Phase III Study to Assess AZD9833+ CDK4/6 Inhibitor in HR+/HER2-MBC With Detectable ESR1m Before Progression (SERENA-6)

Sponsor

AstraZeneca (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04964934

Collaborator

(none)

302

Enrollment

216

Locations

Arms

59.8

Anticipated Duration (Months)

1.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study is intended to show superiority of AZD9833 in combination with CDK4/6 inhibitor (palbociclib or abemaciclib) versus aromatase inhibitors (anastrozole or letrozole) in combination with CDK4/6 inhibitor in patients with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) metastatic breast cancer with detectable ESR1 mutation

Condition or Disease	Intervention/Treatment	Phase
ER-Positive HER2-Negative Breast Cancer	Drug: AZD9833 Drug: AZD9833 Placebo Drug: Anastrozole Drug: Anastrozole placebo Drug: Letrozole Drug: Letrozole placebo Drug: Palbociclib Drug: Abemaciclib Drug: Luteinizing hormone-releasing hormone (LHRH) agonist	Phase 3

Detailed Description

A Randomised, Multicentre, Double-Blind, Phase III study will evaluate the safety and efficacy of AZD9833 (next generation oral SERD) in combination with CDK4/6 inhibitor (palbociclib or abemaciclib) versus aromatase inhibitor (anastrozole or letrozole) in combination with CDK4/6 inhibitor for the treatment of patients with HR-positive, HER2- negative metastatic breast cancer with detectable ESR1 Mutation. The goal of the study is to demonstrate superiority of AZD9833 over anastrozole or letrozole in the context of combination with palbociclib or abemaciclib

Study Design

Study Type:

Interventional

Anticipated Enrollment :

302 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase III, Double-blind, Randomised Study to Assess Switching to AZD9833 (a Next Generation, Oral SERD) + CDK4/6 Inhibitor (Palbociclib or Abemaciclib) vs Continuing Aromatase Inhibitor (Letrozole or Anastrozole)+ CDK4/6 Inhibitor in HR+/HER2-MBC Patients With Detectable ESR1Mutation Without Disease Progression During 1L Treatment With Aromatase Inhibitor+ CDK4/6 Inhibitor- A ctDNA Guided Early Switch Study

Actual Study Start Date :

Jun 30, 2021

Anticipated Primary Completion Date :

Sep 28, 2023

Anticipated Study Completion Date :

Jun 25, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD9833 + palbociclib or abemaciclib The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment) or abemaciclib (PO, twice daily, 150,100 or 50 mg) + anastrozole placebo ( PO, once daily) or letrozole placebo ( PO, once daily)	Drug: AZD9833 Dosage formulation: AZD9833 tablets will be administered orally Drug: Anastrozole placebo Dosage formulation: anastrozole placebo tablets will be administrated orally. Drug: Letrozole placebo Dosage formulation: letrozole placebo tablets will be administered orally. Drug: Palbociclib Dosage formulation: palbociclib tablets/capsules will be administered orally Drug: Abemaciclib Dosage formulation: abemaciclib tablets will be administered orally Drug: Luteinizing hormone-releasing hormone (LHRH) agonist Men (when medically applicable) and pre- or peri-menopausal women are required to receive a monthly LHRH agonist.
Active Comparator: Anastrozole or letrozole + palbociclib or abemaciclib The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125,100 or 75 mg for 21 consecutive days followed by 7 days off treatment) or abemaciclib (PO, twice daily, 150,100 or 50 mg) + AZD9833 placebo (PO, once daily)	Drug: AZD9833 Placebo Dosage formulation: AZD9833 placebo tablets will be administrated orally. Drug: Anastrozole Dosage formulation: anastrozole tablets will be administered orally. Drug: Letrozole Dosage formulation: letrozole tablets will be administered orally. Drug: Palbociclib Dosage formulation: palbociclib tablets/capsules will be administered orally Drug: Abemaciclib Dosage formulation: abemaciclib tablets will be administered orally Drug: Luteinizing hormone-releasing hormone (LHRH) agonist Men (when medically applicable) and pre- or peri-menopausal women are required to receive a monthly LHRH agonist.

Arm

Intervention/Treatment

Experimental: AZD9833 + palbociclib or abemaciclib

The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125, 100 or 75 mg for 21 consecutive days followed by 7 days off treatment) or abemaciclib (PO, twice daily, 150,100 or 50 mg) + anastrozole placebo ( PO, once daily) or letrozole placebo ( PO, once daily)

Drug: AZD9833

Dosage formulation: AZD9833 tablets will be administered orally

Drug: Anastrozole placebo

Dosage formulation: anastrozole placebo tablets will be administrated orally.

Drug: Letrozole placebo

Dosage formulation: letrozole placebo tablets will be administered orally.

Drug: Palbociclib

Dosage formulation: palbociclib tablets/capsules will be administered orally

Drug: Abemaciclib

Dosage formulation: abemaciclib tablets will be administered orally

Drug: Luteinizing hormone-releasing hormone (LHRH) agonist

Men (when medically applicable) and pre- or peri-menopausal women are required to receive a monthly LHRH agonist.

Active Comparator: Anastrozole or letrozole + palbociclib or abemaciclib

The patients will recieve anastrozole (1 mg, PO, once daily) or letrozole (2.5 mg, PO, once daily) + palbociclib (PO, once daily, 125,100 or 75 mg for 21 consecutive days followed by 7 days off treatment) or abemaciclib (PO, twice daily, 150,100 or 50 mg) + AZD9833 placebo (PO, once daily)

Drug: AZD9833 Placebo

Dosage formulation: AZD9833 placebo tablets will be administrated orally.

Drug: Anastrozole

Dosage formulation: anastrozole tablets will be administered orally.

Drug: Letrozole

Dosage formulation: letrozole tablets will be administered orally.

Drug: Palbociclib

Dosage formulation: palbociclib tablets/capsules will be administered orally

Drug: Abemaciclib

Dosage formulation: abemaciclib tablets will be administered orally

Drug: Luteinizing hormone-releasing hormone (LHRH) agonist

Men (when medically applicable) and pre- or peri-menopausal women are required to receive a monthly LHRH agonist.

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) assessed by the Investigator as defined by response evaluation criteria in solid tumors (RECIST version 1.1) [From randomization until the earlier of the progression event or death (approximately 2 years)]
PFS is defined as the time from randomization to objective disease progression (as assessed by RECIST 1.1) or death.

Secondary Outcome Measures

Progression-free survival 2 (PFS2) [From randomization to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death (approximately 3.5 years)]
PFS2 is defined as the time from the randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy or death.
Overall survival (OS) [From randomization until the date of death due to any cause (approximately 5 years)]
The OS is defined as the time from randomization to death due to any cause.
Chemotherapy free survival [From randomization until the earlier of the start date of chemotherapy or death due to any cause (approximately 5 years)]
Time to chemotherapy is defined as the time from randomization until the earlier of the start date of chemotherapy or death due to any cause.
Objective response rate (ORR) assessed by the Investigator as defined by RECIST version 1.1 [From randomization until a response or in the absence of a response from randomization up until progression, or the last evaluable assessment in the absence of progression (approximately 5 years)]
ORR is defined as the proportion of patients who have a complete response (CR) or partial response (PR), as determined by the investigator at local site per RECIST 1.1.
Clinical benefit rate at 24 weeks (CBR24) [At least 23 weeks after randomisation for each patient (1 week window for RECIST assessment)]
CBR at 24 weeks is defined as the percentage of participants who have a complete response (CR) or partial response or who have stable disease (SD) per RECIST 1.1 as assessed by the investigator at local site for At least 23 weeks after randomisation for each patient to allow for an early assessment within the assessment window (1 week window for RECIST assessment)
Change from baseline in EORTC QLQ-C30 scale scores [From baseline until second progression (approximately 5 years)]
Change from baseline in scales scores of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden.
Change from baseline in EORTC QLQ-BR23 scale scores [From baseline until second progression (approximately 5 years)]
Change from baseline in scales scores of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC QLQ-BR23). Scale scores range from 0-100. For functioning scales, higher scores indicate better functioning. For symptom scales, higher scores indicate greater symptom burden.
Plasma concentration of AZD9833 at specified timepoints [on Day 15 for each patient]
To assess the steady state PK of AZD9833 in combination with palbociclib or abemaciclib in all participants who receive at least one dose of AZD9833 per the protocol, for whom there are at least one reportable PK concentration.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent.
Documentation of histologically confirmed diagnosis of estrogen receptor positive (ER+) /HER2- breast cancer based on local laboratory results.
Currently on AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib or abemaciclib) ± LHRH as the initial endocrine based treatment for advanced disease
Eastern Cooperative Oncology Group performance status of 0 or 1.
ESR1m positive detected by central testing of ctDNA
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Adequate organ and marrow function

Exclusion Criteria:

Advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term.
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease.
Any evidence of severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
Patient with known or family history of severe heart disease
Previous treatment with AZD9833, investigational SERDs or fulvestrant.
Currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
Persistent non-haematological toxicities (CTCAE Grade > 2) caused by CDK4/6 inhibitor and/or AI treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Phoenix	Arizona	United States	85054
2	Research Site	Hot Springs National Park	Arkansas	United States	71913
3	Research Site	Little Rock	Arkansas	United States	72205
4	Research Site	Long Beach	California	United States	90806
5	Research Site	San Diego	California	United States	92123
6	Research Site	Santa Rosa	California	United States	92805
7	Research Site	Denver	Colorado	United States	80218
8	Research Site	Grand Junction	Colorado	United States	81501
9	Research Site	Lone Tree	Colorado	United States	80124
10	Research Site	Fort Myers	Florida	United States	33901
11	Research Site	Jacksonville	Florida	United States	32224
12	Research Site	Jacksonville	Florida	United States	32256
13	Research Site	Saint Petersburg	Florida	United States	33705
14	Research Site	Atlanta	Georgia	United States	30322
15	Research Site	Atlanta	Georgia	United States	30342
16	Research Site	Fort Wayne	Indiana	United States	46804
17	Research Site	Indianapolis	Indiana	United States	46250
18	Research Site	Baltimore	Maryland	United States	21202
19	Research Site	Boston	Massachusetts	United States	02215
20	Research Site	Detroit	Michigan	United States	48202
21	Research Site	Grand Rapids	Michigan	United States	49503
22	Research Site	Rochester	Minnesota	United States	55905
23	Research Site	Saint Louis	Missouri	United States	63110
24	Research Site	Billings	Montana	United States	59101
25	Research Site	Omaha	Nebraska	United States	68130
26	Research Site	Camden	New Jersey	United States	08103
27	Research Site	Ridgewood	New Jersey	United States	07450
28	Research Site	New York	New York	United States	10065
29	Research Site	Blue Ash	Ohio	United States	45242
30	Research Site	Columbus	Ohio	United States	43219
31	Research Site	Philadelphia	Pennsylvania	United States	19104
32	Research Site	Pittsburgh	Pennsylvania	United States	15213
33	Research Site	Greenville	South Carolina	United States	29607
34	Research Site	West Columbia	South Carolina	United States	29169
35	Research Site	Knoxville	Tennessee	United States	37916
36	Research Site	Memphis	Tennessee	United States	38120
37	Research Site	Nashville	Tennessee	United States	37203
38	Research Site	Bedford	Texas	United States	76022
39	Research Site	Dallas	Texas	United States	75246
40	Research Site	Houston	Texas	United States	77024
41	Research Site	Irving	Texas	United States	75063
42	Research Site	Longview	Texas	United States	75601
43	Research Site	Lubbock	Texas	United States	79410
44	Research Site	San Antonio	Texas	United States	78240
45	Research Site	Norfolk	Virginia	United States	23502
46	Research Site	Tacoma	Washington	United States	98405
47	Research Site	Birtinya		Australia	4575
48	Research Site	Darlinghurst		Australia	2010
49	Research Site	Subiaco		Australia	6008
50	Research Site	Graz		Austria	8036
51	Research Site	Innsbruck		Austria	6020
52	Research Site	Wien		Austria	1090
53	Research Site	Wien		Austria	1130
54	Research Site	Haskovo		Bulgaria	6300
55	Research Site	Panagyurishte		Bulgaria	4500
56	Research Site	Pleven		Bulgaria	5804
57	Research Site	Plovdiv		Bulgaria	4004
58	Research Site	Sofia		Bulgaria	1303
59	Research Site	Sofia		Bulgaria	1330
60	Research Site	Sofia		Bulgaria	1407
61	Research Site	Sofia		Bulgaria	1527
62	Research Site	Sofia		Bulgaria
63	Research Site	Calgary	Alberta	Canada	T2N 4N2
64	Research Site	Vancouver	British Columbia	Canada	V5Z 4E6
65	Research Site	Montreal	Quebec	Canada	H1T 2M4
66	Research Site	Montreal	Quebec	Canada	H2X 0C1
67	Research Site	Montreal	Quebec	Canada	H3T 1E2
68	Research Site	Ottawa		Canada	K1H 8L6
69	Research Site	Quebec		Canada	G1S 4L8
70	Research Site	Avignon Cedex 09		France	84918
71	Research Site	Brest		France	29200
72	Research Site	Clermont-Ferrand		France	63050
73	Research Site	Limoges		France	83000
74	Research Site	Lorient cedex		France	56322
75	Research Site	Lyon Cedex 08		France	69373
76	Research Site	Marseille		France	13273
77	Research Site	Metz-Tessy		France	74370
78	Research Site	Nimes		France	30029
79	Research Site	Paris Cedex 5		France	75248
80	Research Site	Rouen		France	76021
81	Research Site	Saint Herblain Cedex		France	44805
82	Research Site	Saint-cloud		France	92210
83	Research Site	Toulouse		France	31100
84	Research Site	Tours		France	37000
85	Research Site	Vandoeuvre les Nancy		France	54519
86	Research Site	Vantoux		France	57070
87	Research Site	Ansbach		Germany	91522
88	Research Site	Aschaffenburg		Germany	63739
89	Research Site	Augsburg		Germany	86156
90	Research Site	Bonn		Germany	53111
91	Research Site	Chemnitz		Germany	09116
92	Research Site	Dresden		Germany	01307
93	Research Site	Erlangen		Germany	91054
94	Research Site	Essen		Germany	45130
95	Research Site	Leipzig		Germany	4103
96	Research Site	Mannheim		Germany	68167
97	Research Site	München		Germany	80634
98	Research Site	Paderborn		Germany	33098
99	Research Site	Ravensburg		Germany	88212
100	Research Site	Ulm		Germany	89075
101	Research Site	Budapest		Hungary	1062
102	Research Site	Budapest		Hungary	1122
103	Research Site	Miskolc		Hungary	3526
104	Research Site	Szekszárd		Hungary	7100
105	Research Site	Szolnok		Hungary	5004
106	Research Site	Zalaegerszeg		Hungary	8900
107	Research Site	Bergamo		Italy	24127
108	Research Site	Bologna		Italy	40138
109	Research Site	Milano		Italy	20132
110	Research Site	Napoli		Italy	80131
111	Research Site	Padova		Italy	35128
112	Research Site	Roma		Italy	00168
113	Research Site	Rozzano		Italy	20089
114	Research Site	Chiba-shi		Japan	260-8717
115	Research Site	Chuo-ku		Japan	104-0045
116	Research Site	Hidaka-shi		Japan	350-1298
117	Research Site	Hirakata-shi		Japan	573-1191
118	Research Site	Kitaadachi-gun		Japan	362-0806
119	Research Site	Koto-ku		Japan	135-8550
120	Research Site	Kumamoto-shi		Japan	860-8556
121	Research Site	Matsuyama-shi		Japan	791-0280
122	Research Site	Nagoya-shi		Japan	464-8681
123	Research Site	Nagoya-shi		Japan	467-0001
124	Research Site	Niigata-shi		Japan	951-8566
125	Research Site	Osaka-shi		Japan	540-0006
126	Research Site	Osaka-shi		Japan	541-8567
127	Research Site	Ota-shi		Japan	373-8550
128	Research Site	Sapporo-shi		Japan	003-0804
129	Research Site	Shinagawa-ku		Japan	142-8666
130	Research Site	Shinjuku-ku		Japan	162-8655
131	Research Site	Takasaki-shi		Japan	370-0829
132	Research Site	Tsukuba		Japan	305-8577
133	Research Site	Yokohama-shi		Japan	241-8515
134	Research Site	Cheonan-si		Korea, Republic of	31151
135	Research Site	Daegu		Korea, Republic of	42415
136	Research Site	Goyang-si		Korea, Republic of	10408
137	Research Site	Seongnam-si		Korea, Republic of	13620
138	Research Site	Seongnam-si		Korea, Republic of	463-712
139	Research Site	Seoul		Korea, Republic of	02841
140	Research Site	Seoul		Korea, Republic of	03080
141	Research Site	Seoul		Korea, Republic of	03722
142	Research Site	Seoul		Korea, Republic of	05505
143	Research Site	Seoul		Korea, Republic of	06273
144	Research Site	Seoul		Korea, Republic of	06351
145	Research Site	Seoul		Korea, Republic of	06591
146	Research Site	Gdynia		Poland	81-519
147	Research Site	Konin		Poland	62-500
148	Research Site	Koszalin		Poland	75-581
149	Research Site	Olsztyn		Poland	10-513
150	Research Site	Poznan		Poland	60-693
151	Research Site	Skórzewo		Poland	60-185
152	Research Site	Tomaszów Mazowiecki		Poland	97-200
153	Research Site	Warszawa		Poland	02-781
154	Research Site	Łódź		Poland	90-302
155	Research Site	Guimarães		Portugal	4835-044
156	Research Site	Lisboa		Portugal	1400-038
157	Research Site	Lisboa		Portugal	1449-005
158	Research Site	Lisboa		Portugal	1500-650
159	Research Site	Lisboa		Portugal	1649-035
160	Research Site	Loures		Portugal	2674-514
161	Research Site	Porto		Portugal	4099-001
162	Research Site	Porto		Portugal	4200-072
163	Research Site	Porto		Portugal	4200-319
164	Research Site	Vila Nova de Gaia		Portugal	4434-502
165	Research Site	Moscow		Russian Federation	111123
166	Research Site	Moscow		Russian Federation	129090
167	Research Site	Moscow		Russian Federation	143423
168	Research Site	Nizhny Novgorod		Russian Federation	603126
169	Research Site	Podolsk		Russian Federation	142100
170	Research Site	Saint Petersburg		Russian Federation	197758
171	Research Site	Sankt-Peterburg		Russian Federation	197758
172	Research Site	St. Petersburg		Russian Federation	194017
173	Research Site	Barcelona		Spain	8035
174	Research Site	L'Hospitalet de Llobregat		Spain	08908
175	Research Site	La Coruna		Spain	15006
176	Research Site	Madrid		Spain	28040
177	Research Site	Madrid		Spain	28041
178	Research Site	Murcia		Spain	30008
179	Research Site	Málaga		Spain	29010
180	Research Site	Sevilla		Spain	41013
181	Research Site	Valencia		Spain	46010
182	Research Site	Bern		Switzerland	CH-3010
183	Research Site	Chur		Switzerland	CH-7000
184	Research Site	Winterthur		Switzerland	8401
185	Research Site	Kaohsiung city		Taiwan	833
186	Research Site	Taichung		Taiwan	40705
187	Research Site	Tainan		Taiwan	70403
188	Research Site	Tainan		Taiwan	710
189	Research Site	Taipei 112		Taiwan
190	Research Site	Taipei City		Taiwan	110
191	Research Site	Taipei		Taiwan	100
192	Research Site	Taipei		Taiwan	11259
193	Research Site	Taipei		Taiwan	11490
194	Research Site	Taoyuan		Taiwan	333
195	Research Site	Adana		Turkey	01120
196	Research Site	Ankara		Turkey	06010
197	Research Site	Ankara		Turkey	06100
198	Research Site	Ankara		Turkey	06340
199	Research Site	Ankara		Turkey	06520
200	Research Site	İstanbul		Turkey	34457
201	Research Site	Izmir		Turkey	35100
202	Research Site	Izmir		Turkey	35360
203	Research Site	Kayseri		Turkey	38039
204	Research Site	Blackpool		United Kingdom	FY3 8NR
205	Research Site	Cambridge		United Kingdom	CB2 0QQ
206	Research Site	Guildford		United Kingdom
207	Research Site	Liverpool		United Kingdom	L7 3EW
208	Research Site	London		United Kingdom	SW3 6JJ
209	Research Site	London		United Kingdom	WC1N 3BG
210	Research Site	Newport		United Kingdom	NP10 8FZ
211	Research Site	Nottingham		United Kingdom	NG5 1PB
212	Research Site	Portsmouth		United Kingdom	PO6 3LY
213	Research Site	Reading		United Kingdom	RG2 9LH
214	Research Site	Sheffield		United Kingdom	S10 2SJ
215	Research Site	Sutton		United Kingdom	SM2 5PT
216	Research Site	Taunton		United Kingdom	TA1 5DA