Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer Who Have Progressed on or After Prior Treatments

Phase 2

Completed

Conditions: Breast Cancer

Interventions: Drug: Alpelisib
Drug: Fulvestrant
Drug: Letrozole
Drug: Goserelin
Drug: Leuprolide

Registration Number: NCT03056755

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This was a Phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in subjects (pre- and post-menopausal women and men) with HR-positive, HER2-negative aBC harboring PIK3CA mutation(s) in the tumor, whose disease had progressed on or after prior treatments.

Detailed Description: The study comprised two phases:

1. Core Phase: included a treatment phase for all subjects from first subject first treatment (FSFT) until disease progression, unacceptable toxicity, or death until 18 months post last subject first treatment (LSFT) + 1 month safety follow-up (total 19 months post LSFT), discontinuation from the study treatment for any other reason, or sponsor terminates the study. At the start of the Core Phase, subjects were assigned to Cohort A, Cohort B, or Cohort C based on previous therapy as follows:

* Cohort A: alpelisib (300 mg oral QD) + fulvestrant (500 mg intramuscular (IM)) to subjects whose last prior treatment was a CDK4/6i plus any AI;

* Cohort B: alpelisib (300 mg oral QD) + letrozole (2.5 mg oral QD) to subjects whose last prior treatment was a CDK4/6i plus fulvestrant;

* Cohort C: alpelisib (300 mg oral QD)+ fulvestrant (500 mg IM) to subjects who failed prior AI based therapy and whose last prior treatment was systemic chemotherapy or endocrine therapy (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI). Endocrine therapy included letrozole, fulvestrant and CDK 4/6 inhibitor plus fulvestrant.

2. Extension Phase: included a treatment phase starting at the end of the treatment Core Phase until last subject last visit(LSLV) (up to 36 months). Following the end of the Core Phase, subjects continuing to derive benefit from study treatment who were not eligible for Post-Study Drug Supply (PSDS) in their country based on local regulations were re-consented and transitioned to the Extension Phase. Subjects continued on their existing study treatment assigned in the Core Phase until disease progression/lack of clinical benefit or any other reason for which the subject may have been discontinued from study treatment. If PSDS became available for a subject, the subject was to be discontinued from the study and to access treatment via PSDS. When subjects discontinued treatment for any reason, the end of treatment visit was performed after discontinuation of the medication , followed by safety follow-up 30 days after last dose.

A total of 340 subjects were planned to be enrolled, with approximately 112 subjects in each cohort. In the Core Phase, 379 subjects were analyzed, with 127 subjects in Cohort A, 126 subjects in Cohort B, and 126 subjects in Cohort C. In the Extension Phase, 11 subjects were analyzed, with 1 subject in Cohort A and 10 subjects in Cohort C.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 379

Inclusion Criteria

Subjects eligible for inclusion in the Core Phase of the study fulfilled the following key inclusion criteria:

Subject was an adult male or female ≥ 18 years of age.
Subjects with histologically and/or cytologically confirmed diagnosis of estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive breast cancer by local laboratory.
Subjects with a confirmed human epidermal growth factor receptor-2 (HER2)-negative aBC.
Subjects with gene encoding the p110alpha catalytic subunit of PI3K (phosphatidylinositol-3-kinase) (PIK3CA) mutation.
In case of women, both premenopausal and postmenopausal subjects were allowed to be included in this study.
Subjects with documented evidence of tumor progression on or after:

i. Cyclin-Dependent Kinase 4 and 6 inhibitor (CDK4/6i) treatment as last treatment regimen in Cohorts A and B.

ii. aromatase inhibitor (AI) treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET (monotherapy or combination except CDK4/6i + AI) as last treatment regimen in Cohort C. Upon completion of enrollment of Cohort B, subjects who received CDK4/6i + fulvestrant as immediate prior therapy were eligible for Cohort C.

iii. No more than 2 prior anticancer therapies for aBC. iv. Received no more than 1 prior regimen of chemotherapy for the treatment of advanced/metastatic disease was permitted.

v. Recovered to grade 1 or better from any adverse events (AEs) related to previous anticancer therapy prior to study entry (except alopecia or other toxicities not considered a safety risk for the subject at the investigator's discretion).

Subjects with:

i. Measurable disease, i.e., at least 1 measurable lesion as per RECIST v1.1 criteria; or ii. If no measurable disease was present, at least 1 predominantly lytic bone lesion had to be present.
Subjects with adequate bone marrow and coagulation function, liver function and renal function as shown by laboratory values.
Subjects with Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.

Key exclusion criteria were:

Subjects with a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin, or leuprolide or to any of their excipients.
Subjects with prior treatment with any PI3K inhibitor (PI3Ki).
Subjects with central nervous system (CNS) involvement unless they met all of the following criteria:

i. At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment, ii. Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (magnetic resonance imaging (MRI) or computed tomography (CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment.
Subjects with an established diagnosis of diabetes mellitus type I or uncontrolled type II.
Any concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate subject participation in the study (e.g., chronic active hepatitis, severe hepatic impairment, etc.).
Subjects with a history of noncompliance to medical regimens.
Subjects with impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of the study drugs based on investigator discretion.
Subjects with documented pneumonitis/interstitial lung disease which was active and requiring treatment.
Subjects concurrently using other anticancer therapy. All anticancer therapy had to be discontinued prior to Day 1 of study treatment.
Subjects who had major surgery within 14 days prior to starting treatment with alpelisib, or did not recover from major side effects.
Subjects with significant cardiac abnormalities.
History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
Subjects who did not use highly effective contraception while on alpelisib and through the duration after the final dose of alpelisib (not applicable to postmenopausal women).
Subjects with unresolved osteonecrosis of the jaw.

Other inclusion/exclusion criteria may apply

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A: Pre-treated with CDK 4/6i + AI	Alpelisib	Participants who received any Cyclin-Dependent Kinases 4 and 6 inhibitor (CDK 4/6i) plus aromatase inhibitor (AI) as immediate prior treatment will receive alpelisib + fulvestrant
Cohort A: Pre-treated with CDK 4/6i + AI	Fulvestrant	Participants who received any Cyclin-Dependent Kinases 4 and 6 inhibitor (CDK 4/6i) plus aromatase inhibitor (AI) as immediate prior treatment will receive alpelisib + fulvestrant
Cohort A: Pre-treated with CDK 4/6i + AI	Goserelin	Participants who received any Cyclin-Dependent Kinases 4 and 6 inhibitor (CDK 4/6i) plus aromatase inhibitor (AI) as immediate prior treatment will receive alpelisib + fulvestrant
Cohort A: Pre-treated with CDK 4/6i + AI	Leuprolide	Participants who received any Cyclin-Dependent Kinases 4 and 6 inhibitor (CDK 4/6i) plus aromatase inhibitor (AI) as immediate prior treatment will receive alpelisib + fulvestrant
Cohort B: Pre-treated with CDK 4/6i + fulvestrant	Alpelisib	Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole
Cohort B: Pre-treated with CDK 4/6i + fulvestrant	Letrozole	Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole
Cohort B: Pre-treated with CDK 4/6i + fulvestrant	Goserelin	Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole
Cohort B: Pre-treated with CDK 4/6i + fulvestrant	Leuprolide	Patients who received any CDK 4/6i plus fulvestrant as immediate prior treatment will receive alpelisib + letrozole
Cohort C: Pre-treated with systemic chemotherapy or ET	Alpelisib	Participants who received systemic chemotherapy or endocrine therapy (ET) (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + fulvestrant.
Cohort C: Pre-treated with systemic chemotherapy or ET	Fulvestrant	Participants who received systemic chemotherapy or endocrine therapy (ET) (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + fulvestrant.
Cohort C: Pre-treated with systemic chemotherapy or ET	Leuprolide	Participants who received systemic chemotherapy or endocrine therapy (ET) (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + fulvestrant.
Cohort C: Pre-treated with systemic chemotherapy or ET	Goserelin	Participants who received systemic chemotherapy or endocrine therapy (ET) (as monotherapy or in combination with targeted treatment except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib + fulvestrant.

Primary Outcome Measures

Name	Time	Method
Core Phase: Percentage of Participants Who Were Alive Without Disease Progression at 6 Months	At 6 months	Percentage of participants who were alive without disease progression at 6-month follow-up based on local investigator assessment per RECIST v1.1 in Cohort A, Cohort B and Cohort C. Participants who progressed, died, or discontinued study before 6 months were counted as a failure.

Secondary Outcome Measures

Name	Time	Method
Core Phase: Progression Free Survival (PFS)	From date of first dose to date of first documented progression or death, up to 46 months	PFS is defined as the time from the date of first dose of study medication to the date of the first documented progression or death due to any cause occurring in the study. PFS was assessed based on local investigator's assessment according to RECIST v1.1. PFS was censored if no PFS event was observed before the cut-off date. The censoring date was the date of last adequate tumor assessment before the cut-off date. If a PFS event was observed after two or more missing or non-adequate tumor assessments, then PFS was censored at the last adequate tumor assessment. PFS was estimated using the Kaplan-Meier method.
Core Phase: Progression Free Survival on Next Line Treatment (PFS2)	From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 55 months	PFS2 is defined as time from the date of first dose of study medication to the date of first documented progression on next-line therapy or death from any cause. The first documented progression on next-line treatment is based on investigator assessment of progressive disease. PFS2 was estimated using the Kaplan-Meier method.
Core Phase: Overall Response Rate (ORR)	Up to 46 months	ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST v1.1 in each cohort. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (\<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Core Phase: Clinical Benefit Rate (CBR)	Up to 46 months	CBR is defined as the percentage of participants with a BOR of CR or PR or an overall lesion response of stable disease (SD) or Non-CR/ Non-PD lasting ≥ 24 weeks based on local investigator's assessment according to RECIST v1.1. CR: Disappearance of all non-nodal target lesions and all non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm and all lymph nodes assigned as non-target lesions must be non-pathological in size (\<10 mm short axis) PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Core Phase: Duration of Response (DOR)	From date of first documented response to first documented progression or death, up to 33.3 months	DOR is the time from the date of first documented response (confirmed CR or PR based on local investigator's assessment according to RECIST v1.1) to the date of first documented progression or death due to underlying cancer. Subjects continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. DOR was estimated using the Kaplan-Meier method.
Core Phase: Overall Survival (OS)	From date of first dose and up to approximately 55 months	OS is defined as the time of start of treatment to date of death or lost to follow-up. If a subject was not known to have died, then the OS data was censored at the date of the last known alive status for the patient.
Extension Phase: Percentage of Participants With Clinical Benefit as Assessed by the Investigator During the Extension Phase	From end of core phase up to 12 months	Percentage of participants with clinical benefit as assessed by the Investigator at scheduled visits during the extension phase

Trial Locations

Locations (26): Banner MD Anderson Cancer Center
🇺🇸
Gilbert, Arizona, United States
Mayo Clinic Arizona
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Phoenix, Arizona, United States
Kaiser Permanente Medical Group
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Anaheim, California, United States
Beverly Hills Cancer Center
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Beverly Hills, California, United States
University of Calif Irvine Med Cntr
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Irvine, California, United States
Kaiser Permanent Southern Californi
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San Diego, California, United States
UCSF
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San Francisco, California, United States
Yale University Yale Cancer Center
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New Haven, Connecticut, United States
Advent Health Cancer Institute
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Orlando, Florida, United States
University of Kansas Cancer Center
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Kansas City, Kansas, United States
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Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States