Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. (SOLAR-1)

• ClinicalTrials.gov Identifier: NCT02437318
• Recruitment Status: Completed
• First Posted: May 7, 2015
• Results First Posted: August 13, 2019
• Last Update Posted: November 18, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 22, 2015
• First Posted Date: May 7, 2015
• Results First Submitted Date: June 17, 2019
• Results First Posted Date: August 13, 2019
• Last Update Posted Date: November 18, 2023
• Actual Study Start Date: July 23, 2015
• Actual Primary Completion Date: June 12, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 22, 2019)

Progression-free Survival (PFS) Per Investigator Assessment in the PIK3CA Mutant Cohort [ Time Frame: Once approximately 243 PFS events in this cohort had been observed, up to 32 months ]

PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST 1.1

Original Primary Outcome Measures (submitted: May 4, 2015)

Progression-free survival (PFS) [ Time Frame: Up to approximatly 36 months ]

PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST 1.1

Current Secondary Outcome Measures (submitted: July 22, 2019)

• Overall Survival (OS) for Patients With PI3KCA Mutant Status [ Time Frame: Up to approximatly 59 months ]
  OS is defined as the time from date of randomization to date of death due to any cause.
• Overall Response Rate (ORR) [ Time Frame: Up to approximatly 36 months ]
  ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1.
• Time to Definitive Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Baseline, Up to approximatly 36 months ]
  Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
• Safety and Tolerability of Alpelisib in Combination With Fulvestrant [ Time Frame: Up to approximatly 37 months ]
  Safety will be determined by type, frequency and severity of adverse events per CTCAEv4.03 and type, frequency and severity of laboratory toxicities per CTCAEv4.03. Patients will be followed up for the duration of the study.
• Time to 10% Deterioration in the Global Health Status/Quality of Life (QOL) Scale Score of the EORTC QLQ-C30 [ Time Frame: Up to approximatly 36 months ]
  Composite measure of change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized
• Plasma Concentration-time Profile of Alpelisib Given in Combinatio With Fulvestrant and Appropriate Pharmacokinetics (PK) Parameters [ Time Frame: Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2,4, 6, 8 ]
  Assessment of any potential impact of fulvestrant on the pharmacokinetics of alpelisib by collection of sparse and trough PK samples. PK parameters includes,but not limited to, Cmin, Cmax, t1/2, AUClast for alpelisib (and any relevant metabolites) and fulvestrant
• PFS Based on Radiology Assessments and Using RECIST 1.1 Criteria [ Time Frame: Baseline, Up to approximatly 36 months ]
  PFS in patients with PIK3CA mutant status and patients with PIK3CA non-mutant status as measured in ctDNA.
• Clinical Benefit Rate (CBR) [ Time Frame: Up to approximatly 36 months ]
  Clinical benefit rate is defined as the proportion of patients with a best overall response of CR or PR or SD or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment.
• Change in the Global Health Status/(QOL) Scale Score of the EORTC QLQ-C30 [ Time Frame: Baseline, Up to approximatly 36 months ]
  Composite measure of change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized
• Summary Statistics of Fulvestrant and Alpelisib Plasma Concentrations [ Time Frame: Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2,4, 6, 8 ]
  Assessment of any potential impact of fulvestrant on the pharmacokinetics of alpelisib by collection of sparse and trough PK samples.
• PFS for Patients With PIK3CA Non-mutant Status [ Time Frame: Up to approximatly 36 months ]
  PFS based on local radiology assessments and using RECIST 1.1 criteria in the PIK3CA non-mutant cohort
• OS for Patients With PIK3CA Non-mutant Status [ Time Frame: Up to approximatly 59 months ]
  OS is defined as the time from date of randomization to date of death due to any cause.

Original Secondary Outcome Measures (submitted: May 4, 2015)

• Overall survival (OS) [ Time Frame: Up to approximatly 59 months ]
  OS is defined as the time from date of randomization to date of death due to any cause.
• Overall response rate (ORR) [ Time Frame: Up to approximatly 36 months ]
  ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1.
• Time ro definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status [ Time Frame: Baseline, Up to approximatly 36 months ]
  Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
• Safety and tolerability of alpelisib in combination with fulvestrant [ Time Frame: Up to approximatly 37 months ]
  Safety will be determined by type, frequency and severity of adverse events per CTCAEv4.03 and type, frequency and severity of laboratory toxicities per CTCAEv4.03. Patients will be followed up for the duration of the study.
• Time to 10% deterioration in the global health status/Quality of Life (QOL) scale score of the EORTC QLQ-C30 [ Time Frame: Up to approximatly 36 months ]
  Composite measure of change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized
• Plasma concentration-time profile of alpelisib given in combinatio with fulvestrant and appropriate pharmacokinetics (PK) parameters [ Time Frame: Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2,4, 6, 8 ]
  Assessment of any potential impact of fulvestrant on the pharmacokinetics of alpelisib by collection of sparse and trough PK samples. PK parameters includes,but not limited to, Cmin, Cmax, t1/2, AUClast for alpelisib (and any relevant metabolites) and fulvestrant
• PFS based on radiology assessments and using RECIST 1.1 criteria [ Time Frame: Baseline, Up to approximatly 36 months ]
  PFS in patients with PIK3CA mutant status and patients with PIK3CA non-mutant status as meeasured in ctDNA.
• Progresion free survival (PFS) [ Time Frame: Up to approximatly 36 months ]
  Supportive analysis for PFS based on Blinded Independent Review Committee (BIRC) and using RECIST 1.1 for the mutant and non-mutant cohorts.
• Clinical benefit rate (CBR) [ Time Frame: Up to approximatly 36 months ]
  Clinical benefit rate is defined as the proportion of patients with a best overall response of CR or PR or SD or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment.
• Change in the global health status/(QOL) scale score of the EORTC QLQ-C30 [ Time Frame: Baseline, Up to approximatly 36 months ]
  Composite measure of change from baseline in the domain scores, health states, overall health status, and index values at the time of each assessment will be summarized
• Summary statistics of fulvestrant and alpelisib plasma concentrations [ Time Frame: Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2,4, 6, 8 ]
  Assessment of any potential impact of fulvestrant on the pharmacokinetics of alpelisib by collection of sparse and trough PK samples.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment.
• Official 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
• Brief Summary: To determine whether treatment with alpelisib plus fulvestrant prolongs progression-free survival compared to fulvestrant and placebo in men and postmenopausal women with hormone receptor positive (HR+), HER2-negative advanced breast cancer, who received prior treatment with an Aromatase Inhibitor either as (neo)adjuvant or for advanced disease.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Fulvestrant
  Other Name: Faslodex
• Drug: Alpelisib
• Drug: Alpelisib placebo

Study Arms

• Experimental: fulvestrant + alpelisib
  Alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
  Interventions:

  • Drug: Fulvestrant
  • Drug: Alpelisib
• Placebo Comparator: fulvestrant + placebo
  Placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
  Interventions:

  • Drug: Fulvestrant
  • Drug: Alpelisib placebo

Publications *

• Ciruelos EM, Rugo HS, Mayer IA, Levy C, Forget F, Delgado Mingorance JI, Safra T, Masuda N, Park YH, Juric D, Conte P, Campone M, Loibl S, Iwata H, Zhou X, Park J, Ridolfi A, Lorenzo I, Andre F. Patient-Reported Outcomes in Patients With PIK3CA-Mutated Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer From SOLAR-1. J Clin Oncol. 2021 Jun 20;39(18):2005-2015. doi: 10.1200/JCO.20.01139. Epub 2021 Mar 29.
• Andre F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, Rubovszky G, Yamashita T, Kaufman B, Lu YS, Inoue K, Papai Z, Takahashi M, Ghaznawi F, Mills D, Kaper M, Miller M, Conte PF, Iwata H, Rugo HS. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021 Feb;32(2):208-217. doi: 10.1016/j.annonc.2020.11.011. Epub 2020 Nov 25.
• Rugo HS, Andre F, Yamashita T, Cerda H, Toledano I, Stemmer SM, Jurado JC, Juric D, Mayer I, Ciruelos EM, Iwata H, Conte P, Campone M, Wilke C, Mills D, Lteif A, Miller M, Gaudenzi F, Loibl S. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol. 2020 Aug;31(8):1001-1010. doi: 10.1016/j.annonc.2020.05.001. Epub 2020 May 13.
• Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Papai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 3, 2021): 572
• Original Estimated Enrollment (submitted: May 4, 2015): 820
• Actual Study Completion Date: June 9, 2023
• Actual Primary Completion Date: June 12, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• If female, patient is postmenopausal
• Patient has identified PIK3CA status

• Patients may be:

  • relapsed with documented evidence of progression while on (neo) adjuvant endocrine therapy or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease;
  • relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy and then subsequently; progressed with documented evidence of progression while on or after only one line of endocrine therapy for metastatic disease;
  • newly diagnosed advanced breast cancer, then relapsed with documented evidence of progression while on or after only one line of endocrine therapy
• Patient has recurrence or progression of disease during or after AI therapy (i.e.

letrozole, anastrozole, exemestane).

• Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive breast cancer by local laboratory and has HER2 negative breast cancer
• Patient has either measurable disease per RECIST 1.1 criteria OR at least one predominantly lytic bone lesion must be present
• Patient has adequate bone marrow function

Exclusion Criteria:

• Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment
• Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor (pre-treatment with CDK4/6 inhibitors is allowed)
• Patient with inflammatory breast cancer at screening
• Patients with Child pugh score B or C
• Patients with an established diagnosis of diabetes mellitus type I or not controlled type II
• Patient has Eastern Cooperative Oncology Group (ECOG) performance status 2 or more
• Patient with CNS involvement unless he/she is at least 4 weeks from prior therapy completion to starting the study treatment and has stable CNS tumor at time of screening and not receiving steroids and/or enzyme inducing ant-epileptic medications for brain metastases
• Patient has participated in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
• Patient has a history of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis
• Patient who relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease

Other protocol-defined inclusion/esclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Lebanon, Mexico, Netherlands, Peru, Romania, Russian Federation, Spain, Sweden, Taiwan, Thailand, United Kingdom, United States
• Removed Location Countries: Czech Republic, Denmark, Portugal, Turkey, United Arab Emirates

Administrative Information

• NCT Number: NCT02437318
• Other Study ID Numbers: CBYL719C2301; 2015-000340-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: November 2023