changes from baseline in SLD for target lesions. Maximum percentage changes are shown in (a) part 1 (pictilisib + paclitaxel ± bevacizumab), (b) parts 2A and B (2A: pictilisib + paclitaxel; 2B: pictilisib + paclitaxel + bevacizumab), (c) part 2C (pictilisib + paclitaxel + trastuzumab), and (d) part 3 (pictilisib + letrozole). PTEN categories were defined as PTEN loss (PTEN H-score ≥ 0 but ≤ 100) or nonloss (PTEN H-score > 100). CR Complete response, MND Mutation not detectable, PD Progressive disease, PIK3CA Phosphatidylinositol-45-bisphosphate 3-kinase catalytic subunit-alpha, PR Partial response, PTEN Phosphatase and tensin homolog, SD Stable disease, SLD Sum of the longest diameters, UE Unevaluable
See this image and copyright information in PMC

References

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