A phase Ib/II, multicenter, study of the combination of LEE011 and BYL719 with letrozole in adult patients with advanced ER+ breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Mar 2014 → ongoing

Decision date (initial)

2024-05-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Novartis Pharma Services AG, Switzerland

External identifiers

EU CT number

2023-509511-84-00

EudraCT number

2013-001219-57

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Dose Escalation:
To estimate the MTD and/or RP2D of the following three combinations in patients with HR+/HER2- advanced breast cancer:
1. LEE011 and standard dose letrozole (doublet, Arm 1 escalation)
2. BYL719 and standard dose letrozole (doublet, Arm 2 Cohort 1 escalation)
3. LEE011 3 weeks on/ 1 week off, BYL719 and standard dose letrozole QD
(triplet, Arm 3 escalation)
Dose Expansion:
To characterize the safety and tolerability of LEE011 in combination with letrozole (Arm 1 expansion cohorts), BYL719 in combination with letrozole including both BYL719 morning dosing (Arm 2 Cohort 1 expansion) and BYL719 evening dosing regimens (Arm 2 Cohort 2 expansion), and the triple combination of LEE011 +
BYL719 with letrozole (Arms 3 expansion).

To characterize the PK profiles of LEE011 (FCT formulation) and letrozole when used in combination

Secondary objectives 3

1. To characterize the PK profiles of LEE011 (DiC formulation), BYL719 (morning and evening dosing regimens for doublet and morning dosing regimen for triplet), and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified.
2. To assess preliminary clinical anti-tumor activity of LEE011 in combination with letrozole and BYL719 in combination with letrozole (Arm 2) and triple combination of LEE011 + BYL719 with letrozole (Arm 3)
3. To evaluate the incidence of grade 3/4 hyperglycemia of BYL719 morning dosing regimen in Arm 2 cohort 1 and BYL719 evening dosing regimen in Arm 2 cohort 2.

Conditions and MedDRA coding

Advanced HR+ breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Adult women (age ≥18 years) with advanced (metastatic or locally advanced) breast cancer not amenable to curative treatment by surgery or radiotherapy.
2. Histologic or cytologic confirmation of hormone-receptor positive (ER+ and/or PR+) breast cancer
3. Postmenopausal women
4. Dose Escalation: Any number of prior lines of endocrine therapy is allowed with up to one prior cytotoxic regimen in the advanced (metastatic or locally advanced) setting.
5. Dose Expansion Arm 1, 2 and 3: No prior systemic treatment in the advanced (metastatic or locally advanced) setting with the exception of treatment with letrozole or anastrozole for a maximum duration of one month.
6. Dose Expansion Arms 2 and 3 and Dose Escalation Arm 4: Patient has known PIK3CA status (mutated or non-mutated)
7. Dose Escalation: Presence of measurable or non-measurable disease (as defined by RECIST 1.1 criteria).
8. Dose Expansion: At least one measurable lesion, or lytic or mixed bone lesions in the absence of measurable disease (as defined by RECIST 1.1) for Arm 1 to Arm 3

Exclusion criteria 9

1. HER2-overexpression in the patient’s tumor tissue by local laboratory testing (IHC 3+ or in situ hybridization positive).
2. Patients with active CNS or other brain metastases. Patients with asymptomatic brain metastases that have been adequately treated and do not require corticosteroid therapy and /or enzyme inducing anti–epileptic medication for brain metastases are eligible.
3. Major surgery within 2 weeks
4. Acute or chronic pancreatitis
5. Bilateral diffuse lymphangitic carcinomatosis
6. Another malignancy within 3 years
7. Receiving hormone replacement therapy that cannot be discontinued
8. Impaired cardiac function
9. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 - Phase lb only [Time Frame: 28 days]
2. Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
3. Plasma concentration-time profiles of LEE011, letrozole. PK parameters, including but not limited to AUC0-24h, Cmin, Cmax, Tmax, accumulation ratio (Racc).

Secondary endpoints 4

1. Plasma concentration-time profiles of LEE011, BYL719 and letrozole. PK parameters, including but not limited to AUC0-24h, Cmin, Cmax, Tmax, accumulation ratio (Racc).
2. Tumor response per RECIST v1.1 (by local investigator assessment): Overall Response Rate (ORR), Disease Control Rate (DCR), Clinical benefit Rate (CBR), Duration of Response (DOR) and Progression Free Survival (PFS) CBR is defined as CR, PR, or SD lasting 24 weeks or longer.
3. Incidence of grade 3 or 4 hyperglycemia
4. Incidence of grade 3 or 4 AST/ALT elevations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 8

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications