BYLieve: Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutation With Advanced Breast Cancer Who Have Progressed on or After Prior Treatments

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03056755

Collaborator

(none)

383

Enrollment

Locations

Arms

71.1

Anticipated Duration (Months)

4.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Study assessing the efficacy and safety of alpelisib plus fulvestrant or letrozole, based on prior endocrine therapy, in patients with PIK3CA mutation with advanced breast cancer who have progressed on or after prior treatments

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Alpelisib Drug: Fulvestrant Drug: Letrozole Drug: Goserelin Drug: Leuprolide	Phase 2

Detailed Description

This is a phase II, multicenter, open-label, three-cohort, noncomparative study of alpelisib plus endocrine therapy (either fulvestrant or letrozole) in patients with HR+, HER2-negative 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 until 12 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.

Patients who are benefiting from treatment and are eligible for PSDS will exit the trial at the end of the Core Phase.

Study Design

Study Type:

Interventional

Actual Enrollment :

383 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

BYLieve: A Phase II, Multicenter, Open-label, Three-cohort, Non- Comparative Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole in Patients With PIK3CA Mutant, Hormone Receptor (HR) Positive, HER2-negative Advanced Breast Cancer (aBC), Who Have Progressed on or After Prior Treatments

Actual Study Start Date :

Aug 14, 2017

Actual Primary Completion Date :

Jun 14, 2021

Anticipated Study Completion Date :

Jul 17, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Prior CDK 4/6 + aromatase Patients who received any Cyclin-Dependent Kinases 4 and 6 (CDK 4/6) inhibitor plus aromatase inhibitor as treatment (immediately prior) will receive alpelisib 300 mg oral.+ fulvestrant 500 mg intramuscular (i.m)	Drug: Alpelisib 300 mg; oral; once daily Other Names: BYL719 Drug: Fulvestrant 500 mg; intramuscular injection on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days
Experimental: Cohort B: Prior CDK 4/6 + fulvestrant Patients who received any CDK 4/6 inhibitor plus fulvestrant as treatment (immediately prior) will receive alpelisib 300 mg oral + letrozole 2.5 mg oral	Drug: Alpelisib 300 mg; oral; once daily Other Names: BYL719 Drug: Letrozole 2.5 mg; oral; once daily Drug: Goserelin Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable subcutaneous implant (3.6 mg) Drug: Leuprolide Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable intramuscular depot (7.5 mg)
Experimental: Cohort C: Prior systemic chemo or ET Patients who received systemic chemotherapy or endrocrine therapy (ET) , (including monotherapy or in combination with targeted therapy except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib 300 mg oral + fulvestrant 500 mg i.m.	Drug: Alpelisib 300 mg; oral; once daily Other Names: BYL719 Drug: Fulvestrant 500 mg; intramuscular injection on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days

Arm

Intervention/Treatment

Experimental: Cohort A: Prior CDK 4/6 + aromatase

Patients who received any Cyclin-Dependent Kinases 4 and 6 (CDK 4/6) inhibitor plus aromatase inhibitor as treatment (immediately prior) will receive alpelisib 300 mg oral.+ fulvestrant 500 mg intramuscular (i.m)

Drug: Alpelisib

300 mg; oral; once daily

Other Names:

BYL719

Drug: Fulvestrant

500 mg; intramuscular injection on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days

Experimental: Cohort B: Prior CDK 4/6 + fulvestrant

Patients who received any CDK 4/6 inhibitor plus fulvestrant as treatment (immediately prior) will receive alpelisib 300 mg oral + letrozole 2.5 mg oral

Drug: Alpelisib

300 mg; oral; once daily

Other Names:

BYL719

Drug: Letrozole

2.5 mg; oral; once daily

Drug: Goserelin

Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable subcutaneous implant (3.6 mg)

Drug: Leuprolide

Every 28 days (only for men in cohort B and premenopausal women). Administered as injectable intramuscular depot (7.5 mg)

Experimental: Cohort C: Prior systemic chemo or ET

Patients who received systemic chemotherapy or endrocrine therapy (ET) , (including monotherapy or in combination with targeted therapy except CDK 4/6i + AI) as immediate prior treatment will receive alpelisib 300 mg oral + fulvestrant 500 mg i.m.

Drug: Alpelisib

300 mg; oral; once daily

Other Names:

BYL719

Drug: Fulvestrant

500 mg; intramuscular injection on Days 1, 15 on Cycle 1 and Day 1 at each cycle thereafter. Cycle=28 days

Outcome Measures

Primary Outcome Measures

Percentage of participants who are alive without disease progression at 6 months [At 6 months]
Percentage of participants without disease progression at 6 months of treatment based on local investigator assessment per RECIST v1.1 in cohort A, cohort B and cohort C

Secondary Outcome Measures

Progression free survival (PFS) for each cohort [From date of first dose to date of first documented progression or death, up to approximately 25 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 will be assessed based on local investigator's assessment according to RECIST v1.1
Progression free survival (PFS) on next line treatment PFS2) for each cohort [From date of first dose to date of first documented progression on next-line therapy or death, up to approximately 25 months]
Progression free survival (PFS) on next line treatment (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 (PD)
Overall response rate (ORR) for each cohort [Up to approximately 25 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
Clinical benefit rate (CBR) for each cohort [Up to approximately 25 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.
Duration of response (DOR) [From date of first documented response to first documented progression or death, up to approximately 25 months]
Duration of Response 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
Overall suvivial (OS) for each cohort [From date of first dose and up to approximately 25 months]
Overall Survival is defined as the time of start of treatment to date of death or lost to follow-up.
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient is male or female 18 years or older
Males or females with advanced (locoregionally recurrent or metatstatic) breast cancer not amenable to curative therapy
In case of women, both premenopausal and postmenopausal patients are allowed to be included in study; menopausal status is relevant for the requirement of LHRH agonist (examples for use in this study include but not limited to goserelin, leuprolide or locally available treatment) to be used concomitantly with alpelisib and letrozole/fulvestrant

Patient is postmenopausal woman defined as either:

Prior bilateral oophorectomy or
Age ≥60 or
Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and/or estradiol in the postmenopausal range per local normal range.

If patient is taking tamoxifen or toremifene and age <60, then FSH and plasma estradiol levels should be in post-menopausal range per local normal range.

Note: For women using therapy-induced amenorrhea other than ovarian radiation, goserelin or leuprolide, etc., serial measurements of FSH and/or estradiol are needed to ensure menopausal status

Patient is premenopausal defined as either:

Patient had last menstrual period within the last 12 months or
If on tamoxifen or toremifene with in the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range, or
In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range
Patient has confirmed HER2-negative advanced breast cancer (aBC)
Patient has histological and/or cytological confirmed ER+ and/or PgR+ aBC
Patient has a PIK3CA mutation confirmed by Novartis designated central lab or patient has a pathology report confirming PIK3CA mutant status by certified laboratory (using validated PI3KCA mutation assay) either from tissue or blood and must (mandatory) send tumor tissue to Novartis designated central lab for confirmation of mutational status
Patient must have:
Documented evidence of tumor progression on or after CDK 4/ 6 inhibitor combination treatment; CDK 4/6 inhibitor must be the last treatment regimen prior to study entry,
AI treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET(as monotherapy or in combination except CDK 4/6i + AI) as last treatment regimen in cohort C
Maintenance therapies, where applicable, must be regarded as part of the main treatment.
No more than two (2) prior anti-cancer therapies for aBC
Received no more than one prior regimen of chemotherapy in the metastatic setting
Patient has either measurable disease per RECIST v1.1 or at least one predominantly lytic bone lesion must be present
ECOG performance status ≤ 2
Patient has fasting plasma glucose (FPG) ≤140 mg/dL (7.7 mmol/L) and glycosylated hemoglobin (HbA1c) ≤ 6.4% (both criteria have to be met)
Patient has adequate bone marrow, coagulation, liver and renal function

Exclusion Criteria:

patient has known hypersensitivity to alpelisib, fulvestrant or letrozole
Patient has received prior treatment with any PI3K inhibitors
Patient 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, non-melanoma 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
History of acute pancreatitis within 1 year of screening or past medical history of pancreatitis
Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (MRI or CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment
Patient with severe liver impairment (Child Pugh score B/C)
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs
Patient has documented pneumonitis/interstitial lung disease which is active and requiring treatment
Patient has a history of severe cutaneous reactions like Stevens-Johnson-Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necroloysis (TEN) or Drug Reaction with Eosinphilia and Systemic Symptoms (DRESS).
Patient is concurrently using other anti-cancer therapy. All anti-cancer therapy must be discontinued prior to day one of study treatment.
Subjects with unresolved osteonecrosis of the jaw.

Other inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner MD Anderson Cancer Center	Gilbert	Arizona	United States	85234
2	Mayo Clinic (Arizona)	Phoenix	Arizona	United States	85054
3	Kaiser Permanente Medical Group Kaiser Permanente-Moanalua M.C	Anaheim	California	United States	92807
4	Beverly Hills Cancer Center	Beverly Hills	California	United States	90211
5	University of Calif Irvine Medical Center	Orange	California	United States	92868
6	Kaiser Permanente Southern California	San Diego	California	United States	92120
7	University of California, San Francisco	San Francisco	California	United States	94115
8	Yale University Yale Cancer Center	New Haven	Connecticut	United States	06511
9	Advent Health Cancer Institute	Orlando	Florida	United States	32804
10	University of Kansas Cancer Center	Kansas City	Kansas	United States	66205
11	University of Louisville Hospital/James Brown Cancer Ctr. SC	Louisville	Kentucky	United States	40202
12	Mercy Medical Center	Baltimore	Maryland	United States	21202
13	Greater Baltimore Medical Center Cancer Center	Baltimore	Maryland	United States	21204-6831
14	Massachusetts General Hospital Neuroendocrine Unit	Boston	Massachusetts	United States	02114
15	Lahey Clinic	Burlington	Massachusetts	United States	01805
16	Josephine Ford Cancer Institute	Detroit	Michigan	United States	48202
17	St Vincent Frontier Cancer Center	Billings	Montana	United States	59102
18	New Mexico Cancer Care Alliance	Albuquerque	New Mexico	United States	87106
19	Memorial Sloane Kettering Cancer Center	New York	New York	United States	10065
20	University Hospitals of Cleveland Seidman Cancer Center	Cleveland	Ohio	United States	44106
21	Texas Oncology Charles A. Sammons Cancer Ctr	Dallas	Texas	United States	75246
22	Cancer Care Centers of South Texas HOAST CCC of So. TX- San Antonio(2)	San Antonio	Texas	United States	78229
23	UT Health San Antonio	San Antonio	Texas	United States	78229
24	Virginia Oncology Associates SC	Norfolk	Virginia	United States	23502
25	Northwest Medical Specialists	Tacoma	Washington	United States	98405
26	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1118AAT
27	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1125ABD
28	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1426ANZ
29	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000DSV
30	Novartis Investigative Site	Rosario	Sante Fe	Argentina	S200KZE
31	Novartis Investigative Site	La Rioja		Argentina	5300
32	Novartis Investigative Site	Leuven		Belgium	3000
33	Novartis Investigative Site	Liege		Belgium	4000
34	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 4E6
35	Novartis Investigative Site	Halifax	Nova Scotia	Canada	B3H 2Y9
36	Novartis Investigative Site	Kitchener	Ontario	Canada	N2G 1G3
37	Novartis Investigative Site	Toronto	Ontario	Canada	M5B 1N9
38	Novartis Investigative Site	Temuco	Araucania	Chile	4810469
39	Novartis Investigative Site	Santiago		Chile	7500921
40	Novartis Investigative Site	Santiago		Chile	8420383
41	Novartis Investigative Site	Odense C		Denmark	DK 5000
42	Novartis Investigative Site	Vejle		Denmark	7100
43	Novartis Investigative Site	Nice Cedex 2	Alpes Maritimes	France	06189
44	Novartis Investigative Site	Saint-Cloud	Hauts De Seine	France	92210
45	Novartis Investigative Site	Bordeaux		France	33076
46	Novartis Investigative Site	Caen Cedex		France	14021
47	Novartis Investigative Site	Lille Cedex		France	59020
48	Novartis Investigative Site	Lyon Cedex		France	69373
49	Novartis Investigative Site	Montpellier Cedex 5		France	34298
50	Novartis Investigative Site	Saint Herblain cedex		France	44805
51	Novartis Investigative Site	Strasbourg Cedex		France	F 67098
52	Novartis Investigative Site	Toulouse Cedex 9		France	31059
53	Novartis Investigative Site	Augsburg		Germany	86150
54	Novartis Investigative Site	Berlin		Germany	14169
55	Novartis Investigative Site	Dresden		Germany	01307
56	Novartis Investigative Site	Erlangen		Germany	91054
57	Novartis Investigative Site	Essen		Germany	45136
58	Novartis Investigative Site	Heidelberg		Germany	69120
59	Novartis Investigative Site	Ulm		Germany	89081
60	Novartis Investigative Site	Delhi		India	110 085
61	Novartis Investigative Site	Petach Tikva		Israel	4941492
62	Novartis Investigative Site	Ramat Gan		Israel	52621
63	Novartis Investigative Site	Rehovot		Israel	7610001
64	Novartis Investigative Site	Tel Aviv		Israel	6423906
65	Novartis Investigative Site	Ancona	AN	Italy	60126
66	Novartis Investigative Site	Bergamo	BG	Italy	24127
67	Novartis Investigative Site	Bologna	BO	Italy	40138
68	Novartis Investigative Site	Genova	GE	Italy	16132
69	Novartis Investigative Site	Milano	MI	Italy	20133
70	Novartis Investigative Site	Milano	MI	Italy	20141
71	Novartis Investigative Site	Roma	RM	Italy	00168
72	Novartis Investigative Site	Napoli		Italy	80131
73	Novartis Investigative Site	Osaka-city	Osaka	Japan	540-0006
74	Novartis Investigative Site	Seoul		Korea, Republic of	03080
75	Novartis Investigative Site	Seoul		Korea, Republic of	06351
76	Novartis Investigative Site	Jalisco		Mexico	45640
77	Novartis Investigative Site	Maastricht	AZ	Netherlands	5800
78	Novartis Investigative Site	Singapore		Singapore	169610
79	Novartis Investigative Site	Singapore		Singapore	217562
80	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
81	Novartis Investigative Site	Salamanca	Castilla Y Leon	Spain	37007
82	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
83	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
84	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
85	Novartis Investigative Site	Castellon	Comunidad Valenciana	Spain	12002
86	Novartis Investigative Site	Madrid		Spain	28041
87	Novartis Investigative Site	Tainan		Taiwan	70403
88	Novartis Investigative Site	Taipei		Taiwan	10002
89	Novartis Investigative Site	Taipei		Taiwan
90	Novartis Investigative Site	Sutton	Surrey	United Kingdom	SM2 5PT
91	Novartis Investigative Site	Edinburgh		United Kingdom	EH4 2XU
92	Novartis Investigative Site	Leicester		United Kingdom	LE1 5WW
93	Novartis Investigative Site	London		United Kingdom	SW3 6JJ
94	Novartis Investigative Site	Nottingham		United Kingdom	NG5 1PB