Poseidon: Clinical Trial to Evaluate the Safety and Effectiveness of GDC-0032 When Given Alongside Tamoxifen

Sponsor

The Netherlands Cancer Institute (Other)

Overall Status

Suspended

CT.gov ID

NCT02285179

Collaborator

Genentech, Inc. (Industry), EurocanPlatform (Other), Rather (Other)

290

Enrollment

Locations

Arms

Anticipated Duration (Months)

20.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: GDC-0032 Drug: Tamoxifen	Phase 1/Phase 2

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

290 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

double blinded study

Primary Purpose:

Treatment

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.

Actual Study Start Date :

Nov 1, 2014

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: tamoxifen and GDC-0032 20 mg tamoxifen QD and 4 MG GDC-0032 QOD	Drug: GDC-0032 Dose of GDC-0032 given orally, once daily (total daily dose) level -1: 2 mg Q.O.D GDC-0032 level 1: (starting) 2 mg QD for 21 days, 7 days off and tamoxifen 20 mg qd level 2: 4 mg QD for 21 days, 7 days off and tamoxifen 20 mg qd Drug: Tamoxifen daily dose of 20 mg
Placebo Comparator: tamoxifen and placebo 20 mg tamoxifen QD and placebo QOD	Drug: Tamoxifen daily dose of 20 mg

Arm

Intervention/Treatment

Experimental: tamoxifen and GDC-0032

20 mg tamoxifen QD and 4 MG GDC-0032 QOD

Drug: GDC-0032

Dose of GDC-0032 given orally, once daily (total daily dose) level -1: 2 mg Q.O.D GDC-0032 level 1: (starting) 2 mg QD for 21 days, 7 days off and tamoxifen 20 mg qd level 2: 4 mg QD for 21 days, 7 days off and tamoxifen 20 mg qd

Drug: Tamoxifen

daily dose of 20 mg

Placebo Comparator: tamoxifen and placebo

20 mg tamoxifen QD and placebo QOD

Drug: Tamoxifen

daily dose of 20 mg

Outcome Measures

Primary Outcome Measures

Number of patients with MTD toxicity [4 weeks]
MTD toxicity will be assessed in the first 28 days of treatment

Secondary Outcome Measures

Safety Number of patients with adverse events [2 year]
Number of patients with adverse events
Pharmacokinetics Number of patients with germline DNA sequence [12 months]
Number of patients with germline DNA sequence
Response Number of patients with a response to protocol treatment [2 year]
Number of patients with a response to protocol treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Gustave Roussy	Paris	France
2	Antoni van Leeuwenhoek	Amsterdam	Netherlands	1066 CX
3	Reinier de Graaf Gasthuis	Delft	Netherlands
4	Haaglanden Medisch Centrum	Den Haag	Netherlands
5	Deventer Ziekenhuis	Deventer	Netherlands
6	Ziekenhuis Groep Twente	Hengelo	Netherlands
7	MUMC	Maastricht	Netherlands
8	Hospital Germans Trias i Pujol	Badalona	Spain
9	Vall d'Hebron University Hospital/VHIO	Barcelona	Spain	080035
10	Hospital Clínic de Barcelona	Barcelona	Spain
11	Hospital ICO-Hospitalet (Bellvitge)	Barcelona	Spain
12	Hospital Arnau de Vilanova	Lleida	Spain
13	Hospital Universitari Sant Joan de Reus	Tarragona	Spain
14	University of Cambridge	Cambridge	United Kingdom	CB20QQ