A Study of Dato-DXd Versus Investigator's Choice Chemotherapy in Patients With Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer, Who Are Not Candidates for PD-1/PD-L1 Inhibitor Therapy (TROPION-Breast02)

Breast Cancer Clinical Trial

Official title:

A Phase 3, Open-label, Randomised Study of Datopotamab Deruxtecan (Dato-DXd) Versus Investigator's Choice of Chemotherapy in Patients Who Are Not Candidates for PD-1/PD-L1 Inhibitor Therapy in First-line Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer (TROPION Breast02)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05374512
• Other study ID #: D926PC00001
• Secondary ID: 2021-005223-21
• Status: Recruiting
• Phase: Phase 3
• Start date: May 16, 2022
• Est. completion date: December 3, 2025

Study information

• Verified date: March 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase III, randomised, open-label, 2 arm, multicentre, international study assessing the efficacy and safety of Dato-DXd compared with ICC in participants with locally recurrent inoperable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.

Description:

The primary objectives of the study are to demonstrate superiority of Dato-DXd relative to ICC by assessment of PFS in participants with locally recurrent inoperable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy, per BICR and to demonstrate superiority of Dato-DXd relative to ICC by assessment of OS in participants with locally recurrent inoperable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: December 3, 2025
• Est. primary completion date: December 3, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Age

1. Participant must be = 18 years at the time of screening. Type of Participant and Disease Characteristics

2. Histologically or cytologically documented locally recurrent inoperable TNBC, which cannot be treated with curative intent, or metastatic TNBC. TNBC is defined as:

• Negative for ER with < 1% of tumour cells positive for ER on IHC.

• Negative for progesterone receptor with < 1% of tumour cells positive for progesterone receptor on IHC.

• Negative for HER2 with 0 or 1+ intensity on IHC or 2+ intensity on IHC and negative by in situ hybridisation per the ASCO-CAP HER2 guideline

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

4. Not a candidate for PD-1/PD-L1 inhibitor therapy, defined as:

• Participants whose tumours are PD-L1-negative, or

• Participants whose tumours are PD-L1-positive and have:

1. relapsed after prior PD-1/PD-L1 inhibitor therapy for early-stage breast cancer,

2. comorbidities precluding PD-1/PD-L1 inhibitor therapy, or

3. no regulatory access to pembrolizumab [participant's country does not have regulatory approval at the time of screening]).

5. At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes, which must have short axis = 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and is suitable for accurate repeated measurements.

6. ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.

7. Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin), based on DFI and prior taxane exposure, per investigator assessment.

8. Has had an adequate treatment washout period before Cycle 1 Day 1, defined as:

• Major surgery: = 3 weeks.

• Radiation therapy including palliative radiation to chest: = 4 weeks (palliative radiation therapy to other areas = 2 weeks).

• Corticosteroid therapy for central nervous system metastatic disease: > 3 days.

• Anti cancer therapy including hormonal therapy: = 3 weeks (for small molecule targeted agents: = 2 weeks or 5 half-lives, whichever is longer).

• Nitrosoureas or mitomycin C: = 6 weeks.

• Antibody-based anti cancer therapy: = 4 weeks with the exception of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (eg, denosumab for the treatment of bone metastases).

• Immunotherapy (non-antibody-based therapy), retinoid therapy: = 2 weeks or 5 times the terminal elimination half-life of the agent, whichever is longer.

• Chloroquine/hydroxychloroquine: > 14 days.

9. Written confirmation of tumour sample needs to be available prior to enrolment and tumour samples should be available prior to randomisation. All participants must have a FFPE metastatic (excluding bone) or locally recurrent inoperable tumour sample (block preferred, or a minimum of 20 freshly cut slides) available, collected = 3 months prior to screening. If neither an adequate FFPE block nor the minimum of 20 slides are available from the most recent biopsy, or if a biopsy is not feasible for safety reasons, and this is clearly documented, an archival tumour specimen obtained before the diagnosis of locally recurrent inoperable or metastatic breast cancer may be submitted, pending approval by the Global Study Team.

10. Participants with a history of previously treated neoplastic spinal cord compression or asymptomatic, stable brain metastases, who require no treatment with corticosteroids or anticonvulsants may be included in the study, if they are no longer symptomatic and have recovered from acute toxic effects of radiotherapy. A minimum of 2 weeks must have elapsed between the end of radiotherapy and Cycle 1 Day 1. A minimum of 3 days must have elapsed between the end of corticosteroid therapy for central nervous system metastatic disease and Cycle 1 Day 1.

11. Adequate organ and bone marrow function within 7 days before randomisation as follows:

• Haemoglobin = 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).

• Absolute neutrophil count = 1.5 × 10^9/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).

• Platelet count = 100 × 10^9/L (platelet transfusion is not allowed within 1 week prior to screening assessment).

• Total bilirubin (TBL) = 1.5 × upper limit of normal (ULN) or < 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia).

• Except in the setting of HBV, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 × ULN for AST/ALT (< 5 × ULN in participants with liver metastases). See Exclusion Criterion 5 for requirements in the setting of HBV.

• Calculated CrCL = 30 mL/minute as determined by Cockcroft Gault

12. Minimum life expectancy of 12 weeks.

Sex

13. Male or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Reproduction

14. Negative pregnancy test (serum) for women of childbearing potential.

15. Female participants must be at least 1 year post-menopausal, surgically sterile, or using at least 1 highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) Women of childbearing potential who are sexually active with a non sterilised male partner must agree to use at least 1 highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before Cycle 1 Day 1 and continue for at least 7 months after the last dose. Female participants must refrain from egg cell donation or retrieval for their own use, and breastfeeding from enrolment throughout the study and for at least 7 months after the last dose of study drug. Any non sterilised male partner of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period.

16. Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or use an acceptable method of contraception from the time of screening throughout the total duration of the study and the drug washout period (at least 6 months after the last dose of study intervention), in addition to the female partner using a highly effective contraceptive method, to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. Preservation of sperm should be considered prior to randomisation. Not engaging in heterosexual activity (sexual abstinence) for the duration of the study and drug washout period is an acceptable practice, if this is the preferred usual lifestyle of the participant. Periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.

Informed Consent

17. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

18. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative.

Exclusion Criteria:

Medical Conditions

1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, uncontrolled hypertension, history of allogeneic organ transplant, and active bleeding diseases, ongoing or active infection, or significant cardiac or psychological conditions), and/or substance abuse which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.

2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence (per investigator assessment). Exceptions include adequately resected non-melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease.

3. Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia, not yet improved to Grade = 1 or baseline. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).

4. Uncontrolled infection requiring IV antibiotics, antivirals or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).

5. Known active or uncontrolled hepatitis B or C virus infection.

6. Known human immunodeficiency virus (HIV) infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, cluster of differentiation (CD)4+ count > 350 cells/mm3, no history of an acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications.

7. Uncontrolled or significant cardiac disease including:

• Myocardial infarction or uncontrolled/unstable angina within 6 months prior to Cycle 1 Day 1

• Congestive heart failure (New York Heart Association Class II to IV), or

• Uncontrolled or significant cardiac arrhythmia, or

• Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg).

8. Resting ECG with clinically abnormal findings.

9. Uncontrolled hypercalcaemia: > 1.5 mmol/L (> 6 mg/dL) ionised calcium, or serum calcium (uncorrected for albumin) > 3 mmol/L (> 12 mg/dL), or corrected serum calcium > ULN, or clinically significant (symptomatic) hypercalcaemia.

10. History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening

11. Has severe pulmonary function compromise.

12. Leptomeningeal carcinomatosis.

13. Clinically significant corneal disease.

14. Known active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).

Prior/Concomitant Therapy

15. Prior exposure to:

• Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I

• TROP2-targeted therapy

• Prior treatment with same ICC agent

• Chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days prior to randomisation.

16. Any concurrent anti cancer treatment.

17. Concurrent use of systemic hormone replacement therapy (HRT; eg, oestrogen and progesterone). However, concurrent use of hormones for other non-cancer-related conditions (eg, insulin for diabetes or levothyroxine for hypothyroidism) is acceptable.

18. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.

19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment.

20. Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications except for managing AEs (inhaled steroids or intra articular steroid injections are permitted in this study).

Prior/Concurrent Clinical Study Experience

21. Previous randomisation in the present study.

22. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dose of study intervention (unless the safety profile is known prior to randomisation), randomisation into a prior T-DXd or Dato DXd study regardless of treatment assignment, or concurrent enrolment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow-up period of an interventional study.

23. Participants with a known history of severe hypersensitivity reactions to either the drug or any excipients (including but not limited to polysorbate 80) of Dato-DXd or ICC.

24. Known history of severe hypersensitivity reactions to other monoclonal antibodies.

Other Exclusions

25. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

26. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.

27. Currently pregnant (confirmed with positive pregnancy test) or breast feeding or planning to become pregnant.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Triple Negative Breast Neoplasms

Intervention

Drug:
• Dato-DXd
Experimental drug. Provided in 100mg vials. IV infusion.
• Paclitaxel
IV Infusion. Active comparator
• Nab-paclitaxel
IV infusion. Active comparator
• Carboplatin
IV infusion. Active comparator
• Capecitabine
Tablet. Oral route of administration. Active comparator
• Eribulin mesylate
IV infusion. Active comparator

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	Caba
Argentina	Research Site	Ciudad Autónoma Buenos Aires
Argentina	Research Site	Mar del Plata
Argentina	Research Site	Rosario
Belgium	Research Site	Anderlecht
Belgium	Research Site	Brasschaat
Belgium	Research Site	Gent
Belgium	Research Site	Liège
Belgium	Research Site	Namur
Belgium	Research Site	Sint-Niklaas
Belgium	Research Site	Wilrijk
Brazil	Research Site	Brasilia
Brazil	Research Site	Brasília
Brazil	Research Site	Curitiba
Brazil	Research Site	Goiânia
Brazil	Research Site	Jaú
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	São Paulo
Brazil	Research Site	São Paulo
Brazil	Research Site	São Paulo
Canada	Research Site	Barrie	Ontario
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Greenfield Park	Quebec
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Saskatoon	Saskatchewan
Canada	Research Site	Toronto	Ontario
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Bengbu
China	Research Site	Changchun
China	Research Site	Changsha
China	Research Site	Changsha
China	Research Site	Chengdu
China	Research Site	Chongqing
China	Research Site	Guangzhou
China	Research Site	Guangzhou
China	Research Site	Hangzhou
China	Research Site	Hangzhou
China	Research Site	Hangzhou
China	Research Site	Hefei
China	Research Site	Hefei
China	Research Site	Jinan
China	Research Site	Nanchang
China	Research Site	Nanjing
China	Research Site	Shandong
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shenyang
China	Research Site	Shenzhen
China	Research Site	Tianjin
China	Research Site	Xi'an
China	Research Site	Xian
China	Research Site	Zhengzhou
China	Research Site	Zhengzhou
France	Research Site	Bordeaux
France	Research Site	Dijon
France	Research Site	Limoges Cedex
France	Research Site	Lyon
France	Research Site	Marseille
France	Research Site	Montpellier
France	Research Site	Paris
France	Research Site	Rouen
France	Research Site	Saint Cloud
France	Research Site	Saint Herblain Cedex
France	Research Site	Tours
Germany	Research Site	Aschaffenburg
Germany	Research Site	Bonn
Germany	Research Site	Düsseldorf
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Georgsmarienhuette
Germany	Research Site	Gerlingen
Germany	Research Site	Hamburg
Germany	Research Site	Hannover
Germany	Research Site	Heilbronn
Germany	Research Site	Koblenz Am Rhein
Germany	Research Site	Langen
Germany	Research Site	München
Germany	Research Site	Münster
Germany	Research Site	Wiesbaden
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Gyor
Hungary	Research Site	Miskolc
Hungary	Research Site	Nyíregyháza
Hungary	Research Site	Zalaegerszeg
India	Research Site	Bangalore
India	Research Site	Jaipur
India	Research Site	Kolkata
India	Research Site	Nagpur
India	Research Site	Nashik
India	Research Site	New Delhi
India	Research Site	Pondicherry
India	Research Site	Vadodara
India	Research Site	Vizag
Italy	Research Site	Aviano
Italy	Research Site	Borgo San Lorenzo
Italy	Research Site	Catanzaro
Italy	Research Site	Genova
Italy	Research Site	Livorno
Italy	Research Site	Macerata
Italy	Research Site	Milan
Italy	Research Site	Milano
Italy	Research Site	Modena
Italy	Research Site	Napoli
Italy	Research Site	Roma
Italy	Research Site	Rozzano
Japan	Research Site	Chuo-ku
Japan	Research Site	Fukushima-shi
Japan	Research Site	Gifu-shi
Japan	Research Site	Hiroshima-shi
Japan	Research Site	Isehara-shi
Japan	Research Site	Kagoshima-shi
Japan	Research Site	Kashiwa
Japan	Research Site	Kitaadachi-gun
Japan	Research Site	Koto-ku
Japan	Research Site	Kyoto-shi
Japan	Research Site	Matsuyama-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Niigata-shi
Japan	Research Site	Nishinomiya-shi
Japan	Research Site	Sendai-shi
Japan	Research Site	Shinagawa-ku
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Tsu-shi
Japan	Research Site	Tsukuba
Japan	Research Site	Yokohama-shi
Korea, Republic of	Research Site	Busan-si
Korea, Republic of	Research Site	Daegu
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Mexico	Research Site	CD Mexico
Mexico	Research Site	Guadalajara
Mexico	Research Site	Guadalajara Jalisco
Mexico	Research Site	Mexico
Mexico	Research Site	Mexico
Mexico	Research Site	Mexico City
Philippines	Research Site	Bacolod
Philippines	Research Site	Cagayan De Oro City
Philippines	Research Site	Cebu
Philippines	Research Site	Cebu City
Philippines	Research Site	Iloilo City
Philippines	Research Site	Muntinlupa City
Philippines	Research Site	Quezon City
Philippines	Research Site	Quezon City
Philippines	Research Site	San Juan
Poland	Research Site	Bialystok
Poland	Research Site	Bydgoszcz
Poland	Research Site	Lódz
Poland	Research Site	Skórzewo
Poland	Research Site	Tomaszów Mazowiecki
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
Singapore	Research Site	Bukit Merah
Singapore	Research Site	Singapore
Singapore	Research Site	Singapore
Singapore	Research Site	Singapore
South Africa	Research Site	Amanzimtoti
South Africa	Research Site	Cape Town
South Africa	Research Site	Johannesburg
South Africa	Research Site	Parktown
South Africa	Research Site	Pretoria
South Africa	Research Site	Pretoria
South Africa	Research Site	Richards Bay
South Africa	Research Site	Soweto
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Granada
Spain	Research Site	L'Hospitalet de Llobregat
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda
Spain	Research Site	Málaga
Spain	Research Site	Santiago de Compostela
Spain	Research Site	Sevilla
Taiwan	Research Site	Hsinchu
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Tainan City
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei City
Taiwan	Research Site	Taoyuan
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Chiang Mai
Thailand	Research Site	Dusit
Thailand	Research Site	Hat Yai
Thailand	Research Site	Khon Kaen
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Diyarbakir
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Turkey	Research Site	Izmir
Turkey	Research Site	Konya
Turkey	Research Site	Malatya
United Kingdom	Research Site	Bristol
United Kingdom	Research Site	Cardiff
United Kingdom	Research Site	Edinburgh
United Kingdom	Research Site	Inverness
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	London
United Kingdom	Research Site	Newcastle upon Tyne
United Kingdom	Research Site	Northampton
United Kingdom	Research Site	Nottingham
United Kingdom	Research Site	Swansea
United Kingdom	Research Site	Warwick
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Atlanta	Georgia
United States	Research Site	Austin	Texas
United States	Research Site	Baltimore	Maryland
United States	Research Site	Baton Rouge	Louisiana
United States	Research Site	Boston	Massachusetts
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Charlottesville	Virginia
United States	Research Site	Columbus	Ohio
United States	Research Site	Detroit	Michigan
United States	Research Site	Duarte	California
United States	Research Site	Florham Park	New Jersey
United States	Research Site	Fort Worth	Texas
United States	Research Site	Grand Junction	Colorado
United States	Research Site	Hackensack	New Jersey
United States	Research Site	Houston	Texas
United States	Research Site	Kingwood	Texas
United States	Research Site	Lexington	Kentucky
United States	Research Site	Longmont	Colorado
United States	Research Site	Los Angeles	California
United States	Research Site	Louisville	Kentucky
United States	Research Site	Madison	Wisconsin
United States	Research Site	Memphis	Tennessee
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Midlothian	Virginia
United States	Research Site	Morgantown	West Virginia
United States	Research Site	Nashville	Tennessee
United States	Research Site	New Haven	Connecticut
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Newport Beach	California
United States	Research Site	Norfolk	Virginia
United States	Research Site	Paramus	New Jersey
United States	Research Site	Providence	Rhode Island
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Antonio	Texas
United States	Research Site	San Francisco	California
United States	Research Site	Santa Rosa	California
United States	Research Site	Shreveport	Louisiana
United States	Research Site	Sioux Falls	South Dakota
United States	Research Site	Spokane Valley	Washington
United States	Research Site	Spring	Texas
United States	Research Site	Stanford	California
United States	Research Site	Syracuse	New York
United States	Research Site	Washington	District of Columbia
United States	Research Site	Westbury	New York
United States	Research Site	Wilmington	North Carolina
United States	Research Site	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Daiichi Sankyo

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  China,  France,  Germany,  Hungary,  India,  Italy,  Japan,  Korea, Republic of,  Mexico,  Philippines,  Poland,  Singapore,  South Africa,  Spain,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.; The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti-cancer 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 hazard ratio [HR] of PFS.	From randomization until progression as assessed by BICR or death due to any cause (anticipated to be up to 26 months)
Primary	Overall Survival (OS)	OS is defined as the time from randomisation until the date of death due to any cause.; The analysis will include all randomised participants, by treatment group as randomised. The measure of interest is the hazard ratio [HR] of OS.	From randomisation until the date of death due to any cause (approximately 42 months)
Secondary	Objective Response Rate (ORR)	ORR is defined as the proportion of participants who have a confirmed CR or PR, as determined by BICR/investigator assessment, per RECIST 1.1.; The analysis will include all randomised participants, by treatment group as randomised.; Data obtained from randomisation up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR, regardless of whether the participant withdraws from therapy. Participants who go off treatment without a response or progression, receive a subsequent anti-cancer therapy, and then respond will not be included as responders in the ORR.; The measure of interest is the odds ratio of the ORR.	From randomisation up until progression (anticipated to be up to 26 months)
Secondary	Duration of Response (DoR)	DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause.; The analysis will include all randomised participants as randomised who have a confirmed response, regardless of whether the participant withdraws from therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST 1.1 progression.; The measure of interest is the median of DoR,	From the date of first documented confirmed 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 26 months)
Secondary	Progression-Free Survival (PFS) by Investigator assessment	PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause.; The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST 1.1 progression.; The measure of interest is the hazard ratio [HR] of PFS.	From randomisation until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause (anticipated to be up to 26 months)
Secondary	Disease Control Rate (DCR)	DCR at 12 weeks is defined as the percentage of participants who have a confirmed CR or PR or who have SD, per RECIST 1.1, as assessed by BICR/investigator assessment and derived from the raw tumour data for at least 11 weeks after randomisation.; The analysis will include all randomised participants by treatment group as randomised.; Data obtained from randomisation up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of DCR, regardless of whether the participant withdraws from therapy. Participants who receive a subsequent anticancer therapy prior to Week 11 will not be considered to have disease control in the analysis.; The measure of interest is the odds ratio of the DCR.	At least 11 weeks after randomization to 23 months
Secondary	Time to deterioration (TTD) in pain in participants treated with Dato DXd compared with ICC	TTD in pain as measured by the pain scale from EORTC IL146. 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. The analysis will include all randomised participants.; The measure of interest is the hazard ratio [HR] of TTD in pain.	From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression)
Secondary	Time to deterioration (TTD) in physical functioning in participants treated with Dato DXd compared with ICC	TTD in physical functioning as measured by the physical functioning scale from EORTC IL146.; 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. The analysis will include all randomised participants.; The measure of interest is the hazard ratio [HR] of TTD in physical functioning.	From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression)
Secondary	Time to deterioration (TTD) in breast and arm symptoms in participants treated with Dato DXd compared to ICC	TTD in breast symptoms as measured by the breast symptoms scale from EORTC IL116; TTD in 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. The analysis will include all randomised participants.; The measure of interest is the hazard ratio [HR] of TTD in breast symptoms/arm symptoms.	From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression)
Secondary	Time to deterioration (TTD) in GHS/QoL in participants treated with Dato DXd compared with ICC	TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC IL146. 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. The analysis will include all randomised participants.; The measure of interest is the hazard ratio [HR] of TTD in GHS/QoL.	From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression)
Secondary	Time to First Subsequent Therapy (TFST)	TFST is defined as the time from randomisation until the start date of the first subsequent anti-cancer therapy after discontinuation of randomised treatment, or death due to any cause.; The analysis will include all randomised participants as randomised, regardless of progression status.; The measure of interest is the hazard ratio [HR] of TFST.	From randomisation until the start date of the first subsequent anti-cancer therapy after discontinuation of randomised treatment, or death due to any cause (anticipated to be up to 26 months)
Secondary	Time to Second Subsequent Therapy (TSST)	TSST is defined as the time 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.; The analysis will include all randomised participants as randomised, regardless of progression status on study treatment or first subsequent treatment.; The measure of interest is the hazard ratio [HR] of 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 26 months)
Secondary	Progression Free Survival 2 (PFS2)	PFS2 will be defined as the time from randomisation to the earliest of the 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.; The analysis will include all randomised participants as randomised regardless of whether the participant withdraws from subsequent therapy and regardless of missed visits.; The measure of interest is the hazard ratio [HR] of PFS2.	From randomisation to the earliest of the progression event (following the initial progression), subsequent to first subsequent therapy, or death (anticipated to be up to 26 months)
Secondary	Pharmacokinetics of Dato-DXd	Concentration of Dato DXd, total anti-TROP2 antibody, and MAAA-1181a in plasma.	From first dose to end of treatment (anticipated to be up to 26 months)
Secondary	Immunogenicity of Dato-DXd	Presence of ADAs for Dato-DXd (confirmatory results: positive or negative, titres).	From first dose to end of treatment safety follow-up (anticipated to be up to 26 months)
Secondary	Safety of Dato-DXd	Safety will be evaluated in terms of AEs (graded by CTCAE version 5.0)	From first dose to end of treatment safety follow-up (anticipated to be up to 26 months)