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
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT03056755
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
Study assessing the efficacy and safety of alpelisib plus fulvestrant or letrozole, based on prior endocrine therapy, in patients with hormone receptor (HR) positive, HER2-negative advanced breast cancer (aBC), harboring PIK3CA mutations, who have progressed on or after prior treatments.
- Detailed Description
This is a phase II, multicenter, open-label, three-cohort, non-comparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2- aBC harboring PIK3CA mutation(s) in the tumor whose disease has progressed on or after prior treatments.
The study includes two phases:
* Core Phase: includes treatment phase for all patients from First Patient First Treatment (FPFT) until 18 months post Last Patient First Treatment (LPFT) + 1 month Safety follow-up (total 19 months post LPFT)
* Extension Phase: includes treatment phase starting at the end of the treatment Core Phase up to 36 months. The extension treatment phase is only for patients who are continuing to benefit from treatment at the end of the Core Phase and are not eligible for PSDS (Post-Study Drug Supply) in their country based on local regulations. Patients will continue on their existing treatment assigned in the Core Phase. If PSDS becomes available for a patient, the patient should be discontinued from the study and access treatment via PSDS. During the Extension Phase there will be no per protocol efficacy assessments other than physician's determination as per standard of care of whether or not the patient is continuing to derive clinical benefit from the study treatment.
Patients who are benefiting from treatment and are eligible for PSDS will exit the trial at the end of the Core Phase.
After discontinuation of study treatment, all patients will be followed for safety for at least 30 days except in case of death, loss to follow-up or withdrawal of consent.
During the Core Phase only: If a patient discontinues study treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent for efficacy follow-up, tumor assessments should continue to be performed until documented disease progression, death, lost to follow-up, or withdrawn consent to efficacy follow-up or end of study (Post-treatment efficacy follow-up). Moreover, all participants will be followed for survival status (after progression) regardless of treatment discontinuation reason (except if consent is withdrawn, death or patient is lost to follow-up) until death, lost to follow-up, or withdrawal of consent for survival follow-up or end of the Core Phase
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 379
- 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
- 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)
Kaiser Permanente Medical Group
🇺🇸Anaheim, California, United States
UCSF
🇺🇸San Francisco, California, United States
University of Louisville James Graham Brown Cancer Center
🇺🇸Louisville, Kentucky, United States
Greater Baltimore Med Center Cancer Center
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Josephine Ford Cancer Center
🇺🇸Detroit, Michigan, United States
Texas Oncology
🇺🇸Dallas, Texas, United States
Cancer Care Centers of South Texas HOAST
🇺🇸San Antonio, Texas, United States
Virginia Oncology Associates
🇺🇸Norfolk, Virginia, United States
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, 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
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
Mercy Medical Center
🇺🇸Baltimore, Maryland, United States
Lahey Clinic
🇺🇸Burlington, Massachusetts, United States
St Vincent Frontier Cancer Center
🇺🇸Billings, Montana, United States
New Mexico Cancer Care Alliance
🇺🇸Albuquerque, New Mexico, United States
Memorial Sloane Ketterin Cancer Ctr
🇺🇸New York, New York, United States
Uni Hosp of Cleveland Cancer Center
🇺🇸Cleveland, Ohio, United States
UT Health San Antonio
🇺🇸San Antonio, Texas, United States
Northwest Medical Specialists
🇺🇸Tacoma, Washington, United States
Novartis Investigative Site
🇬🇧Nottingham, United Kingdom
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