Phase I/prospective randomized phase II trial Of the Safety and Efficacy of tamoxifen in combination with the Isoform selective Pi3K inhibitor GDC-0032 compared with tamoxifen alONe in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment (POSEIDON trial)

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 120

Inclusion Criteria

Phase II
- Minimum age for inclusion 18 years
- The patient has a WHO performance status * 2
- Premenopausal/Postmenopausal female breast cancer patient with histological
proven ER and/or PR positive, HER2 negative breast cancer (based on the most
recent assessment of ER and PR status from primary breast cancer or from
recurrent or metastatic disease). Premenopausal patient should also receive a
LHRH agonist.
- The patient*s breast cancer must be negative for HER2 over-expression by IHC
(IHC score *1+) or for HER2 gene amplification by FISH or CISH or SISH
- Patients must have either measurable or evaluable disease by RECIST criteria
version 1.1.
- The patient has recurrent or metastatic breast cancer that is refractory to
an endocrine therapy defined as the occurrence of either of the following while
the patient is on endocrine therapy:
*Disease progression of locally advanced or metastatic breast cancer
*Disease recurrence of early stage breast cancer (i.e., recurrence while
receiving adjuvant treatment with endocrine therapy)
- Availability of a representative tumour tissue specimen
- The patient has adequate organ and marrow function, as defined here:
* Absolute Neutrophil Count (ANC) * 1.5 x 109/L
* Hemoglobin (Hgb) * 9 g/dl (<=5.6 mmol/L)
* Platelets (plt) * 100 x 109/L
* AST/SGOT and ALT/SGPT * 2.5 x Upper Limit of Normal (ULN) (or < 5 x ULN in
case of liver metastasis)
* Serum bilirubin * 1.5 x ULN (or < 3 x ULN in case of known Gilbert syndrome)
* Serum creatinine * 1.5 x ULN or 24-hour clearance * 60 mL/min

Exclusion Criteria

Exclusion Criteria
- Patients with premenopausal follicle stimulating hormone (FSH) and/or plasma
estradiol levels who are not treated with a LHRH agonist
- Prior treatment with PI3K-pathway-targeted therapies (including PI3K, PDK,
AKT and mTOR inhibitors) is not permitted, except for everolimus. Up to 50% of
all patients may be pretreated with everolimus.
- The following restrictions on prior anticancer therapy apply;
- Endocrine therapies or small molecule targeted (non-cytotoxic) inhibitors
(including investigational kinase inhibitors) within 2 weeks or 5 half-lives of
the compound or active metabolites, whichever is longer but not more than 4
weeks, before the first dose of the study treatment are not allowed
- Previous treatment with tamoxifen, unless tamoxifen was administered in the
adjuvant setting and stopped >1 year before metastatic relapse (exception:
patient who cross over to tamoxifen + GDC-0032 arm after progression on
tamoxifen+placebo)
- No more than 5 prior chemotherapeutic regimens for metastatic breast cancer
- Radiation therapy within 2 weeks before the first dose of study treatment,
unless of palliative intent, not compromising bone marrow function
- Cytotoxic chemotherapy within 3 weeks, or nitrosoureas or mitomycin C within
6 weeks before the first dose of the study treatment
- Antibody therapy within 4 weeks before the first dose of the study treatment
- Major surgery or not recovered from major surgery, within 4 weeks before the
first dose of study treatment
- The patient has not recovered from toxicity due to prior therapy to grade *1
or to pre-therapy baseline. Patients with grade 2 peripheral neuropathy or
grade 2 alopecia related to prior therapies are eligible
- The patient has untreated, symptomatic, or progressive brain metastases

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Dose escalation (phase Ib):<br /><br>- The recommended phase II dose of GDC-0032 in combination with tamoxifen<br /><br><br /><br>Phase II;<br /><br>Progression free survival in hormone receptor positive, HER2 negative,<br /><br>metastatic breast cancer patients randomized to (tamoxifen and placebo)<br /><br>compared with<br /><br>(tamoxifen plus GDC-0032)</p><br>

Secondary Outcome Measures