Hormone receptor positive metastatic breast cancer MedDRA version: 19.0 Level: LLT Classification code 10072737 Term: Advanced breast cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: GDC-0032/ Taselisib ®/ RG 7604
Pharmaceutical Form: Tablet
INN or Proposed INN: Taselisib ®
CAS Number: 1282512484
Current Sponsor code: GDC-0032
Other descriptive name: GDC-0032 (RO5537
Sponsors
NKI-AVL
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Phase Ib (dose escalation) • Minimum age for inclusion 18 years • Breast cancer patients with ER and/or PR positive tumours, or patients with other cancer types whom the investigator considers might benefit from endocrine therapy combined with PI3K inhibition (for example ovarian cancer and cancer of the uterus). • Patients with WHO performance status = 2 • Adequate organ and marrow function • Fasting glucose = 120 mg/dL (=6.66 mmol/L) and HbA1c = ULN. Randomized phase II: • Pre- and Postmenopausal patients with histology-/cytology- proven ER and/or PR positive*, HER2 negative breast cancer with recurrent or metastatic disease which has progressed on prior endocrine therapy Premenopausal patients should also receive LHRH agonist. • Patient with WHO performance status = 2 • Adequate organ and marrow function • Fasting glucose = 120 mg/dL (=6.66 mmol/L) and HbA1c = ULN. • Patients must have either measurable or evaluable disease by RECIST criteria. • Availability of a representative tumour tissue specimen Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 300 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 22
Exclusion criteria
Exclusion criteria: Exclusion Criteria • Patients with premenopausal follicle stimulating hormone (FSH) and/or plasma estradiol levels who are not treated with a LHRH agonist • More than 5 prior chemotherapeutic regimens for metastatic breast cancer • Endocrine therapies or small molecule targeted (non-cytotoxic) inhibitors (including investigational kinase inhibitors) within 5 half-lives of the compund or active metabolites with a maximum of 4 weeks.. • 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 • Radiation therapy within 2 weeks before the first dose of study treatment • Untreated, symptomatic, or progressive brain metastases. • PT/ INR (PTT) test results at screening > 1.3 x the laboratory upper limit of normal. • Corticosteroid use equivalent to more than 10mg prednisone daily • Patients with a history of - Thrombo-embolic disease or is currently receiving therapeutic doses of warfarin - Crohn’s disease or ulcerative colitis or other forms of autoimmune colitis - Clinically significant cardiac or pulmonary dysfunction - Type 1 or 2 diabetes requiring daily anti-hyperglycaemic medication
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Dose escalation (phase Ib): • To determine the recommended phase II dose (RPTD) of GDC-0032 in combination with tamoxifen in hormone receptor positive metastatic breast cancer patients who have progressed after prior endocrine treatment Randomized phase II: • To compare progression free survival (PFS) in hormone receptor positive, HER2 negative, metastatic breast cancer patients (both lobular and non-lobular) with prior exposure to endocrine therapy, randomized to treatment with (tamoxifen and placebo) versus (tamoxifen and GDC-0032) at the recommended phase II dose defined in the phase 1b study ;Secondary Objective: phase Ib: •safety and tolerability using CTCAE v. 4.03 criteria •pharmacokinetics of GDC-0032 in combination with tamoxifen •investigate the possibility of major drug-drug interactions (PK) •obtain proof of target inhibition by selected pharmacodynamic measurements •look for preliminary evidence of anti-tumour activity •assess the status of potential biomarkers for drug response •assess germline DNA sequence for pharmacogenetics studies Randomized phase II: •compare OS, ORR, CBR in both treatment arms •compare PFS, ORR, CBR and OS in patients randomised to tamoxifen and placebo versus tamoxifen in combination with GDC-0032 in lobular breast cancer patients and in prespecified subgroups •compare toxicity profiles in each treatment arm using CTCAE v. 4.03 criteria •compare differences in tamoxifen and tamoxifen metabolite levels between treatment arms •assess potential biomarkers of drug response •assess germline DNA sequence for pharmacogenetic studies ;Primary end point(s): Dose escalation (phase Ib): • The recommended phase II dose of GDC-0032 in combination with tamoxifen Randomized phase II: • Progression free survival in hormone receptor positive, HER2 negative, metastatic breast cancer patients randomized to (tamoxifen and placebo) compared with (tamoxifen plus GDC-0032) ;Timepoint(s) of evaluation of this end point | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Dose escalation (phase Ib): • Toxicity profile, severity and frequency of adverse events (based on the CTCAE Version 4.03 • Pharmacokinetic measurements for GDC-0032 and tamoxifen • Pharmacodynamic measurements of PI3K inhibition like: p-AKT, p-mTOR, p-p70S6K, p-S6RP, p-4EBP1; changes in markers of glucose metabolism; and treatment induced cellular responses such as inhibition of proliferation in tumour biopsies • Assessment of objective response measured by RECIST criteria. • Assessment of gene mutation status (like PIK3CA), the level of relevant proteins and phospho-proteins in PI3K pathway, serial circulating tumour DNA measurements and the association with therapy response • Exploratory assessment of germline DNA sequence for pharmacogenetics studies (including CYP2D6 genotype) Randomized phase II: • Differences in ORR, CBR and OS between both treatment arms • PFS, ORR, CBR and OS in patients randomized to (tamoxifen and placebo) compared with (tamoxifen plus GDC-0032) in the predefined subgroups. • Toxicity profile, severity and frequency of adverse events (based on the CTCAE Version 4.03) in both treatment arms (including PRO-CTCAE criteria in a subgroup of patients) • Differences in tamoxifen and tamoxifen metabolite levels between both arms • Assessment of gene mutation status (like PIK3CA), the level of relevant proteins and phospho-proteins in PI3K pathway, serial circulating tumour DNA measurements and the association with therapy response • Exploratory assessment of germline DNA sequence for pharmacogenetics studies (including CYP2D6 genotype) in relation to tamoxifen and GDC-0032 pharmacokinetics / toxicity ;Timepoint(s) of evaluation of this end point: Dose escalation (phase Ib): • 6 months after end of treatment Randomized phase II: • to be assesses every 3 months after end of treatment, until death | — |
Countries
Netherlands, United Kingdom
Contacts
Public ContactProf. Dr. S. Linn
NKI-AVL
Outcome results
None listed