Breast Cancer
Conditions
Keywords
Hormone-receptor positive
Brief summary
The purpose of this trial is to inform the future clinical development of the two investigational agents in ER+ breast cancer, LEE011 (CDK4/6 inhibitor) and BYL719 (PI3K-alpha inhibitor). This is a multi-center, open-label Phase Ib study. The Phase Ib dose escalation will estimate the MTD and/or RP2D for three regimens: two double combinations, LEE011 with letrozole and BYL719 with letrozole, followed by triple combinations of LEE011 + BYL719 with letrozole (Arms 3 and 4). The Phase Ib dose escalation part will be followed by Phase Ib dose expansions to further characterize the safety, tolerability, PK and preliminary clinical anti-tumor activity of the combinations. Optional crossover for patients who have progressed while on dose escalation or dose expansion with doublet treatment on Arms 1 or 2 to be treated with the triplet combination (Arm 3) after the determination of the RP2D for Arm 3; is no longer permitted after protocol amendment 6. Approximately 270 adult women with ER+/HER2- locally advanced or metastatic breast cancer will be enrolled.
Interventions
DRUGLEE011
LEE011 - 28 day cycles (21 days followed by a 7 day break) for Arms 1, 3. LEE011 28 days cycles (continuous) Arm 4.
DRUGLetrozole
Letrozole 2.5 mg/day
DRUGBYL719
BYL719 - 28 days cycle (continuous) for Arm 2; 3 and 4
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Postmenopausal, Estrogen-receptor positive and/or Progesterone-receptor positive breast cancer * Phase Ib dose escalation only: Any number of prior lines of endocrine therapy is allowed with the exception of cytotoxic therapy which is limited to one prior line administered in the advanced (metastatic or locally advanced) setting. * Phase Ib dose expansions Arms 1, 2 and 3 * No prior systemic treatment in the advanced (metastatic or locally advanced) setting with the exception of treatment with letrozole for a maximum of one month prior to starting study treatment. * Patients who received (neo)adjuvant therapy for breast cancer are eligible. Prior therapy with letrozole or anastrozole in the (neo)adjuvant setting is permitted if the disease-free interval is greater than 12 months from the completion of treatment.
Exclusion criteria
* HER2-overexpression in the patient's tumor tissue * Patients with active CNS or other brain metastases * Major surgery within 2 weeks * Acute or chronic pancreatitis * Bilateral diffuse lymphangitic carcinomatosis * Another malignancy within 3 years * Receiving hormone replacement therapy that cannot be discontinued * Impaired cardiac function * Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or with fasting glucose ≥ 126 mg/dL / 7.0 mmol/L or hemoglobin A1c \>6.5%), history of gestational diabetes mellitus or documented steroid-induced diabetes mellitus. * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose limiting toxicities (DLTs) - Phase lb only | 28 days | — |
| Safety and tolerability | Average 18 months | Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity. |
| PK profiles of LEE011 and letrozole | 18 months | To characterize PK profiles of LEE011 and Letrozole. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability of LEE011 in combination with letrozole, BYL719 in combination with letrozole, and the triple combination of LEE011 +BYL719 with letrozole | Average 24 months | Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
| Plasma concentration-time profiles of LEE011, BYL719 and letrozole | Average 24 months | To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. |
| Overall Response Rate (ORR) | Average 24 months | ORR is defined as the proportion of patients with a best overall response of complete response or partial response. |
| Duration of Response (DOR) | Average 24 months | DOR 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. |
| Progression Free Survival (PFS) | Average 24 months | 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. |
| Pharmacokinetics (PK) parameters, including but not limited to AUCtau, Cmin, Cmax, Tmax, accumulation ratio (Racc) | Average 24 months | To characterize the PK profiles of LEE011, BYL719, and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified. |
| Safety and tolerability of the triple combination of LEE011 +BYL719 with letrozole in patients previously treated with either doublet | Average 24 months | Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
Countries
Australia, France, Italy, South Korea, Spain, Switzerland, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed