A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator's Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01)

Study Overview
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Brief Summary
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The study will evaluate the safety and efficacy of datopotamab deruxtecan (also known as Dato-DXd, DS-1062a), when compared with Investigator's choice of standard of care single-agent chemotherapy (eribulin, capecitabine, vinorelbine, or gemcitabine) in participants with inoperable or metastatic HR-positive, HER2- negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy.

Detailed Description
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The primary objective of this study will assess the safety and efficacy of datopotamab deruxtecan (Dato-DXd) in participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy. The study will be stratified based on number of previous lines of chemotherapy (1 vs. 2), prior use of CDK4/6 inhibitors (Yes vs. no) and geographic region of participant (US/Canada/Europe vs. rest of world). This study aims to see if datopotamab deruxtecan allows patients to live longer without their breast cancer getting worse, or simply to live longer, compared to patients receiving standard of care chemotherapy. This study is also looking to see how the treatment and the breast cancer affects patients' quality of life.

Official Title
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A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator's Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Dato-DXd
* Drug: Capecitabine
* Drug: Gemcitabine
* Drug: Eribulin
* Drug: Vinorelbine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age • Participant must be ≥ 18 years at the time of screening. Type of Participant and Disease Characteristics Inoperable or metastatic HR+, HER2-negative breast cancer Progressed on and not suitable for endocrine therapy per investigator assessment and treated with 1 to 2 lines of prior chemotherapy in the inoperable/metastatic setting. Participant must have documented progression on their most recent line of chemotherapy. Eligible for one of the chemotherapy options listed as ICC (eribulin, capecitabine, vinorelbine, gemcitabine), per investigator assessment. ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to day of first dosing. At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1. Note: Participants with bone-only metastases are not permitted. Participants with a history of previously treated neoplastic spinal cord compression, or clinically inactive brain metastases, who require no treatment with corticosteroids or anticonvulsants, may be included in the study, if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of radiotherapy and study enrolment. Adequate organ and bone marrow function within 7 days before day of first dosing as follows: Hemoglobin: ≥ 9.0 g/L. Absolute neutrophil count: 1500/mm3. Platelet count: 100000/mm3. • Total bilirubin: ≤ 1.5 × ULN if no liver metastases; or ≤ 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline. ALT and AST: ≤ 3 × ULN for AST/ALT; however, if elevation is due to liver metastases, ≤ 5.0 × ULN is allowed. Calculated creatinine clearance: ≥ 30 mL/min as calculated using the Cockcroft-Gault equation (using actual body weight). LVEF ≥ 50% by either an echocardiogram or MUGA within 28 days of first dosing. 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). Anticancer therapy including hormonal therapy: ≥ 3 weeks (for small molecule targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer). Antibody-based anticancer 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): ≥ 2 weeks or 5 times the terminal elimination T½ of the agent, whichever is longer. Chloroquine/hydroxychloroquine: > 14 days. Have available a FFPE tumor sample (block preferred, or a minimum of 20 freshly cut slides), at the time of screening. Note: Sample collection in China will comply with local regulatory approval. Minimum life expectancy of 12 weeks at screening. Sex • Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; (oral estrogens are not permitted). Reproduction Negative pregnancy test (serum) for women of childbearing potential Female participants must be post-menopausal for at least 1 year, surgically sterile, or using one highly effective form of birth control. Female participants must refrain from egg cell donation and breastfeeding while on study and for at least 7 months after the last dose of study intervention. Non-sterilized male partners of a woman of childbearing potential must use a male condom plus spermicide throughout this period. Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using a highly effective method of contraception from the time of screening throughout the total duration of the study and the drug washout period (at least 4 months after the last dose of study intervention) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. 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; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Female partners of male participants are allowed to use HRT for contraception. Informed Consent Capable of giving signed informed consent. 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 Any evidence of 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. 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. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy, adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated. Persistent toxicities caused by previous anticancer therapy (excluding alopecia), not yet improved to CTCAE Version 5.0 Grade ≤ 1 or baseline. Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to first dosing and managed with SoC treatment) which the investigator deems related to previous anticancer therapy. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections. Known active or uncontrolled hepatitis B or C infection; or positive for hepatitis B or C virus based on the evaluation of results of tests for hepatitis B (HBsAg, anti-HBs, anti-HBc, or HBV DNA) or hepatitis C (HCV antibody or HCV RNA) infection at screening. Known HIV infection that is not well controlled. Uncontrolled or significant cardiac disease, including myocardial infarction or uncontrolled/unstable angina within 6 months prior to C1D1, CHF (New York Heart Association Class II to IV), uncontrolled or significant cardiac arrhythmia, or uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg). Investigator judgment of 1 or more of the following: Mean resting corrected QTcF interval > 470 ms , obtained from triplicate ECGs performed at screening. History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder, or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement, or prior pneumonectomy. Leptomeningeal carcinomatosis. Clinically significant corneal disease. Known active tuberculosis infection Prior/Concomitant Therapy Any of the following prior anticancer therapies: Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I TROP2-targeted therapy Prior treatment with same ICC agent Any concurrent anticancer treatment, with the exception of bisphosphonates, denosumab, for the treatment of bone metastases. Concurrent use of systemic hormonal replacement therapy (eg, estrogen). However, concurrent use of hormones for non-cancer related conditions (eg, insulin for diabetes) is acceptable. 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. Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment. Prior/Concurrent Clinical Study Experience Previous treatment in the present study. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dosing, randomization into a prior Dato-DXd or T-DXd (trastuzumab deruxtecan) study regardless of treatment assignment, or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. Participants with a known hypersensitivity to Dato-DXd, or any of the excipients of the product (including, but not limited to, polysorbate 80). Known history of severe hypersensitivity reactions to other monoclonal antibodies. Other Exclusions Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 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. For women only, currently pregnant (confirmed with positive pregnancy test) or breastfeeding, or who are planning to become pregnant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dato-DXd<br>Arm 1: Dato-DXd | Drug: Dato-DXd<br>* Experimental drug. Provided in 100mg vials. IV infusion.<br>* Other names: Datopotamab deruxtecan (Dato-DXd, DS-1062a);|
| Active Comparator: Investigators Choice of Chemotherapy (ICC)<br>Arm 2: ICC Capecitabine Gemcitabine Eribulin mesylate Vinorelbine | Drug: Capecitabine<br>* Tablet. Oral route of administration. Active comparator<br>Drug: Gemcitabine<br>* IV Infusion. Active comparator<br>Drug: Eribulin<br>* IV Infusion. Active comparator<br>* Other names: Eribulin Mesylate;Drug: Vinorelbine<br>* IV Infusion. Active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | PFS is defined as time from randomization until progression per RECIST 1.1, as assessed by BICR, or death due to any cause. The analysis will include all randomized participants as randomized regardless of whether the participant withdraws from therapy, receives another anti-cancer therapy, or clinically progresses prior to RECIST 1.1. The measure of interest is the hazard ratio of PFS. | From randomization until progression as assessed by BICR or death due to any cause (anticipated to be 21 months after the first participant has been randomized) | 
| Overall Survival | OS is defined as time from randomization until the date of death due to any cause. The comparison will include all randomized participants as randomized, regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy. The measure of interest is the hazard ratio of OS. | Approximately 44 months after the first participant has been randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective response rate is defined as the proportion of participants who have a confirmed CR or PR, as determined by the BICR/Investigator assessment, per RECIST 1.1. | Randomization to event (response, progression, last evaluable assessment) anticipated to be up to 21 months | 
| Duration of Response (DoR) | Duration of response 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. | From randomization to event up to 21 months; from date of first response until progression or death up to 20 months | 
| Progression-Free Survival by Investigator assessment | PFS by Investigator assessment will be defined as the time from the date of randomization until the date of PD per RECIST 1.1 (by Investigator assessment) or death (by any cause in the absence of progression), (ie, date of event or censoring - date of randomization + 1). | From randomization to progression (investigator assessment) or death (anticipated to be up to 21 months) | 
| Disease Control Rate (DCR) | Disease control rate 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 BICR/per investigator assessment and derived from the raw tumor data for at least 11 weeks after randomization. | At least 11 weeks after randomization up to 18 months. | 
| Time to First Subsequent Therapy (TFST) | Time to first subsequent therapy is defined as the time from randomization until the start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment, or death due to any cause. | From randomization to start of first subsequent anti-cancer therapy post discontinuation of randomized treatment (anticipated to be up to 21 months) | 
| Time to Second Subsequent Therapy (TSST) | Time to second subsequent therapy is defined as the time from randomization to until the start date of the second subsequent anti-cancer therapy after discontinuation of first subsequent treatment, or death due to any cause. | From randomization to start of second subsequent anti-cancer therapy post discontinuation of first subsequent therapy (anticipated to be up to 21 months) | 
| Time from randomization to second progression or death (PFS2) | Time to second progression of death will be defined as the time from the randomization 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. | From randomization to second progression or death (anticipated to be up to 21 months) | 
| Clinical Outcome Assessment- TTD in pain | The secondary PRO endpoints include: TTD in pain as measured by the pain scale from EORTC QLQ-C30 | From randomization to 18 weeks post-progression | 
| Pharmacokinetics of Dato-DXd | Plasma concentrations of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a (payload). | From first dose to end of treatment (anticipated to be up to 21 months). | 
| Immunogenicity | To test for the presence of ADA to investigate the immunogenicity of Dato-DXd. | From first dose to end of treatment safety follow-up (anticipated to be up to 22 months). | 
| Clinical Outcome Assessment- TTD in physical Functioning | The secondary PRO endpoints include: TTD in physical functioning as measured by the physical functioning scale from EORTC QLQ-C30 | From randomization to 18 weeks post-progression | 
| Clinical Outcome Assessment- TTD in GHS | The secondary PRO endpoints include: TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC QLQ-C30 | From randomization to 18 weeks post-progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, HR positive, Hormone Receptor positive, ER positive, PR positive, HER2 negative, Inoperable, Metastatic, Datopotamab Deruxtecan, Dato-DXd, DS1062, DS1062a, Capecitabine, Eribulin, Gemcitabine, Vinorelbine, TROP2, Antibody Drug Conjugate, ADC