Clinical trial NCT04544189: 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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Neoplasms
Keywords: Alpelisib
Fulvestrant
PIK3CA mutant advanced breast cancer
randomized cohort
PK cohort
Chinese population
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-09-10
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From the date of randomization to the date of the first documented progression or death due to any cause, up to approximately 34 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: From date of randomization to date of death due to any cause, up to approximately 48 months.
measure: Overall response rate (ORR)
timeFrame: Up to approximately 34 months
measure: Clinical benefit rate (CBR) with confirmed response
timeFrame: Up to approximately 34 months
measure: Pharmacokinetics (PK): Trough concentration of alpelisib in plasma
timeFrame: Predose at Cycle (C) 1 Day (D) 15, C2 D1, C4 D1 and C6 D1 (Cycle=28 days)
measure: Time to definitive deterioration in Eastern Cooperative Oncology Group (ECOG) performance status (PS)
timeFrame: Up to approximately 30 months.
measure: Number of participants with Adverse Events (AEs)
timeFrame: From date of randomization until the end of the study, up to approximately 48 months
measure: Number of participants with dose interruptions
timeFrame: Up to approximately 30 months
measure: Number of participants with dose reductions
timeFrame: Up to approximately 30 months
measure: Dose intensity
timeFrame: Up to approximately 30 months
measure: PFS based on local radiology assessments and using RECIST 1.1 criteria by PIK3CA mutation status measured in baseline ctDNA
timeFrame: Baseline and from randomization up to approximately 34 months
measure: Pharmacokinetics (PK) of alpelisib when given in combination with fulvestrant (PK cohort): Maximum observed plasma concentration (Cmax)
timeFrame: 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
measure: Pharmacokinetics (PK) of alpelisib when given in combination with fulvestrant (PK cohort): Time to reach maximum plasma concentration (Tmax)
timeFrame: 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
measure: Pharmacokinetics (PK) of alpelisib when given in combination with fulvestrant (PK cohort): Area under the curve from time 0 to 24h (AUC0-24h)
timeFrame: 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
Other outcomes:
Locations:
city: Hefei
country: China
facility: Novartis Investigative Site
state: Anhui
city: Hefei
country: China
facility: Novartis Investigative Site
state: Anhui
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Shijiazhuang
country: China
facility: Novartis Investigative Site
state: Hebei
city: Harbin
country: China
facility: Novartis Investigative Site
state: Heilongjiang
city: Zhengzhou
country: China
facility: Novartis Investigative Site
state: Henan
city: Wuhan
country: China
facility: Novartis Investigative Site
state: Hubei
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanchang
country: China
facility: Novartis Investigative Site
state: Jiangxi
city: Chang Chun
country: China
facility: Novartis Investigative Site
state: Jilin
city: Shengyang
country: China
facility: Novartis Investigative Site
state: Liaoning
city: Shenyang
country: China
facility: Novartis Investigative Site
state: Liaoning
city: Jinan
country: China
facility: Novartis Investigative Site
state: Shandong
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Bengbu
country: China
facility: Novartis Investigative Site
city: Dalian
country: China
facility: Novartis Investigative Site
city: Qingdao
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: