Study to assess the efficacy and safety of alpelisib (BYL719) in combination with trastuzumab and pertuzumab as maintenance therapy in patients with HER2-positive advanced breast cancer with a PIK3CA mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Sep 2020 → 7 Nov 2025

Decision date (initial)

2024-07-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512050-13-00

EudraCT number

2019-002741-37

ClinicalTrials.gov

NCT04208178

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacokinetic, Safety, Others, Therapy, Efficacy

Safety run-in Part 1:
To confirm the Recommended Phase 3 Dose of alpelisib in combination with trastuzumab and pertuzumab
Double-blind, randomized, placebo-controlled Part 2: To determine whether treatment with alpelisib in combination with trastuzumab and pertuzumab prolongs PFS compared to placebo in combination with trastuzumab and pertuzumab in adult participants with HER2-positive advanced breast cancer with a PIK3CA mutation.

Secondary objectives 9

1. Safety run-in Part 1: To determine the safety and tolerability of alpelisib in combination with trastuzumab and pertuzumab
2. Safety run-in Part 1: To characterize exposure of alpelisib when administered in combination with trastuzumab and pertuzumab
3. Double-blind, randomized, placebo-controlled Part 2: To determine whether treatment with alpelisib in combination with trastuzumab and pertuzumab prolongs OS compared to placebo in combination with trastuzumab and pertuzumab in adult participants with HER2-positive advanced breast cancer with a PIK3CA mutation
4. Double-blind, randomized, placebo-controlled Part 2: To assess safety and tolerability
5. Double-blind, randomized, placebo-controlled Part 2: To assess additional efficacy parameters
6. Double-blind, randomized, placebo-controlled Part 2: To characterize exposure of alpelisib, when administered in combination with trastuzumab and pertuzumab
7. Double-blind, randomized, placebo-controlled Part 2: To evaluate patient-reported outcomes (PRO) of alpelisib in combination with trastuzumab and pertuzumab compared to placebo with trastuzumab and pertuzumab
8. Double-blind, randomized, placebo-controlled Part 2: To evaluate the association between PIK3CA mutation status as measured in ctDNA at baseline with PFS upon treatment with alpelisib
9. Double-blind, randomized, placebo-controlled Part 2: To evaluate alpelisib in combination with trastuzumab and pertuzumab compared to alpelisib matching-placebo with trastuzumab and pertuzumab with respect to time to deterioration of ECOG (Eastern Cooperative Oncology Group) performance status

Conditions and MedDRA coding

HER2-positive advanced breast cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Participant has histologically-confirmed HER2-positive breast cancer that is advanced (loco-regionally recurrent not amenable to surgery or metastatic).
2. Participant has received pre-study induction therapy with up to and including a maximum of 8 cycles of a taxane (docetaxel, paclitaxel, or nab-paclitaxel), plus trastuzumab and pertuzumab. A minimum of 4 cycles of induction therapy is permitted if discontinuation of taxane was due to taxane toxicity.
3. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4. Participant has adequate bone marrow and organ function
5. Applies only to Part 2: Participant has a PIK3CA mutation(s) present in tumor tissue prior to enrollment, as determined by a Novartis designated central laboratory.

Exclusion criteria 7

1. Participant with inflammatory breast cancer at screening.
2. Participant with evidence of disease progression during or following completion of pre-study induction therapy and prior to first dose of alpelisib (or alpelisib/alpelisib matching-placebo for Part 2)
3. Participant with an established diagnosis of diabetes mellitus type I or not controlled type II based on fasting plasma glucose (FPG) and HbA1c.
4. Participant has a known history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
5. Participant has clinically significant, uncontrolled heart disease and/or recent cardiac events
6. Participant has a history of Steven-Johnson Syndrome (SJS), erythema multiforme (EM), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS).
7. Participant has currently documented pneumonitis/interstitial lung disease

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety run-in Part 1: Incidence of DLTs during the first 6 weeks of treatment for each dose level associated with administration of alpelisib in combination with trastuzumab and pertuzumab
2. Double-blind, randomized, placebo-controlled Part 2: PFS based on Investigator assessment using RECIST 1.1 criteria

Secondary endpoints 9

1. Safety run-in Part 1: Safety: Incidence, type, and severity of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria including changes in laboratory values, vital signs, liver assessments and cardiac assessments Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all drug components
2. Safety run-in Part 1: Summary statistics of alpelisib concentrations by timepoint and dose level
3. Double-blind, randomized, placebo-controlled Part 2: OS
4. Double-blind, randomized, placebo-controlled Part 2: Safety: Incidence, type, and severity of adverse events per CTCAE version 4.03 criteria including changes in laboratory values, vital signs, liver assessments and cardiac assessments Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all drug components
5. Double-blind, randomized, placebo-controlled Part 2: ORR with confirmed response, CBR with confirmed response, DOR with confirmed response, and TTR based on local radiology assessments and using RECIST 1.1 criteria.
6. Double-blind, randomized, placebo-controlled Part 2: Summary statistics of concentrations for alpelisib by time point
7. Double-blind, randomized, placebo-controlled Part 2: Change from baseline in the FACT-B Trial Outcomes Index (TOI) score. Time to 5-point definitive deterioration in the TOI score of the FACT-B
8. Double-blind, randomized, placebo-controlled Part 2: PFS based on local radiology assessments and using RECIST 1.1 criteria for participants by PIK3CA mutation status assessed in ctDNA at baseline
9. Double-blind, randomized, placebo-controlled Part 2: Time to definitive deterioration of the ECOG performance status from baseline

Investigational products

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

Test 4

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 4

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

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

Documents 15 files

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

Application history

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