Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer

Novartis

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Breast Cancer

Treatments: Drug: BYL719; Drug: LEE011; Drug: Letrozole

Study type: Interventional

Funder types: Industry

Identifiers

NCT01872260

2013-001219-57 (EudraCT Number)

CLEE011X2107

Details and patient eligibility

About

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.

Enrollment: 256 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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/exclusion criteria may apply

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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256 participants in 4 patient groups

LEE011 + letrozole Arm 1

Experimental group

Description:

LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day

Treatment:

Drug: Letrozole

Drug: LEE011

BYL719 + letrozole Arm 2

Experimental group

Description:

BYL719 - daily (dose escalating) letrozole - 2.5 mg/day

Treatment:

Drug: Letrozole

Drug: BYL719

LEE011 + BYL719 + letrozole Arm 3

Experimental group

Description:

LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day

Treatment:

Drug: Letrozole

Drug: BYL719

Drug: LEE011

LEE011+ BYL719+letrozole Arm 4

Experimental group

Description:

LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day

Treatment:

Drug: Letrozole

Drug: BYL719

Drug: LEE011