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Exemestane

Palbociclib

Goserelin

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Antineoplastic Agents, Hormonal

Palbociclib (Pfizer) 125mg/day orally for 3 weeks followed by 1 week off plus Exemestane (Pfizer) 25mg/day orally continuously plus Goserelin (Astrazeneca) 3.6 mg SC given every 28 days

Exemestane (Pfizer) 25mg/day orally continuously plus Goserelin (Astrazeneca) 3.6 mg SC given every 28 days

Loay M. Kassem, MD

Georgia Demetriou, M.D

This is an open label, randomized, multicenter, international phase II study for premenopausal patients with hormone receptor positive, HER2 negative metastatic or locally advanced breast cancer. Patients will be randomized to receive either palbociclib + exemestane + OFS (Arm 1) or exemestane +OFS (Arm 2).

Treatment will be continued until disease progression, unacceptable toxicities, or withdrawal of consent.

There is a strong in-vitro and clinical evidence suggesting that the dual inhibition of CDK 4/6 and ER signaling is a highly effective therapeutic strategy in HR+ MBC. With the unprecedented success of palbociclib in PALOMA-1 trial, several phase 2 and 3 trials are underway to evaluate this agent (and other CDK4/6 inhibitors as well) in the different clinical scenarios of HR+ breast cancer \[28\].The vast majority of these trials -if not all- are testing these novel agents in postmenopausal patients, which would render the clinical experience of these agents restricted to postmenopausal women (median age was 62 years in PALOMA-1 trial) The scarcity of clinical trials addressing endocrinal therapy in premenopausal women with MBC is, at least in part, related to the fact that the majority of women in western countries are diagnosed with breast cancer during their postmenopausal life. However the situation is rather different in many countries, including those in the Middle East region, where the median age of women diagnosed with breast cancer is below 50 years, and where approximately 50% of these patients are still menstruating.

This study will be the first to explore the therapeutic effects of palbociclib when combined with exemestane and ovarian function suppression (OFS) in premenopausal with hormone receptor positive and HER2 negative MBC, and how it will compare to the classic approach of using OFS plus an aromatase inhibitor.

PalbocIclib in PreMenopausal Women With ER Positive/HER-2 Negative MetAstatic Breast Cancer

A Phase II Study of Ovarian Function Suppression And ExemesTane With or Without PalbocIclib in PreMenopausal Women With ER Positive / HER-2 Negative MetAstatic Breast Cancer

Presentation in a conference proceedings in mid 2022 Full publication in January 2023

Hamdy A. Azim

Prof

Symptoms and General Pathology

Recurrence

Fulvestrant

LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BKM120 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle.

LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BYL719 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle.

LEE011 - 28 day cycles (3 weeks on, 1 week off) or (continuous daily dosing - dose escalating) fulvestrant - 500 mg i.m. given on Day 1 and Day 15 of Cycle 1, then on Day 1 of each subsequent cycle.

LEE011: supplied as capsules of dosage strength of 50 mg or 200 mg. The capsules will be differentiated through different sizes

LEE011

BYL719: supplied as tablets of dosage strength of 10 mg, 50 mg or 200 mg. Tablets will be differentiated through different sizes and/or colors.

BYL719

Fulvestrant will be supplied according to local practice and regulation. Fulvestrant is a commercially available product, comes in 500 mg dose and is an injection for intramuscular (i.m.) administration.

fulvestrant

BKM120: supplied as 10 mg or 50 mg capsules. The capsules will be differentiated through different sizes.

BKM120

Novartis Pharmaceuticals

The purpose of this trial is to explore the clinical utility of the three investigational agents in HR+, HER2- breast cancer. LEE011 (CDK4/6 inhibitor), BKM120 (PI3K-pan class I-inhibitor) and BYL719 (PI3K-alpha specific class I inhibitor) in combination with fulvestrant.

This is a multi-center, open-label Phase Ib/II study. The Phase Ib portion of the study is a dose escalation to estimate the MTD and/or RP2D for three regimens: LEE011 with fulvestrant; LEE011 and BKM120 with fulvestrant; LEE011and BYL719 with fulvestrant.

The Phase II portion of the study was planned to be a randomized study to assess the anti-tumor activity as well as safety and tolerability of LEE011 with fulvestrant to LEE011 and BKM120 with fulvestrant, and LEE011 and BYL719 with fulvestrant in patients with ER+/HER2- locally advanced or metastatic breast cancer.

Approximately 216 adult women with ER+/HER2- locally advanced or metastatic breast cancer were planned to be enrolled.

On 31-May-2016 Novartis's made the decision decision to not open the Phase II portion of the study, for business reasons. Sufficient data had already been collected and no additional data for the triplet combinations was needed. As a result, the Phase II portion of the trial was not opened.

Study of LEE011 With Fulvestrant and BYL719 or BKM120 in Advanced Breast Cancer

A Phase Ib/II Study of LEE011 in Combination With Fulvestrant and BYL719 or BKM120 in the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative Locally Recurrent or Advanced Metastatic Breast Cancer

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Progression Free Survival per RECIST v 1.1 by local investigator assessment

Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity

To characterize the PK profiles of LEE011, BKM120, BYL719, and fulvestrant when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. PK parameters for LEE011, BKM120 and BYL719, including but not limited to Cmax, Cmin, Tmax, AUCtau, accumulation ratio (Racc),and Ctrough values for fulvestrant.

ORR is defined as the proportion of patients with a best overall response of complete response or partial response.

Duration of Response is calculated as the time from the date of first documented response (complete response (CR) or partial response (PR)) to the first documented date of progression or death due to underlying cancer.

PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.

OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PalbocIclib in PreMenopausal Women With ER Positive/HER-2 Negative MetAstatic Breast Cancer	NCT02917005	Metastatic Brea...	Palbociclib Exemestane Goserelin	18 Years -	Africa Middle East Cancer Intergroup
Study of LEE011 With Fulvestrant and BYL719 or BKM120 in Advanced Breast Cancer	NCT02088684	Breast Cancer	LEE011 BYL719 fulvestrant BKM120	18 Years -	Novartis

Spots Global Cancer Trial Database for hormone receptor positive, her2 negative