A Phase III Study of Dato-DXd With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer

• Sponsor: AstraZeneca (Industry)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT06103864
• Collaborator: Daiichi Sankyo, Inc. (Industry)
• Enrollment: 625
• Locations: 112
• Arms: 3
• Anticipated Duration (Months): 64.9
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase III, randomised, open-label, 3-arm, multicentre, international study assessing the efficacy and safety of Dato-DXd with or without durvalumab compared with investigator's choice chemotherapy in combination with pembrolizumab in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Dato-DXd; Drug: Durvalumab; Drug: Paclitaxel; Drug: Nab-paclitaxel; Drug: Gemcitabine; Drug: Carboplatin; Drug: Pembrolizumab	Phase 3

Detailed Description

The primary objective of the study is to demonstrate superiority of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of PFS as assessed by BICR in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.

The study will be stratified based on geographic location (US/Canada/Europe vs. Dato-DXd monotherapy enrolling countries vs. rest of world), disease-free interval (DFI) history (de novo vs. prior DFI 6 to 12 months vs. prior DFI > 12 months), and prior PD-1/PD-L1 treatment for early stage TNBC (yes vs. no).

This study aims to see if Dato-DXd with durvalumab allows patients to live longer without their breast cancer getting worse, or simply to live longer, compared to patients receiving standard of care chemotherapy and pembrolizumab. This study is also looking to see how the treatment and the breast cancer affects patients' quality of life.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 625 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants will be randomised either 1:1 to Arm 1 (Dato-DXd + durvalumab) and Arm 2 (ICC + pembrolizumab), or in selected countries, 1:1:1 to Arms 1, 2 and 3 (Dato-DXd monotherapy). Once approximately 75 participants are randomised to Arm 3, this cohort will close, and all countries will continue with a 1:1 randomisation strategy for Arms 1 and 2.Participants will be randomised either 1:1 to Arm 1 (Dato-DXd + durvalumab) and Arm 2 (ICC + pembrolizumab), or in selected countries, 1:1:1 to Arms 1, 2 and 3 (Dato-DXd monotherapy). Once approximately 75 participants are randomised to Arm 3, this cohort will close, and all countries will continue with a 1:1 randomisation strategy for Arms 1 and 2.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Open-label, Randomised Study of Datopotamab Deruxtecan (Dato-DXd) With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy (Paclitaxel, Nab-paclitaxel or Gemcitabine + Carboplatin) in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer (TROPION-Breast05)
• Anticipated Study Start Date: Nov 15, 2023
• Anticipated Primary Completion Date: Sep 14, 2026
• Anticipated Study Completion Date: Apr 13, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dato-DXd + durvalumab Arm 1: Dato-DXd + durvalumab	Drug: Dato-DXd; Provided in 100mg vials. IV infusion. Experimental drug.; Other Names: Datopotamab deruxtecan (Dato-DXd, DS-1062a) ; Drug: Durvalumab; Provided in 500mg vials. IV infusion. Experimental drug.; Other Names: MEDI4736
Active Comparator: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)	Drug: Paclitaxel; IV infusion. Active comparator.; Drug: Nab-paclitaxel; IV infusion. Active comparator.; Drug: Gemcitabine; IV infusion. Active comparator.; Drug: Carboplatin; IV infusion. Active comparator.; Drug: Pembrolizumab; IV infusion. Active comparator.
Experimental: Dato-DXd Arm 3: Dato-DXd	Drug: Dato-DXd; Provided in 100mg vials. IV infusion. Experimental drug.; Other Names: Datopotamab deruxtecan (Dato-DXd, DS-1062a)

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [From randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause (anticipated to be up to 33 months).]

   PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. The comparison will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anticancer therapy or clinically progresses prior to RECIST 1.1 progression. However, if the participant progresses or dies immediately after 2 or more consecutive missed visits, the participant will be censored at the time of the latest evaluable assessment prior to the 2 missed visits. The measure of interest is the HR of PFS.

Secondary Outcome Measures

1. Overall Survival (OS) [From randomisation until the date of death due to any cause (anticipated to be up to 64 months).]

   OS is defined as the time from randomisation until the date of death due to any cause.

2. Objective Response Rate (ORR) [From randomisation up until progression (anticipated to be up to 33 months).]

   ORR is defined as the proportion of participants who have a CR or PR, as determined by the BICR/investigator assessment, per RECIST 1.1.

3. Duration of Response (DoR) [From the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause (anticipated to be up to 33 months).]

   DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause.

4. Progression-Free Survival (PFS) by Investigator assessment [From randomisation until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause (anticipated to be up to 33 months).]

   PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator, or death due to any cause.

5. Clinical Benefit Rate (CBR) at 24 weeks [From randomisation up until progression, or the last evaluable assessment in the absence of progression (anticipated to be up to 33 months).]

   CBR at 24 weeks is defined as the percentage of participants who have a CR or PR or who have SD, per RECIST 1.1, as assessed by BICR/per investigator assessment and derived from the raw tumour data for at least 23 weeks after randomisation.

6. Time to deterioration (TTD) in breast and arm symptoms in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab [From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).]

   TTD in breast symptoms and arm symptoms as measured by the arm symptoms scale from EORTC IL116 TTD is defined as time from the date of randomisation to the date of deterioration. Deterioration is defined as change from baseline that reaches a clinically meaningful deterioration threshold.

7. Time to deterioration (TTD) in pain in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab [Time from the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).]

   TTD in pain as measured by the EORTC IL199.

8. Time to deterioration (TTD) in physical functioning in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab [From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).]

   TTD in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c.

9. Time to deterioration (TTD) in GHS/QoL in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab [From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression).]

   TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172.

10. Time to First Subsequent Therapy (TFST) [From randomisation until the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause (anticipated to be up to 64 months).]

    TFST is defined as the time from randomisation until the start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause.

11. Time to Second Subsequent Therapy (TSST) [From randomisation until the start date of the second subsequent anti cancer therapy after discontinuation of first subsequent treatment, or death due to any cause (anticipated to be up to 64 months).]

    TSST is defined as the time from randomisation until the start date of the second subsequent anticancer therapy after discontinuation of first subsequent treatment, or death due to any cause.

12. Progression Free Survival 2 (PFS2) [From the randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy, or death (anticipated to be up to 64 months).]

    PFS2 will be defined as the time from the randomisation to the earliest progression event (following the initial progression), subsequent to first subsequent therapy, or death. The date of second progression will be recorded by the investigator in the eCRF and defined according to local standard clinical practice based on radiological or clinical progression.

13. Pharmacokinetics of Dato-DXd in combination with durvalumab [From first dose to end of treatment (anticipated to be up to 33 months).]

    Concentration of Dato-DXd, total anti-TROP2 antibody, and DXd (payload) in plasma.

14. Immunogenicity of Dato-DXd in combination with durvalumab [From first dose to end of treatment safety follow-up (anticipated to be up to 33 months).]

    Presence of antidrug antibodies for Dato-DXd (confirmatory results: positive or negative, titres).

15. Safety and tolerability of Dato-DXd + durvalumab as compared with ICC + pembrolizumab [From first dose to end of treatment safety follow-up (anticipated to be up to 33 months).]

    Safety and tolerability will be evaluated in the safety population in terms of AEs.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria

• Histologically or cytologically documented locally recurrent inoperable, which cannot be treated with curative intent, or metastatic TNBC, as defined by the ASCO-CAP guidelines.

• ECOG PS 0 or 1.

• All participants must provide a FFPE metastatic or locally recurrent inoperable tumour sample.

• PD-L1 positive TNBC based on results from an appropriately validated investigational PD-L1 (22C3) assay (CPS ≥ 10) from a sponsor designated central laboratory.

• No prior chemotherapy or targeted systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer.

• Patients with recurrent disease will be eligible if they have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months have elapsed between completion of treatment with curative intent and the first documented recurrence.

• Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin).

• Measurable disease as per RECIST 1.1.

• Adequate bone marrow reserve and organ function.

• Male and female participants of childbearing potential must agree to use protocol-specified method(s) of contraception.

Key Exclusion Criteria

• As judged by investigator, severe or uncontrolled medical conditions including systemic diseases, history of allogeneic organ transplant and active bleeding diseases, ongoing or active infection, significant cardiac or psychological conditions.

• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before Cycle 1 Day 1 and of low potential risk for recurrence.

• Neoplastic spinal cord compression or active brain metastases, leptomeningeal carcinomatosis or history of leptomeningeal carcinomatosis.

• Participants with treated clinically inactive brain metastases that are no longer symptomatic, who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered from acute toxic effects of radiotherapy.

• Uncontrolled infection requiring IV antibiotics, antivirals or antifungals.

• Active or uncontrolled hepatitis B or C virus infection.

• Known HIV infection that is not well controlled.

• Uncontrolled or significant cardiac disease.

• History of non-infectious ILD/pneumonitis (including radiation pneumonitis) that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

• Severe pulmonary function compromise.

• Clinically significant corneal disease.

• Active or prior documented autoimmune or inflammatory disorders.

• Prior exposure to any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I and TROP2-targeted therapy.

• Any concurrent anti-cancer treatment.

• Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors or Dato-DXd.

• Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Duarte	California	United States	91010
2	Research Site	Glendale	California	United States	91204
3	Research Site	Santa Rosa	California	United States	95403
4	Research Site	New Haven	Connecticut	United States	06510
5	Research Site	Miami	Florida	United States	33176
6	Research Site	Honolulu	Hawaii	United States	96819
7	Research Site	Chicago	Illinois	United States	60637
8	Research Site	New Albany	Indiana	United States	47150
9	Research Site	Lexington	Kentucky	United States	40503
10	Research Site	Louisville	Kentucky	United States	40202
11	Research Site	Louisville	Kentucky	United States	40207
12	Research Site	Baton Rouge	Louisiana	United States	70808
13	Research Site	Baltimore	Maryland	United States	21215
14	Research Site	Boston	Massachusetts	United States	02111
15	Research Site	Detroit	Michigan	United States	48201
16	Research Site	Grand Rapids	Michigan	United States	49503
17	Research Site	Hattiesburg	Mississippi	United States	39401
18	Research Site	Saint Louis	Missouri	United States	63129
19	Research Site	New York	New York	United States	10065
20	Research Site	Cincinnati	Ohio	United States	45245
21	Research Site	Providence	Rhode Island	United States	02903
22	Research Site	Houston	Texas	United States	77090
23	Research Site	Houston	Texas	United States	77098
24	Research Site	Kingwood	Texas	United States	77339
25	Research Site	Charlottesville	Virginia	United States	22903
26	Research Site	Midlothian	Virginia	United States	23114
27	Research Site	Madison	Wisconsin	United States	53792
28	Research Site	Melbourne		Australia	3000
29	Research Site	Melbourne		Australia	3065
30	Research Site	Perth		Australia	6009
31	Research Site	Waratah		Australia	2298
32	Research Site	Toronto	CA	Canada	M5G 2M9
33	Research Site	Montreal	Quebec	Canada	H4A 3J1
34	Research Site	Chengdu		China	610000
35	Research Site	Chongqing		China	400030
36	Research Site	Guangzhou		China	510060
37	Research Site	Guangzhou		China	510700
38	Research Site	Nanchang		China	330009
39	Research Site	Nanning		China	530021
40	Research Site	Wuhan		China	430022
41	Research Site	Wuhan		China	430079
42	Research Site	Xi'an		China	710061
43	Research Site	Düsseldorf		Germany	40479
44	Research Site	Essen		Germany	45136
45	Research Site	Georgsmarienhütte		Germany	49124
46	Research Site	Hamburg		Germany	20357
47	Research Site	Hannover		Germany	30625
48	Research Site	Heidelberg		Germany	69120
49	Research Site	Heilbronn		Germany	74078
50	Research Site	Leipzig		Germany	04103
51	Research Site	Calicut		India	673601
52	Research Site	Kolkata		India	700160
53	Research Site	Marg Jaipur		India	302004
54	Research Site	Mohali		India	160055
55	Research Site	Mysuru		India	570017
56	Research Site	Nagpur		India	440001
57	Research Site	Nashik		India	422009
58	Research Site	New Delhi		India	110075
59	Research Site	Pondicherry		India	605006
60	Research Site	Surat		India	395002
61	Research Site	Vadodara		India	391760
62	Research Site	Vishakapatnam		India	530053
63	Research Site	Fukuoka		Japan	811-1395
64	Research Site	Fukushima-shi		Japan	960-1295
65	Research Site	Gifu-shi		Japan	501-1194
66	Research Site	Hiroshima-shi		Japan	730-8518
67	Research Site	Isehara-shi		Japan	259-1193
68	Research Site	Nagoya-shi		Japan	466-8560
69	Research Site	Nagoya-shi		Japan	467-0001
70	Research Site	Nishinomiya-shi		Japan	663-8501
71	Research Site	Osakasayama-shi		Japan	589-8511
72	Research Site	Shinagawa-ku		Japan	142-8666
73	Research Site	Shinjuku-ku		Japan	162-8655
74	Research Site	Yokohama-shi		Japan	241-8515
75	Research Site	Busan		Korea, Republic of	49241
76	Research Site	Daegu		Korea, Republic of	41404
77	Research Site	Goyang-si		Korea, Republic of	10408
78	Research Site	Seoul		Korea, Republic of	02841
79	Research Site	Seoul		Korea, Republic of	03722
80	Research Site	Seoul		Korea, Republic of	05505
81	Research Site	Seoul		Korea, Republic of	06273
82	Research Site	Seoul		Korea, Republic of	06351
83	Research Site	Seoul		Korea, Republic of	06591
84	Research Site	Seoul		Korea, Republic of	13620
85	Research Site	Guadalajara		Mexico	44638
86	Research Site	Mexico City		Mexico	0 3100
87	Research Site	México		Mexico	04700
88	Research Site	Singapore		Singapore	119228
89	Research Site	Singapore		Singapore	308433
90	Research Site	Singapore		Singapore	329563
91	Research Site	Barcelona		Spain	08028
92	Research Site	Barcelona		Spain	8035
93	Research Site	Granada		Spain	18016
94	Research Site	Hospitalet deLlobregat		Spain	08907
95	Research Site	Madrid		Spain	28034
96	Research Site	Hsinchu		Taiwan	300
97	Research Site	Kaohsiung		Taiwan	80756
98	Research Site	Taichung		Taiwan	40447
99	Research Site	Tainan		Taiwan	704
100	Research Site	Taipei		Taiwan	100
101	Research Site	Taipei		Taiwan	10449
102	Research Site	Taipei		Taiwan	11259
103	Research Site	Taoyuan		Taiwan	333
104	Research Site	Cardiff		United Kingdom	CF14 2TL
105	Research Site	Chelsea		United Kingdom	SW3 6JJ
106	Research Site	Leicester		United Kingdom	Le5 4PW
107	Research Site	Liverpool		United Kingdom	L7 8YA
108	Research Site	London		United Kingdom	EC1A 7BE
109	Research Site	London		United Kingdom	SW17 0QT
110	Research Site	Oxford		United Kingdom	OX3 7LE
111	Research Site	Surrey		United Kingdom	GU2 7XX
112	Research Site	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• AstraZeneca
• Daiichi Sankyo, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT06103864
• Other Study ID Numbers: D7630C00001
• First Posted: Oct 27, 2023
• Last Update Posted: Oct 27, 2023
• Last Verified: Oct 1, 2023

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Breast Cancer; Triple-negative; Metastatic; Inoperable; Datopotamab deruxtecan; Dato-DXd; DS1062a; DS1062; Durvalumab; Paclitaxel; Nab-paclitaxel; Gemcitabine; Carboplatin; Pembrolizumab; PD-1/PD-L1 Therapy; TROP2; Antibody Drug Conjugate (ADC); Immune Checkpoint Inhibitor (ICI)
• Additional relevant MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Gemcitabine; Pembrolizumab; Durvalumab

Study Results

No Results Posted as of Oct 27, 2023