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: The purpose of this study was to assess the efficacy and safety of treatment with alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients with hormone receptor (HR) positive, HER2-negative advanced breast cancer (aBC), harboring PIK3CA mutations, 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: 383

Inclusion Criteria

Patient has adequate tumor tissue for the analysis of PIK3CA mutational status by a Novartis designated laboratory. It is recommended to provide a tumor sample collected after the most recent progression or recurrence.
Advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy
Patient has been confirmed as PIK3CA mutant as determined by a certified designated laboratory
Patient has histologically and/or cytologically confirmed ER+ and/ or PgR+ BC
Patient has confirmed, HER2-negative aBC. HER2-negative defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+.
Patients must be diagnosed with aBC, with documented evidence of tumor progression on or after prior treatments. No more than one prior regimen of chemotherapy for the treatment of metastatic disease is permitted. The maximum number of prior therapies for aBC or mBC is limited to two (maintenance therapies, where applicable, must be regarded as part of the main therapy). Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to study entry.
Patient has either measurable disease, i.e. at least one measurable lesion as per RECIST v1.1 criteria or if no measurable disease is present than at least one predominantly lytic bone lesion must be present
Patient has ECOG performance status of ≤ 2
Patient has adequate bone marrow function

Key

Exclusion Criteria

Patient has received prior treatment with any PI3K inhibitors
Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II
Patient has a concurrent malignancy or malignancy within 3 years of study screening period, with the exception of adequately treated basal or squamous cell carcinoma, nonmelanoma skin cancer or curatively resected cervical cancer
Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to enrollment, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia)
Patients receiving systemic corticosteroids ≤ 2 weeks prior to treatment with alpelisib
History of acute pancreatitis within 1 year of screening or past medical history of pancreatitis
Patient has impaired GI function or GI disease that may affect the absorption of study drugs
Patient has documented pneumonitis
Patients being concurrently treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme Cytochrome P (CYP)3A within the last 5 days prior to study entry

Other inclusion/exclusion criteria may apply

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
🇺🇸
Phoenix, Arizona, United States
Kaiser Permanente Medical Group
🇺🇸
Anaheim, California, United States
Beverly Hills Cancer Center
🇺🇸
Beverly Hills, California, United States
University of Calif Irvine Med Cntr
🇺🇸
Irvine, California, United States
Kaiser Permanent Southern Californi
🇺🇸
San Diego, California, United States
UCSF
🇺🇸
San Francisco, California, United States
Yale University Yale Cancer Center
🇺🇸
New Haven, Connecticut, United States
Advent Health Cancer Institute
🇺🇸
Orlando, Florida, United States
University of Kansas Cancer Center
🇺🇸
Kansas City, Kansas, United States
Scroll for more (16 remaining)
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States