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Study Assessing the Efficacy and Safety of Treatment With Alpelisib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Chinese Men and Postmenopausal Women With Advanced Breast Cancer

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ClinicalTrials.gov Identifier: NCT04544189
Recruitment Status : Recruiting
First Posted : September 10, 2020
Last Update Posted : March 24, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

The primary objective is to evaluate whether treatment with alpelisib in combination with fulvestrant prolongs Progression Free Survival (PFS) compared to treatment with placebo in combination with fulvestrant.

The primary scientific question of interest is: what is the treatment effect based on PFS for alpelisib in combination with fulvestrant versus placebo in combination with fulvestrant in Chinese men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation, who received prior treatment with an aromatase inhibitor (AI) either as (neo) adjuvant treatment or as treatment for advanced disease, regardless of study treatment discontinuation or start of new anti-neoplastic therapy.


Condition or disease Intervention/treatment Phase
Breast Neoplasms Drug: Alpelisib Drug: Fulvestrant Drug: Placebo Phase 2

Detailed Description:

This is a Phase II, randomized, double-blind, placebo-controlled, multi-center study conducted in Chinese men and postmenopausal women with HR- positive, HER2-negative, PIK3CA mutant advanced breast cancer which progressed on or after AI treatment. The study also includes a single arm, open-label cohort (the PK cohort) to conduct pharmacokinetic analysis.

For the randomized cohort, in the randomized treatment phase, subjects will be randomized 1:1 to receive alpelisib or matching placebo plus fulvestrant.

A total of approximately 120 subjects will be enrolled; randomization will be stratified by:

  1. Lung and/or liver metastases (yes versus no)
  2. Previous treatment with any CDK4/6 inhibitor (yes versus no) The total number of subjects pre-treated with any CDK4/6 inhibitor will be limited to 30% of the total number of subjects.

Approximately 15 subjects meeting the same inclusion/exclusion criteria as the randomized cohort will be enrolled into the PK cohort. Subjects in the PK cohort will receive alpelisib plus fulvestrant.

Subjects will continue to receive study treatment until disease progression as determined by investigator, unacceptable toxicity, or until discontinuation of study treatment due to any other reason.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II Randomized Double-blind, Placebo-controlled Study of Alpelisib in Combination With Fulvestrant for Chinese Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, PIK3CA Mutant Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor (AI) Treatment, Including a Subset With Pharmacokinetic Analysis
Actual Study Start Date : January 20, 2021
Estimated Primary Completion Date : November 13, 2023
Estimated Study Completion Date : July 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Fulvestrant

Arm Intervention/treatment
Experimental: Alpelisib+Fulvestrant (randomized cohort)
Alpelisib (300 mg by mouth once daily, in a 28-day cycle) plus fulvestrant (500 mg intramuscular [as two 250mg/5 ml injections] on Day 1 and 15 of Cycle 1 and on Day 1 of every Cycle thereafter)
Drug: Alpelisib
300mg (oral) once daily, in a 28-day cycle
Other Name: BYL719

Drug: Fulvestrant
Fulvestrant 500 mg (intramuscular, as two 250mg/5 mL injections) on Day 1 and 15 of Cycle 1 and on Day 1 of every Cycle thereafter

Placebo Comparator: Placebo+Fulvestrant (randomized cohort)
Placebo (300 mg by mouth once daily, in a 28-day cycle) plus fulvestrant (500 mg intramuscular [as two 250mg/5 ml injections] on Day 1 and 15 of Cycle 1 and on Day 1 of every Cycle thereafter)
Drug: Fulvestrant
Fulvestrant 500 mg (intramuscular, as two 250mg/5 mL injections) on Day 1 and 15 of Cycle 1 and on Day 1 of every Cycle thereafter

Drug: Placebo
300 mg by mouth once daily, in a 28-day cycle

Experimental: PK cohort (open label cohort)
Alpelisib (300 mg by mouth once daily, in a 28-day cycle) plus fulvestrant (500 mg intramuscular [as two 250mg/5 ml injections] on Day 1 and 15 of Cycle 1 and on Day 1 of every Cycle thereafter)
Drug: Alpelisib
300mg (oral) once daily, in a 28-day cycle
Other Name: BYL719

Drug: Fulvestrant
Fulvestrant 500 mg (intramuscular, as two 250mg/5 mL injections) on Day 1 and 15 of Cycle 1 and on Day 1 of every Cycle thereafter




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: From the date of randomization to the date of the first documented progression or death due to any cause, up to approximately 34 months ]
    PFS is defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. The primary analysis for PFS will be performed based on local radiology assessment according to RECIST 1.1.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: From date of randomization to date of death due to any cause, up to approximately 48 months. ]
    OS is defined as the time from date of randomization to date of death due to any cause. OS will be analyzed in the FAS population according to the randomized treatment arm and strata assigned at randomization.

  2. Overall response rate (ORR) [ Time Frame: Up to approximately 34 months ]
    Overall response rate (ORR) with confirmed response is defined as the proportion of subjects with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on local investigator's assessment according to RECIST 1.1

  3. Clinical benefit rate (CBR) with confirmed response [ Time Frame: Up to approximately 34 months ]
    CBR is defined as the proportion of subjects with a best overall response of confirmed complete response (CR), or confirmed partial response (PR) or an overall response of confirmed stable disease (SD), lasting for a duration of at least 24 weeks. CR, PR and SD are defined as per local review according to RECIST 1.1.

  4. Pharmacokinetics (PK): Trough concentration of alpelisib in plasma [ Time Frame: Predose at Cycle (C) 1 Day (D) 15, C2 D1, C4 D1 and C6 D1 (Cycle=28 days) ]
    Pre-dose concentration of alpelisib at steady state on planed days. Measurement of alpelisib will be performed only in subjects randomized to the alpelisib arm.

  5. Time to definitive deterioration in Eastern Cooperative Oncology Group (ECOG) performance status (PS) [ Time Frame: Up to approximately 30 months. ]
    PS will be assessed using ECOG scale. The scale consists of 4 grades (from 0 to 4) where 0 implies fully active and 4 implies completely disabled. Subjects will be censored if no definitive deterioration in ECOG PS is observed before the analysis cut-off date. The censoring date will be the date of the last PS assessment prior to cut- off. (Approximately up to 30 months)

  6. Number of participants with Adverse Events (AEs) [ Time Frame: From date of randomization until the end of the study, up to approximately 48 months ]
    Incidence, type, and severity of AEs per CTCAE version 4.03 criteria including changes in laboratory values, vital signs, liver assessments and cardiac assessments

  7. Number of participants with dose interruptions [ Time Frame: Up to approximately 30 months ]
    Tolerability measured by the number of subjects who have interruptions of study treatment

  8. Number of participants with dose reductions [ Time Frame: Up to approximately 30 months ]
    Tolerability measured by the number of subjects who have reductions of study treatment.

  9. Dose intensity [ Time Frame: Up to approximately 30 months ]
    Tolerability measured by the dose intensity of study drug

  10. PFS based on local radiology assessments and using RECIST 1.1 criteria by PIK3CA mutation status measured in baseline ctDNA [ Time Frame: Baseline and from randomization up to approximately 34 months ]
    PFS defined as the time from the date of randomization to the date of the first documented progression based on local radiology assessment and according to RECIST 1.1 or death due to any cause. Results will be presented by PIK3CA mutation status measured in baseline ctDNA

  11. Pharmacokinetics (PK) of alpelisib when given in combination with fulvestrant (PK cohort): Maximum observed plasma concentration (Cmax) [ Time Frame: Cycle (C) 1 Day (D) 1 and 15 pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post-dose; and pre-dose on C2D1, C4D1 and C6D1 ]
    Blood samples are collected at indicated time-points for analysis of Cmax in PK cohort.

  12. Pharmacokinetics (PK) of alpelisib when given in combination with fulvestrant (PK cohort): Time to reach maximum plasma concentration (Tmax) [ Time Frame: Cycle (C) 1 Day (D) 1 and 15 pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post-dose; and pre-dose on C2D1, C4D1 and C6D1 ]
    Blood samples are collected at indicated time-points for analysis of Tmax in PK cohort.

  13. Pharmacokinetics (PK) of alpelisib when given in combination with fulvestrant (PK cohort): Area under the curve from time 0 to 24h (AUC0-24h) [ Time Frame: Cycle (C) 1 Day (D) 1 and 15 pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post-dose; and pre-dose on C2D1, C4D1 and C6D1 ]
    Blood samples are collected at indicated time-points for analysis of AUC0-24h in PK cohort



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Participant 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 (3 slides minimum from a surgical specimen, or 7 slides minimum from a core needle biopsy) must be provided. It is recommended to provide a tumor sample collected after the most recent progression or recurrence.
  • Chinese man or postmenopausal woman ≥ 18 years of age
  • Participant has identified PIK3CA mutation (as determined by a Novartis designated laboratory)
  • Participant has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory.
  • Participant has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH or SISH) test is required by local laboratory testing
  • Participant has either
  • 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
  • If no measurable disease is present, then at least one predominantly lytic bone lesion must be present (Participants 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).
  • Participant has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer.
  • Participants 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 ECOG performance status 0 or 1.
  • Patient has adequate bone marrow function.

Key Exclusion Criteria

  • Participant with symptomatic visceral disease or any disease burden that makes the Participant ineligible for endocrine therapy per the investigator's best judgment.
  • Participant has received prior treatment with chemotherapy (except for (neo)adjuvant/ adjuvant chemotherapy), fulvestrant, any PI3K, mTOR or AKT inhibitor.
  • Participant has a known hypersensitivity to alpelisib or fulvestrant, or to any of the excipients of alpelisib or fulvestrant.
  • Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 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 ≥ 25% of the bone marrow was irradiated.
  • Participant 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.
  • Participant with an established diagnosis at screening of diabetes mellitus type I or not controlled type II
  • Participant has currently documented pneumonitis/interstitial lung disease
  • History of acute pancreatitis within 1 year of screening or a past medical history of chronic pancreatitis
  • Participant with unresolved osteonecrosis of the jaw
  • Participant has a history of severe cutaneous reactions like Stevens- Johnson-Syndrome (SJS), Erythema Multiforme (EM), or Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Other protocol-defined inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04544189


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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China, Anhui
Novartis Investigative Site Recruiting
Hefei, Anhui, China, 230022
China, Guangdong
Novartis Investigative Site Recruiting
Guangzhou, Guangdong, China, 510000
China, Hubei
Novartis Investigative Site Recruiting
Wuhan, Hubei, China, 430022
China, Hunan
Novartis Investigative Site Recruiting
Changsha, Hunan, China, 410013
China, Jilin
Novartis Investigative Site Recruiting
Chang Chun, Jilin, China, 130021
China, Tianjin
Novartis Investigative Site Recruiting
Tianjin, Tianjin, China, 300060
China, Zhejiang
Novartis Investigative Site Recruiting
Hangzhou, Zhejiang, China, 310016
Novartis Investigative Site Recruiting
Hangzhou, Zhejiang, China, 310022
China
Novartis Investigative Site Recruiting
Beijing, China, 100021
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04544189    
Other Study ID Numbers: CBYL719C2201
First Posted: September 10, 2020    Key Record Dates
Last Update Posted: March 24, 2021
Last Verified: March 2021
Individual Participant Data (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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Alpelisib
Fulvestrant
PIK3CA mutant advanced breast cancer
randomized cohort
PK cohort
Chinese population
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs