[177Lu]Lu-NeoB in Combination With Ribociclib and Fulvestrant in Participants With ER+, HER2-, GRPR+ Breast Cancer

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05870579

Collaborator

(none)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The purpose of this phase 1b, single arm, multicenter, open label, dose finding study is to estimate the RD of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in adult female participants with ER+, HER2-, GRPR+, advanced or metastatic breast cancer who have relapsed during or within 12 months from completion of prior (neo)adjuvant ET (escalation part). Additionally this study aims to characterize the safety and tolerability of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in post-menopausal participants and in combination with ribociclib, fulvestrant and goserelin in pre/peri-menopausal participants (expansion part) in the same indications.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: [68Ga]Ga-NeoB Drug: [177Lu]Lu-NeoB Drug: Ribociclib Drug: fulvestrant Other: Goserelin	Phase 1

Detailed Description

The study comprises of a dose escalation part, followed by a dose expansion part.

The dose escalation part will estimate the RD of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant; four provisional dose levels are planned to be tested: 100 millicurie (mCi) (initial dose), 150mCi, 200 mCi and 250mCi in cohorts of 3 to 6 participants. After inclusion of each cohort of 3 to 6 participants, the incidence rate of DLTs will be compared to the pre-defined toxicity rate boundaries to decide whether the next cohort will receive a lower, higher or same dose or whether the trial will be terminated.
The expansion part will assess the safety, tolerability and anti-tumor activity of the RD dose of [177Lu]Lu-NeoB, as established in the dose escalation part, in combination with ribociclib and fulvestrant in both post menopausal and pre-/peri-menopausal participants (who will additionally receive goserelin). A total of 15 participants will be enrolled in the expansion part.

During screening, study participants will receive the investigational imaging agent [68Ga]Ga-NeoB. An additional administration of the [68Ga]Ga-NeoB will be performed within 2-8 weeks from the last administration of [177Lu]Lu-NeoB for a positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI).

Study treatment will include [177Lu]Lu-NeoB on day 1 of each 28-day cycle (+≤3 days) for 6 cycles, ribociclib (once daily; days 1 to 21 in a 28-day cycle) and fulvestrant (C1D1, C1D15, C2D1 and every 28 days thereafter) until disease progression. Pre- and perimenopausal participants in the expansion part will additionally receive goserelin on day 1 of every cycle.

During the treatment period participants will be required to attend a site visit approximately every 28 days, on the first day of each cycle (as well as on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3 and C5D3), to undergo study treatment administration, dosimetry and safety assessments. Tumor assessments are performed every 8 weeks until month 18, every 12 weeks until month 36 and as clinically indicated thereafter, until disease progression. After study treatment discontinuation, participants will be followed up for safety for 8 weeks after their last study treatment administration. Beyond the initial 8 weeks of safety follow-up, all participants will be followed up every 12 weeks until month 36 and every 24 weeks thereafter until month 60, for a total of 5 years from the participant's enrollment in the study, or until death, lost to follow-up, or withdrawal of consent (WoC).

The end of study is defined as the date of the last visit, scheduled procedure or follow up (or date of death, WoC or lost to follow up, whichever occurs first) of the last participant in the study globally, or at 5 years from the date of the last participant enrolled, whichever occurs earlier.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib Dose Finding Study Assessing Safety and Activity of [177Lu]Lu-NeoB in Combination With Ribociclib and Fulvestrant in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Receptor-2 Negative and Gastrin Releasing Peptide Receptor Positive Breast Cancer Experiencing Early Relapse From (Neo)Adjuvant Endocrine Therapy

Anticipated Study Start Date :

Sep 30, 2023

Anticipated Primary Completion Date :

Nov 29, 2024

Anticipated Study Completion Date :

Dec 31, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Participants will receive [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant, in the dose escalation and the dose expansion parts of the study. Goserelin administration is only applicable for pre/peri-menopausal participants, in the dose expansion part.	Drug: [68Ga]Ga-NeoB [68Ga]Ga-NeoB serves as a radioactive imaging compound to be used for PET imaging for localization of GRPR positive lesions, at screening. [68Ga]Ga-NeoB will be administered as a single intravenous (i.v.) dose. Other Names: gallium neoB Drug: [177Lu]Lu-NeoB Study participants will receive [177Lu]Lu-NeoB once every cycle Other Names: lutetium neoB Drug: Ribociclib 600 mg once daily (OD) days 1 to 21 every 28 days Other Names: kisqali Drug: fulvestrant 500 mg at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 and every 28 days thereafter Other: Goserelin For pre/peri-menopausal women in the Dose Expansion only. Other Names: zoladex

Arm

Intervention/Treatment

Experimental: Arm 1

Participants will receive [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant, in the dose escalation and the dose expansion parts of the study. Goserelin administration is only applicable for pre/peri-menopausal participants, in the dose expansion part.

Drug: [68Ga]Ga-NeoB

[68Ga]Ga-NeoB serves as a radioactive imaging compound to be used for PET imaging for localization of GRPR positive lesions, at screening. [68Ga]Ga-NeoB will be administered as a single intravenous (i.v.) dose.

Other Names:

gallium neoB

Drug: [177Lu]Lu-NeoB

Study participants will receive [177Lu]Lu-NeoB once every cycle

Other Names:

lutetium neoB

Drug: Ribociclib

600 mg once daily (OD) days 1 to 21 every 28 days

Other Names:

kisqali

Drug: fulvestrant

500 mg at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 and every 28 days thereafter

Other: Goserelin

For pre/peri-menopausal women in the Dose Expansion only.

Other Names:

zoladex

Outcome Measures

Primary Outcome Measures

Dose escalation part: Incidence and nature of DLTs during the DLT observation period [28 days after the first administration of [177Lu]Lu-NeoB]
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the DLT period from C1D1 of treatment with [177Lu]Lu-NeoB, ribociclib and fulvestrant. The National Cancer Institute (NCI) CTCAE version 5.0 will be used for all grading.
Dose expansion part: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) [From date of enrollment till 8 weeks after end of Treatment, assessed up to approximately 70 months]
The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

Secondary Outcome Measures

Dose escalation part: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) [From date of enrollment till 8 weeks after end of Treatment, assessed up to approximately 70 months]
The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Dose escalation and expansion part: Objective Response Rate (ORR) [From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 110 months]
Objective Response Rate (ORR) is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), as per local review and according to RECIST 1.1.
Dose escalation and expansion part: Duration of Response (DoR) [From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 110 months]
Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented radiographic progression or death due to any cause as per local review and according to RECIST 1.1.
Dose escalation and expansion part: Clinical Benefit Rate (CBR) [From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 110 months]
Clinical Benefit Rate (CBR) is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), or maintaining an overall response of Stable Disease (SD) for at least 24 weeks. CR, PR, and SD are defined as per local review according to RECIST 1.1.
Dose expansion part: Progression Free Survival (PFS) [From the date of first dose to the date of confirmed progression or death due to any cause, whichever comes first, assessed up to approximately 70 months]
Progression Free Survival (PFS) is defined as the time from the date of first dose of [177Lu]Lu-NeoB to the date of confirmed progression or death due to any cause. PFS will be assessed via local review according to RECIST 1.1.
Dose escalation and expansion part: Time activity curves (TACs) of [177Lu]Lu-NeoB in organs and tumor lesions [Cycles 1, 3 and 5: Day 1 (1-4 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i) (1 cycle = 4 weeks)]
Time activity curves (TACs) for the various organs and lesions will be produced as percentage of injected dose in selected organs and lesions.
Dose escalation and expansion part: Absorbed radiation doses of [177Lu]Lu-NeoB in organs and tumor lesions [Cycles 1, 3 and 5: Day 1 (1-4 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i) (1 cycle = 4 weeks)]
The absorbed dose in target organs will be summarized with descriptive statistics.
Dose escalation and expansion part: Concentration of [177Lu]Lu-NeoB in blood over time [Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)]
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Blood concentration of [177Lu]Lu-NeoB will be summarized with descriptive statistics.
Dose escalation and expansion part: Observed maximum blood concentration (Cmax) of [177Lu]Lu-NeoB [Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)]
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Cmax will be listed and summarized using descriptive statistics.
Dose escalation and expansion part: Time of maximum observed drug concentration occurrence (Tmax) of [177Lu]Lu-NeoB [Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)]
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Tmax will be listed and summarized using descriptive statistics.
Dose escalation and expansion part:Area under the blood concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-NeoB [Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)]
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. AUClast will be listed and summarized using descriptive statistics.
Dose escalation and expansion part: Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-NeoB [Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)]
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. CL will be listed and summarized using descriptive statistics.
Dose escalation and expansion part: Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-NeoB [Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)]
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. Vz will be listed and summarized using descriptive statistics.
Dose escalation and expansion part: Terminal elimination half-life (T^1/2) of [177Lu]Lu-NeoB [Cycle 1: Day 1 (Pre-dose (before start of infusion), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)]
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-NeoB. T^1/2 will be listed and summarized using descriptive statistics.
Dose escalation and expansion part: Incidence and severity of AEs following [68Ga]Ga-NeoB administration [3 days after [68Ga]Ga-NeoB administration]
Incidence and severity of AEs following [68Ga]Ga-NeoB administration at screening will be done via the analysis of frequencies for Adverse Event (AEs), Serious Adverse Event (SAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent must be obtained prior to participation in the study
Adult female >= 18 years of age at the time of informed consent
Histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive with ER >10% (regardless of PgR expression) breast cancer by local laboratory testing (based on the most recently analyzed tissue sample)
HER2 negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (e.g. FISH, CISH, or SISH) test is required by local laboratory testing (based on the most recently analyzed tissue sample)
Disease relapse during (neo)adjuvant ET or =<12 months from completion of (neo)adjuvant ET (which may have included a CDK4/6 inhibitor)
Advanced [loco regionally recurrent not amenable to curative therapy (e.g. surgery and/or RT)] or metastatic disease
Dose escalation part only: Participant is post-menopausal at the time of starting study treatment. Post-menopausal status is defined by any of the following (NCCN

Guideline Breast Cancer Version 4.2022):

Prior surgical bilateral oophorectomy
Age >= 60
Age <60 and amenorrhoeic for >= 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression, and FSH and estradiol in the postmenopausal range per local normal range
Age <60 years: chemotherapy-induced amenorrhea for >= 12 months with FSH and estradiol in post-menopausal range on serial assessments
Age <60 years: on tamoxifen with FSH and estradiol level in post-menopausal range

Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (LHRHa) (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression for the purpose of the escalation part.

Dose expansion part only

Participant is post-menopausal at the time of starting study treatment.
Participant is pre/peri-menopausal at the time of starting study treatment

Pre-menopausal status is defined as either:

Patient had last menstrual period within the last 12 months OR
If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the pre-menopausal range per local normal range OR
In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the pre-menopausal range per local normal range.

Peri-menopausal status is defined as neither pre-menopausal nor post-menopausal (see definition above) 8. A confirmed negative serum pregnancy test (β-hCG) within 24 hours before starting study treatment in all pre/peri-menopausal participants in the expansion part (unless the participant has had a hysterectomy).

Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1. (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation) OR If only lytic bone lesions are present, at least one lesion must have a soft tissue component that can be evaluated by CT or MRI and meets the definition of measurability as per RECIST criteria 1.1 (participants with only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).
Participant has at least one target lesion (RECIST 1.1, based on the baseline stand-alone CT/MRI) with [68Ga]Ga-NeoB uptake at PET/CT or PET/MRI The same identified measurable lesion shows the following [68Ga]Ga-NeoB uptake on PET/CT or PET/MRI based on the Visual Scoring Scale, see Section 8.5.2

Escalation part: at least 1 target lesion (RECIST 1.1) scoring 1 or above
Expansion part: at least 1 target lesion (RECIST 1.1) scoring 2 or above 11. Adequate bone marrow and organ function as defined by the following laboratory values:
Absolute neutrophil count (ANC) >= 1.5 × 109/L
Platelets (PLT) >= 100 × 109/L
Hemoglobin (Hb) >= 9.0 g/dL
International Normalized Ratio (INR) =< 1.5
Estimated glomerular filtration rate (eGFR) >= 60 ml/min/1.73m2 measured or calculated by the Cockcroft Gault method.
Total bilirubin < upper limit of normal (ULN) except for participants with Gilbert's syndrome who may only be included if the total bilirubin is =< 3.0 × ULN or direct bilirubin =< 1.5 × ULN.
AST < 2.5 × ULN, except for participants with liver metastasis, who are only included if the AST is < 5 × ULN
ALT < 2.5 × ULN, except for participants with liver metastasis, who are only included if the ALT is < 5 × ULN

Participant must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication:

Potassium
Magnesium
Total Calcium (corrected for serum albumin) 12. Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed locally:
QTcF interval at screening < 450 msec
Mean resting heart rate 50-90 bpm (determined from the ECG) 13. ECOG performance status 0 or 1 14. Be able to communicate with the investigator and comply with the requirements of the study procedures 15. Willing to remain at the clinical site as required by the protocol

Exclusion Criteria:

Prior treatment in the advanced/metastatic setting
Symptomatic visceral disease or any disease burden that makes the patient ineligible for ribociclib plus endocrine treatment per the Investigator's best judgment.
Presence of CNS involvement unless meeting BOTH of the following criteria:

At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment.
Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.

Currently receiving warfarin or other Coumadin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin, or fondaparinux is allowed
Diagnosis of inflammatory breast cancer at screening
Child Pugh score B or C
History or current diagnosis of impaired cardiac function, clinically significant cardiac disease or ECG abnormalities indicating significant risk of safety for participants in the study such as:

History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment
Documented cardiomyopathy
Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
Long QT syndrome or family history of idiopathic sudden death or congenital long

QT syndrome, or any of the following:

Risk factors for TdP including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
Inability to determine the QTcF interval
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third-degree AV block)
Systolic Blood Pressure (SBP) >160 or <90 mmHg

Major surgery within 14 days prior to [68Ga]Ga-NeoB administration at screening or has not recovered from major side effects.
Use of tamoxifene or toremifene within a washout a period of 5 half-lives or goserelin =< 28 days from C1D1
Participant is concurrently using hormone replacement therapy.
Known or expected hypersensitivity to any of the study drugs or any of their excipients
Concurrent bladder outflow obstruction or unmanageable urinary incontinence
Prior administration of a radiopharmaceutical unless 10 or more half-lives have elapsed before injection of [68Ga]Ga-NeoB
Participant has received extended-field RT =< 4 weeks or limited field RT =< 2 weeks prior to start of treatment and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the participant at Investigator's discretion) and/or prior EBRT to more than 25% of the bone marrow.
Presence of concurrent malignancy or malignancy within 3 years of starting study treatment, with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer.
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
Patient is currently receiving or has received systemic corticosteroids =< 2 weeks prior to starting study treatment, or who have not fully recovered from side effects of such treatment.

Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)

Participant has a history of ongoing acute pancreatitis within 1 year from screening
Presence of any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to starting study treatment:

Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pummelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study treatment)

Participation in a prior investigational study within 30 days prior to start of treatment or within 5-half lives of the investigational product, whichever is shorter. If the participant is enrolled or planned to be enrolled in another study that does not involve an investigational product, the agreement of the Novartis study medical lead is required to establish eligibility.
For expansion part

Pregnant or breast-feeding women
Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for up to 7 months after the last dose of [177Lu]Lu-NeoB or 2 years after the last dose of fulvestrant, whichever is longer. Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
Male partner sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for the study participant.
Placement of an intrauterine device (IUD) and concurrent use of barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

If local regulations deviate from the recommendations provided above, local regulations apply and will be described in the ICF.

Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child-bearing potential.

Note: Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or intrauterine system (IUS) or any other form of hormonal contraception for example hormone vaginal ring, IUD or transdermal hormone contraception is not allowed in this study.