Clinical study to determine the efficacy and safety of alpelisib and fulvestrant in men and postmenopausal women with advanced stage of breast cancer which progressed on or after the treatment of Aromatase Inhibitor.

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2016/06/007016
• Date of registration: 13-06-2016
• Prospective Registration: Yes
• Primary sponsor: Novartis Healthcare Private Limited
• Public title: Clinical study to determine the efficacy and safety of alpelisib and fulvestrant in men and postmenopausal women with advanced stage of breast cancer which progressed on or after the treatment of Aromatase Inhibitor.
• Scientific title: A phase III randomized double-blind, placebo controlled study of alpelisib in combination with fulvestrant for men and postmenopausal women with hormone receptor positive, HER2-negative advanced breast cancer which progressed on or after aromatase inhibitor treatment
• Date of first enrolment: 26-07-2016
• Target sample size: 560
• Recruitment status: Closed to Recruitment of Participants
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=12531
• Study type: Interventional
• Study design: Randomized, Parallel Group, Placebo Controlled Trial; Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:On-site computer system Blinding and masking:Participant and Investigator Blinded
• Phase: Phase 3

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czech Republic, Denmark, France, Germany, Greece, Hong Kong, India, Israel, Italy, Japan, Lebanon, Mexico, Netherlands, Peru, Portugal, Republic of Korea, Romania, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, United Arab Emirates, United Kingdom, United States of America

Contacts

• Name: Dr Manish Mistry
• Affiliation: Novartis India Limited

• Name: Dr Manish Mistry
• Affiliation: Novartis India Limited

Key inclusion & exclusion criteria

Inclusion criteria: 1. Patient is an adult >= 18 years old at the time of informed consent and has signed informed

consent before any trial related activities and according to local guidelines.

2. Patient has adequate tumor tissue for the analysis of PIK3CA mutational status by a

Novartis designated laboratory. One new or recent biopsy(collected at screening if feasible) or archival tumor block or slides(15 slides

minimum from a surgical specimen, 20 slides minimum from a biopsy) must be provided. it is recommended to provide a tumor sample collected after the most recent progression or recurrence.

3. Patient has identified PIK3CA status (mutant or non-mutant; determined by a Novartis

designated laboratory).

4. If female, then the patient is postmenopausal. Postmenopausal status is defined either by:

a. Prior bilateral oophorectomy

b. Age less than or equal to 60

c. Age greater than 60 and amenorrheic for 12 or more months in the absence of chemotherapy,

tamoxifen, toremifene, or ovarian suppression and Follicle-stimulating Hormone

(FSH) and estradiol in the postmenopausal range per local normal range.

5. Patient has radiological or objective evidence of recurrence or progression.

6. Patient has a histologically and/or cytologically confirmed diagnosis of ER positive and/or PgR positive breast cancer by local laboratory.

7. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or

an IHC status of 0, 1 positive or 2 positive.If IHC is 2 positive,a negative in situ hybridization (FISH, CISH, or

SISH) test is required by local laboratory testing.

8. Patient has either:

a. Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria (a

lesion at a previously irradiated site may only be counted as a target lesion if there is

clear sign of progression since the irradiation ) OR

b. If no measurable disease is present, then at last one predominantly lytic bone lesion

must be present (patients with no measurable disease and only one predominantly

lytic bone lesion that has been previously irradiated are eligible if there is documented

evidence of disease progression of the bone lesion after irradiation).

9. Patient has advanced (loco regionally recurrent not amenable to curative therapy or

metastatic) breast cancer.

Patients may be:

a.relapsed with documented evidence of progression while on or after

completion of (neo)adjuvant endocrine therapy with no treatment for metastatic

disease

b.relapsed with documented evidence of progression more than 12 months from

completion of adjuvant endocrine therapy and then subsequently progressed with

documented evidence of progression after one line of endocrine therapy for metastatic

disease

c.newly diagnosed advanced breast cancer, then relapsed with documented evidence of

progression while on or after one line of endocrine therapy.

10. Patient has recurrence or progression of disease during or after AI therapy (i.e. letrozole,

anastrozole, exemestane). AI therapy does not need to be the latest treatment regimen.

11. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

12. Patient has adequate bone marrow and organ function as defined by the following
Exclusion criteria: 1. Patient with symptomatic visceral disease or any disease burden that makes the patientineligible for endocrine therapy per the investigatorâ??s best judgment.

2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant

chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor

3. Patient has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients

of alpelisib or fulvestrant.

4. Patient with inflammatory breast cancer at screening.

5. Patient is concurrently using other anti-cancer therapy.

6. Patient has had surgery within 14 days prior to starting study drug or has not recovered

from major side effects.

7. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI

CTCAE version 4.03 Grade less than or equal to 1. Exception to this criterion: patients with any grade of

alopecia are allowed to enter the study.

8. Patients with Child pugh score B or C.

9. Patient has received radiotherapy less than or equal to 4 weeks or limited field radiation for palliation less than or equal to 2

weeks prior to randomization, and who has not recovered to grade 1 or better from related

side effects of such therapy (with the exception of alopecia) and/or from whom greater than or equal to 25percentage of

the bone marrow was irradiated.

10. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with

the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.

11. Patients with an established diagnosis of diabetes mellitus type I or not controlled type II

(based on FPG and HbA1c, see inclusion criterion 12)

12. Patient has impairment of gastrointestinal (GI) function or GI disease that may

significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled

nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

13. Patient has a known history of Human Immunodeficiency Virus (HIV) infection (testing

not mandatory)

14. Patient has any other concurrent severe and/or uncontrolled medical condition that would,

in the investigatorâ??s judgment, contraindicate patient participation in the clinical study (e.g chronic active hepatitis, severe hepatic impairment, etc.)

15. Patient has currently documented pneumonitis (the chest CT scan performed at baseline

for the purpose of tumor assessment should be reviewed to confirm that there are no

relevant pulmonary complications present).

16. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac events

including any of the following:

a.History of angina pectoris, coronary artery bypass graft (CABG) symptomatic pericarditis, or myocardial infarction within

12 months prior to study entry

b. History of documented congestive heart failure (New York Heart Association

functional classification III-IV)

c. Documented cardiomyopathy

d.Patient has a Left Ventricular Ejection Fraction (LVEF) less than 50percentage as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)

d.History of any cardiac arrhythmias, (e.g., ventricular tachycardia),complete left bundle block,

Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Health Condition 1: null- The study will include approximately 560 men and postmenopausal women with HR postive, HER2-negative advanced breast cancer which progressed on or after AI treatment.

Intervention(s)

Intervention1: Alpelisib 300 mg p.o. Plus fulvestrant 500 mg i.m. administered orally once daily. A complete cycle of treatment is defined as 28 days (± 3 days) of once daily continuous
treatment of alpelisib or placebo in combination with fulvestrant.: Alpelisib 300 mg p.o. Plus fulvestrant 500 mg i.m. administered orally once daily. A complete cycle of treatment is defined as 28 days (± 3 days) of once daily continuous
treatment of alpelisib or placebo in combination with fulvestrant.
Control Intervention1: Alpelisib Placebo 300 mg p.o. plus fulvestrant 500 mg i.m.once daily: Alpelisib Placebo 300 mg p.o. plus fulvestrant 500 mg i.m.once daily

Primary Outcome(s)

To determine whether treatment with alpelisib in combination with

fulvestrant prolongs PFS compared to treatment with placebo in

combination with fulvestrant for patients with PIK3CA mutant statusTimepoint: Time at which progression free survival is achieved.

Secondary Outcome(s)

To characterize the pharmacokinetics (PK) of fulvestrant and

alpelisib when given in combination with fulvestrantTimepoint: Summary statistics for PK: plasma concentration-time profiles of

alpelisib given in combination with fulvestrant and appropriate

individual PK parameters based on population PK model

Summary statistics of fulvestrant trough plasma concentrations in

each treatment arm (alpelisib/placebo)

To describe time to response and duration of response in the

two treatment arms and cohorts of interest.Timepoint: Time to response and duration of response in each of the PIK3CA

mutant and non-mutant cohorts

To evaluate change in global health status/QOL in the two

treatment arms and cohorts of interestTimepoint: - Time to 10% deterioration in the global health status/QOL scale

score of the EORTC QLQ-C30

- Change from baseline in the global health status/QOL scale

score of the EORTC QLQ-C30

in each of the PIK3CA mutant and non-mutant cohorts

To explore potential role of ctDNA as surrogate endpoint for

monitoring disease responseTimepoint: Molecular analysis of ctDNA over time of treatment and correlation

with PFS

To assess additional molecular alterations associated with

response or resistance to treatmentTimepoint: Molecular analysis of tumor tissue and blood ctDNA such as but

not limited to NGS, NanoString, IHC (tissue only) and association with clinical parameters such as OS, ORR, CBR

To evaluate the association between PIK3CA mutation status

as measured in ctDNA at baseline with PFS upon treatment with

alpelisib.Timepoint: PFS based on local radiology assessments and using RECIST 1.1

criteria for each of (i) patients with PIK3CA mutant status and (ii)

patients with PIK3CA non-mutant status as measured in ctDNA at

baseline.

to establish proof of concept of treatment benefit with alpelisib in combination with fulvestrant with respect to PFS for patients with PIK3CA non-mutant statusTimepoint: PFS based on local radiology assessments and using RECIST 1.1 criteria in the PIK3CA non mutant cohort

To explore exposure/response relationshipTimepoint: Alpelisib PK concentration versus selected safety and efficacy

endpoints

To determine whether treatment with alpelisib in combination with

fulvestrant prolongs overall survival (OS) compared to treatment

with placebo in combination with fulvestrant for patients with PIK3CA mutant statusTimepoint: OS in the PIK3CA mutant cohorts. Time-point is overall survival of patient.

To evaluate the two treatment arms and cohorts of interest

with respect to centrally assessed PFSTimepoint: PFS based on Blinded Independent Review Committee (BIRC)

and using RECIST 1.1 criteria in each of the PIK3CA mutant and

non-mutant cohorts

To evaluate the safety and tolerability of alpelisib in

combination with fulvestrantTimepoint: - Type, frequency and severity of adverse events per CTCAEv4.03

- Type, frequency and severity of laboratory toxicities per

CTCAEv4.03

To evaluate the two treatment arms and cohorts of interest

with respect to time to deterioration of ECOG performance statusTimepoint: Time to definitive deterioration of the ECOG performance status of

the score from baseline in each of the PIK3CA mutant and nonmutant

cohorts

To evaluate the two treatment arms with respect to OS for patients with PIK3CA non-mutant statusTimepoint: OS in the PIK3CA non-mutant cohort

To explore potential differences in hospital resource utilization

in the two treatment arms and cohorts of interest.Timepoint: Number of patients hospitalized, total number of hospitalizations,

and length of stay in each of the PIK3CA mutant and non-mutant

cohorts

To explore the benefit of alpelisib on bone lesionsTimepoint: Quantification of bone biomarkers such as bone BAP or CTX

To evaluate the two treatment arms and cohorts of interest

with respect to overall response rate (ORR), clinical benefit rateTimepoint: ORR and CBR in each of the PIK3CA mutant and non-mutant

cohorts

To explore changes in patient reported global health status

and pain in the two treatment arms and cohorts of interestTimepoint: - Change from baseline in the overall health status of the EQ-5D-

5L

- Change from baseline in the worst pain item of the BPI-SF

in each of the PIK3CA mutant and non-mutant/unknown cohorts

Secondary ID(s)

CBYL719C2301 version 00 Dated 09 Apr 2015

Source(s) of Monetary Support

Novartis Healthcare Pvt Ltd GDO Trial Monitoring, India 6 & 7 floor , Inspire BKC G Block, BKC Main Road Bandra Kurla Complex Bandra (East) Mumbai Mumbai MAHARASHTRA 400051 India

Ethics review

Status: Approved
Approval date: 06/11/2015
Contact:

Institutional Ethics Committee

Status: Approved
Approval date: 17/12/2015
Contact:

Integrity Ethics Committee

Status: Approved
Approval date: 21/07/2016
Contact:

Institutional Ethics Committee

Status: Approved
Approval date: 27/09/2016
Contact:

Institutional Ethics Committee