Phase 3 Randomized Study of Datopotamab Deruxtecan vs. Chemotherapy in HR-Positive, HER2-Negative Metastatic Breast Cancer Post-Chemotherapy
- Trial ID
- 2023-509631-37-00
- Protocol
- D9268C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, open-label, randomized study is to demonstrate the superiority of **Datopotamab deruxtecan** (Dato-DXd) compared to the investigator's choice of chemotherapy (ICC) in terms of progression-free survival (PFS) and overall survival (OS) in participants with inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer. These participants have been previously treated with one or two lines of systemic chemotherapy in the inoperable/metastatic setting. The clinical relevance of this objective lies in potentially offering a more effective treatment option that could improve survival outcomes for this patient population.
Secondary objectives include:
- Demonstrating the superiority of Dato-DXd over ICC by assessing objective response rate (ORR), duration of response (DoR), disease control rate (DCR), time to first subsequent therapy (TFST), time to second subsequent therapy (TSST), and PFS2.
- Assessing pain, physical functioning, and global health status/quality of life (GHS/QoL) in participants treated with Dato-DXd compared to ICC.
- Evaluating the pharmacokinetics (PK) and immunogenicity of Dato-DXd administered intravenously at a dose of 6 mg/kg every three weeks.
Participants
The clinical trial involves a total of **444 participants** diagnosed with **inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their progression on one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting and their ineligibility for further endocrine therapy. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate organ and bone marrow function and a life expectancy of at least 12 weeks. The trial population is diverse, including individuals with a history of treated neoplastic spinal cord compression or clinically inactive brain metastases, provided they meet specific recovery criteria. Lifestyle considerations such as contraceptive use are mandated to align with local regulations, and participants must refrain from certain activities like egg cell donation and sperm banking during the study. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the investigational treatment's efficacy and safety across a broad demographic.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study comparing the efficacy of Datopotamab deruxtecan against the investigator's choice of chemotherapy in participants with inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer. The trial aims to demonstrate the superiority of Datopotamab deruxtecan in terms of progression-free survival (PFS) and overall survival (OS) compared to standard chemotherapy options, which include **eribulin mesylate**, **capecitabine**, **vinorelbine**, and **gemcitabine**. The study is expected to conclude by August 2025, with recruitment having commenced in January 2022.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, cancer status, and previous treatment history. The inclusion criteria require participants to be at least 18 years old, have documented progression on their most recent line of chemotherapy, and be eligible for one of the chemotherapy options listed. The screening visit will also assess organ and bone marrow function, among other health parameters. Following the screening, participants will be randomized to receive either Datopotamab deruxtecan or one of the investigator's choice chemotherapies. Regular follow-up visits will be scheduled to monitor treatment response, side effects, and overall health status. The end-of-study visit will occur after the final treatment cycle or upon early termination from the study.
The expected duration of participant involvement in the trial is contingent upon individual response to treatment and disease progression. Participants may be withdrawn from the study early due to reasons such as adverse events, withdrawal of consent, or if the investigator deems it in the participant's best interest. The primary endpoints of the study include PFS and OS, while secondary endpoints encompass objective response rate, duration of response, and disease control rate, among others. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Datopotamab deruxtecan** is the primary investigational drug, administered as a **solution for infusion**. It is delivered via **intravenous infusion**. The dosing is calculated based on **milligrams per kilogram (mg/kg)**, although specific dosing schedules and maximum daily doses are not provided. The treatment period is extensive, with a maximum duration of 9999999 units of time, indicating a long-term administration plan. Participant compliance will be monitored through standard clinical trial procedures.
**Gemcitabine** is used as a comparator treatment in this study. It is provided in the form of a **powder for solution for infusion** and administered through **intravenous infusion**. The dosage is measured in **milligrams per square meter (mg/m²)**, but specific dosing details are not specified. The treatment period is set to a maximum of 999999 units of time, suggesting prolonged administration.
**Eribulin mesylate** is another comparator drug, administered as a **solution for injection** via **intravenous infusion**. The dosage is also calculated in **milligrams per square meter (mg/m²)**. The maximum treatment period is 9999999 units of time, indicating extended use in the trial.
**Vinorelbine** is included as a comparator treatment, available as a **solution for injection/infusion** and administered through **intravenous infusion**. The dosing is in **milligrams per square meter (mg/m²)**, with a maximum treatment period of 9999999 units of time, allowing for long-term administration.
**Capecitabine** is utilized in two forms: **film-coated tablets** and **coated tablets**. Both forms are administered **orally**. The dosage for the film-coated tablets is in **milligrams (mg)**, while the coated tablets are dosed in **milligrams per gram (mg/g)**. The maximum treatment period for the film-coated tablets is 9999999 units of time, whereas the coated tablets have a shorter maximum period of 99999 units of time.
All treatments are chemical in origin, except for Datopotamab deruxtecan, which is a protein-based drug. The trial does not include any **orphan drugs** or **paediatric formulations**. Compliance with the dosing regimen will be monitored throughout the study to ensure adherence to the protocol.
Efficacy
Efficacy in this clinical trial will be assessed using dual primary endpoints: **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS is defined as the time from randomization until disease progression, as determined by RECIST 1.1 criteria and assessed by Blinded Independent Central Review (BICR), or death from any cause. OS is defined as the time from randomization until death from any cause. The analysis will include all randomized participants, regardless of withdrawal from therapy or receipt of another anti-cancer therapy.
Secondary endpoints include Objective Response Rate (ORR), Duration of Response (DoR), PFS by Investigator assessment, Disease Control Rate (DCR) at 12 weeks, Time to First Subsequent Therapy (TFST), Time to Second Subsequent Therapy (TSST), and Time from randomization to second progression or death (PFS2). Additionally, Clinical Outcome Assessments will be conducted, including Time to Deterioration (TTD) in pain, physical functioning, and Global Health Status/Quality of Life (GHS/QoL) as measured by the EORTC QLQ-C30 scales. Pharmacokinetics and immunogenicity will also be evaluated.
The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with assessments conducted according to standardized and validated methods. The trial will ensure rigorous data collection and analysis to accurately determine the efficacy of the investigational treatment compared to the investigator's choice of chemotherapy in participants with inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥ 18 years at the time of screening. 2. Inoperable or metastatic HR+, HER2-negative breast cancer 3. 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. 4. Eligible for one of the chemotherapy options listed as ICC (eribulin, capecitabine, vinorelbine, gemcitabine), per investigator assessment. 5. ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to day of first dosing. 6. At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1. Note: Participants with bone-only metastases are not permitted. 7. 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. 8. 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). 9. 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. 11. 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. 12. Minimum life expectancy of 12 weeks at screening. 13. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; (estrogens are not permitted). 14. Negative pregnancy test (serum) for women of childbearing potential 15. 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 X 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. 16. 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 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. 17. Capable of giving signed informed consent.
Exclusion Criteria
- 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. 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. 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. 3. 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. 4. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections. 5. 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. 6. Known HIV infection that is not well controlled. 7. 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). 8. Investigator judgment of 1 or more of the following: • Mean resting corrected QTcF interval > 470 ms • 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. 9. 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. 11. Leptomeningeal carcinomatosis. 12. Clinically significant corneal disease. 13. Known active tuberculosis infection 14. Any of the following prior anticancer therapies: o Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I - - TROP2-targeted therapy o Prior treatment with same ICC agent 15. Any concurrent anticancer treatment, with the exception of bisphosphonates, denosumab, for the treatment of bone metastases. 16. 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. 17. 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. 18. Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment. 20. Previous treatment in the present study. 21. 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. 22. Participants with a known hypersensitivity to Dato-DXd, or any of the excipients of the product (including, but not limited to, polysorbate 80). 23. Known history of severe hypersensitivity reactions to other monoclonal antibodies. 24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 25. 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. 26. For women only, currently pregnant (confirmed with positive pregnancy test) or breastfeeding, or who are planning to become pregnant.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 21 Jan 2022 | 15 |
 France | Not Recruiting | 21 Jan 2022 | 61 |
 Germany | Not Recruiting | 21 Jan 2022 | 6 |
 Hungary | Not Recruiting | 21 Jan 2022 | 16 |
 Italy | Not Recruiting | 21 Jan 2022 | 56 |
 Poland | Not Recruiting | 21 Jan 2022 | 33 |
 Spain | Not Recruiting | 21 Jan 2022 | 66 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ERIBULIN MESYLATE | Comparator | — | INTRAVENIOUS INFUSION | 00 | 9999999 | SUB31126 |
VINORELBINE | Comparator | — | INTRAVENIOUS INFUSION | 00 | 9999999 | SUB00069MIG |
GEMCITABINE | Comparator | — | INTRAVENIOUS INFUSION | 00 | 999999 | SUB07892MIG |
CAPECITABINE | Comparator | — | ORAL | 00 | 99999 | SUB12474MIG |
CAPECITABINE | Comparator | — | ORAL USE | 00 | 9999999 | SUB12474MIG |
Datopotamab deruxtecan | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 00 | 9999999 | PRD9684738 |