Description:
This study is designed as a phase 1 dose escalation study followed by a randomised phase II
study. The study will be performed in three different centres: Addenbrooke & Cambridge
university (Cambridge, UK), Netherlands Cancer Institute Amsterdam), and Vall d'Hebron
Hospital (Barcelona, Spain).
Three to six patients will be followed for one completed cycle of therapy (28 days) and
subsequent enrolment of new cohorts will be based on the safety assessment in that first
cycle and the documentation of dose limiting toxicities. To determine the safety and efficacy
of tamoxifen in combination with the isoform selective Pi3K inhibitor GDC-0032 compared with
tamoxifen alone.
Title
- Brief Title: Clinical Trial to Evaluate the Safety and Effectiveness of GDC-0032 When Given Alongside Tamoxifen
- Official Title: Phase I/Prospective Randomized Phase II Trial Of the Safety and Efficacy of Tamoxifen in Combination With GDC-0032 Compared With Tamoxifen alONe.
Clinical Trial IDs
- ORG STUDY ID:
M14POS
- NCT ID:
NCT02285179
Conditions
Interventions
Drug | Synonyms | Arms |
---|
GDC-0032 | | tamoxifen and GDC-0032 |
Tamoxifen | | tamoxifen and GDC-0032 |
Purpose
This study is designed as a phase 1 dose escalation study followed by a randomised phase II
study. The study will be performed in three different centres: Addenbrooke & Cambridge
university (Cambridge, UK), Netherlands Cancer Institute Amsterdam), and Vall d'Hebron
Hospital (Barcelona, Spain).
Three to six patients will be followed for one completed cycle of therapy (28 days) and
subsequent enrolment of new cohorts will be based on the safety assessment in that first
cycle and the documentation of dose limiting toxicities. To determine the safety and efficacy
of tamoxifen in combination with the isoform selective Pi3K inhibitor GDC-0032 compared with
tamoxifen alone.
Detailed Description
To determine the recommended phase II dose (RPTD) of GDC-0032 in combination with tamoxifen
in hormone receptor positive, HER2 negative metastatic breast cancer patients who have
progressed after prior endocrine treatment .Description of toxicity profile, severity and
frequency of adverse events (observed with the combination of GDC-0032 and tamoxifen To
evaluate the safety and tolerability of GDC-0032 in combination with tamoxifen, recording
adverse events using CTCAE v. 4.0 criteria To describe the pharmacokinetics of GDC-0032 in
combination with tamoxifen To investigate the possibility of major drug-drug interactions
(PK) To obtain proof of target inhibition by selected pharmacodynamic measurements To look
for preliminary evidence of anti-tumour activity To assess the status of potential biomarkers
for drug response like PIK3CA gene mutations, relevant proteins and phospho-proteins in the
PI3K pathway, circulating tumour DNA (ct-DNA) To assess germline DNA sequence for
pharmacogenetics studies
Trial Arms
Name | Type | Description | Interventions |
---|
tamoxifen and GDC-0032 | Experimental | 20 mg tamoxifen QD and 4 MG GDC-0032 QOD | |
tamoxifen and placebo | Placebo Comparator | 20 mg tamoxifen QD and placebo QOD | |
Eligibility Criteria
Inclusion criteria:
Minimum age for inclusion 18 years
- The patient has a WHO performance status ≤ 2
- Premenopausal and 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). If a patient is premenopausal by clinical and analytical
assessment (defined as having premenopausal follicle stimulating hormone (FSH) and/or
plasma estradiol levels), she 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:
- If a patient is currently receiving bisphosphonates, the patient must have received
the bisphosphonates for at least 1 month before starting study treatment.
- The patient has adequate organ and marrow function, as defined in protocol.
- The patient has no other diagnosis of malignancy or evidence of other malignancy for 2
years before screening for this study (except non-melanoma skin cancer or in situ
carcinoma of the cervix).
- Life expectancy ≥ 12 weeks.
- Fasting glucose ≤ 120 mg/dL (=6.66 mmol/L) and HbA1c ≤ ULN.
exclusion criteria:
- The following restrictions on prior anticancer therapy apply;
- Endocrine therapies or small molecule targeted (non-cytotoxic) inhibitors within 2
weeks or 5 half-lives of the compound or active metabolites, whichever is longer,
before the first dose of the study treatment are not allowed
--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
- Other malignancy with the exclusion of carcinoma in situ.
- 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. -The patient
has a history of thrombo-embolic disease or is currently receiving anticoagulation
with therapeutic doses of warfarin.
- The patient has prothrombin time/ International Normalized Ratio (PT/ INR) or partial
thromboplastin time (PTT) test results at screening that are above 1.3 x the
laboratory upper limit of normal.
- Patients with a history of Crohn's disease or ulcerative colitis or other forms of
autoimmune colitis
- The patient has uncontrolled significant intercurrent illness
- History of clinically significant cardiac or pulmonary dysfunction-The patient has a
type 1 or 2 diabetes requiring daily anti-hyperglycemic medication
- Corticosteroid use equivalent to more than 10mg prednisone daily
- The patient is known to be positive for the human immunodeficiency virus (HIV).
- The patient has a previously identified allergy or hypersensitivity to components of
the study treatment formulation(s).
- The patients is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee
- Pregnant or nursing women
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | Female |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Number of patients with MTD toxicity |
Time Frame: | 4 weeks |
Safety Issue: | |
Description: | MTD toxicity will be assessed in the first 28 days of treatment |
Secondary Outcome Measures
Measure: | Safety Number of patients with adverse events |
Time Frame: | 2 year |
Safety Issue: | |
Description: | Number of patients with adverse events |
Measure: | Pharmacokinetics Number of patients with germline DNA sequence |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Number of patients with germline DNA sequence |
Measure: | Response Number of patients with a response to protocol treatment |
Time Frame: | 2 year |
Safety Issue: | |
Description: | Number of patients with a response to protocol treatment |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Suspended |
Lead Sponsor: | The Netherlands Cancer Institute |
Trial Keywords
- GDC-0032
- Pi3K inhibitor
- tamoxifen
- hormone receptor positive
- RECIST
- pharmacodynamic
Last Updated
January 22, 2021