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-   -   A Study of PI3-Kinase Inhibitor GDC-0941 (https://her2support.org/vbulletin/showthread.php?t=59249)

'lizbeth 10-08-2013 07:51 PM

A Study of PI3-Kinase Inhibitor GDC-0941
A Study of PI3-Kinase Inhibitor GDC-0941 in Combination With Paclitaxel, With and Without Bevacizumab or Trastuzumab, in Patients With Locally Recurrent Or Metastatic Breast Cancer

This is an open-label, multicenter, Phase Ib dose-escalation study to assess the safety, tolerability, and pharmacokinetics of oral (PO) GDC-0941 administered with intravenous (IV) paclitaxel with and without and IV bevacizumab or IV trastuzumab in patients with locally recurrent or metastatic breast cancer.


donocco 10-13-2013 11:29 PM

Re: A Study of PI3-Kinase Inhibitor GDC-0941
Im a pharmacist interested in learning about
new drugs. Ill study this P13 Kinase inhibitor
and see what I can gleen from the articles about
its pharmacology


donocco 10-14-2013 12:58 AM

Re: A Study of PI3-Kinase Inhibitor GDC-0941
I did some basic research on the drug GDC-0941. Apparently its generic name is Pictilsib. I saw references to its possible use in a number of types of cancer such as Multiple Myeloma, Breast Cancer, various types of Lymphomas and Im sure there are others.

There was one Phase one study of GDC-0941 in the treatment of Multiple Myeloma aqnd some advanced solid tumours. There were a range of doses listed, but one metastatic myeloma patient had a partial response at 330mg GDC-041 daily. The maximum tolerated daily dose was determined to be 450mg daily.

The main side effects are nausea, vomiting, diarrhea, taste disturbances, loss of appetite, and fatigue. Hyperglycemia was seen in one patient taking 130mg daily and Diabetes is listed as a reason for exclusion in a clinical trial I saw.

Hope this info helps


schoonder 10-14-2013 06:20 AM

Re: A Study of PI3-Kinase Inhibitor GDC-0941
GDC-0941 is also being evaluated in a phase I trial with T-DM1. Trial is active, no longer recruiting candidates and approaching anticipated completion date.

'lizbeth 10-14-2013 08:07 AM

Re: A Study of PI3-Kinase Inhibitor GDC-0941
Paul - that is a nice summary. I appreciate having a pharmacist's point of view.

Schoonder, I did not realize it was being combined with T-DM1.

schoonder 10-14-2013 11:53 AM

Re: A Study of PI3-Kinase Inhibitor GDC-0941
Report from SABCS 2010
[P6-15-02] A Phase Ib Study Evaluating Safety, Tolerability, Pharmacokinetics (PK), and Activity of the Phosphoinositide-3 Kinase (PI3K) Inhibitor GDC-0941 in Combination with Trastuzumab-MCC-DM1 (T-DM1) in Patients with Advanced HER2-Positive Breast Cancer.

Krop IE, Wolff AC, Winer EP, Miller KD, Park BH, Ware J, Holden S, Levy GG, Derynck M, Storniolo AM. Dana-Farber Cancer Institute, Boston, MA; Johns Hopkins Kimmel Cancer Center, Baltimore, MD; Indiana University Simon Cancer Center, Indianapolis; Genentech Inc, South San Francisco, CA

Background: Aberrant activation of the PI3K pathway has been hypothesized to reduce the efficacy of trastuzumab-based therapy in patients with HER2-positive breast cancer. Inhibition of the PI3K pathway in combination with continued suppression of HER2 signaling is one strategy that may enhance sensitivity to HER2-directed therapy. GDC-0941 is a potent and selective oral pan-inhibitor of class I PI3K (in vitro IC50 for the p110-alpha subunit is 3 nM) and demonstrates single-agent activity in preclinical xenograft models. T-DM1 is a novel antibody-drug conjugate that combines the biological properties of trastuzumab with the highly potent anti-microtubule agent DM1 and has shown promising activity in two Phase II studies in heavily pretreated patients with advanced HER2-positive breast cancer. In vivo studies of GDC-0941 dosed in combination with T-DM1 have shown increased anti-tumor activity relative to either T-DM1 or GDC-0941 alone in trastuzumab-resistant and PI3K mutant breast cancer xenograft models.
Material and Methods: Patients with histologically confirmed advanced HER2-positive breast cancer who have progressed on prior trastuzumab therapy were enrolled in a Phase Ib study (GDC4627g) of GDC-0941 and T-DM1 using a 3+3 dose escalation design. Treatment consists of T-DM1 IV on a 21-day schedule (q3wks) and GDC-0941 orally given daily for 14 of 21 days. Objectives include an evaluation of the safety, tolerability and PK of GDC-0941 administered with T-DM1, as well as determining the maximum tolerated dose of this combination.
Results: Thirteen patients have been enrolled in three successive cohorts. Starting doses of T-DM1 and GDC-0941 were 3.6 mg/kg and 80 mg, respectively (T-DM1 administered one day after GDC-0941, cycle 1 only). A dose-limiting toxicity (DLT) of Grade 4 thrombocytopenia was seen in the first cohort. The cohort was expanded without any additional DLTs. Two DLTs were observed in the second cohort (T-DM1 3.6 mg/kg and GDC-0941 115 mg): Grade 4 thrombocytopenia in one patient and Grade 3 fatigue in a second patient in the setting of newly diagnosed brain metastases. A third cohort was enrolled with a reduced dose of T-DM1 of 3.0 mg/kg and GDC-0941 at 100 mg (both starting the same day on cycle 1). No DLTs were observed and dose escalation continues. Preliminary PK for GDC-0941, T-DM1 and free DM1 were similar to historical profiles from previous studies of these molecules. Evidence of clinical activity has been reported in a number of participants.
Conclusions: This trial represents the first report of a regimen combining a HER2-targeted agent with a PI3K inhibitor. DLTs observed with this combination to date have been Grade 4 thrombocytopenia and Grade 3 fatigue. Encouraging evidence of clinical activity has been observed. Dose-escalation continues and updated PK/PD, safety and efficacy data will be presented. Data from this study will inform plans for a subsequent Translational Breast Cancer Research Consortium clinical trial.

Sunday, December 12, 2010 7:00 AM

'lizbeth 10-14-2013 04:59 PM

Re: A Study of PI3-Kinase Inhibitor GDC-0941
Pictilisib is @ Genentech:


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