| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Inoperable or Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer that Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10083232 |
| E.1.2 | Term | HER2 negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dual Primary:
1. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of PFS in participants with inoperable or metastatic HR-positive,HER2-negative breast cancer, who have been treated with 1 or 2 lines of chemotherapy in the inoperable/metastatic setting, per BICR.
2. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of OS in participants with inoperable or metastatic HR-positive,HER2-negative breast cancer, who have been treated with 1 or 2 lines of chemotherapy in the inoperable/metastatic setting. |
|
| E.2.2 | Secondary objectives of the trial |
1. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of ORR.
2. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of DoR.
3. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of PFS.
4. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of DCR.
5. To assess pain in participants treated with Dato-DXd compared to ICC.
6. To assess physical functioning.
7. To assess global health status/quality of life (GHS/QoL).
8. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of TFST.
9. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of TSST.
10. To demonstrate the superiority of Dato-DXd compared to ICC by assessment of PFS2.
11. To assess the PK of Dato-DXd 6mg/kg IV Q3W.
12. To investigate the immunogenicity of Dato-DXd 6mg/kg IV Q3W. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥ 18 years (≥ 20 years in Japan) at the time of screening.
2. Inoperable or metastatic HR+, HER2-negative breast cancer
3. Progressed on or not suitable for endocrine therapy per investigator assessment, and treated with 1 to 2 lines of prior chemotherapy in the inoperable/metastatic setting.
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/dL.
- 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: ≤ 2.5 × 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.
10. 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, which ever is longer)
- Antibody-based anticancer therapy: ≥ 4 weeks with the exception of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors
- 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 (urine and/or 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 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.
16. Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) 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.
17. Capable of giving signed informed consent.
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. |
|
| E.4 | Principal exclusion criteria |
1. 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.
3. Persistent toxicities caused by previous anticancer therapy (excluding alopecia), not yet resolved to CTCAE Version 5.0 Grade ≤ 1 or baseline.
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.
10. 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:
- Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I - - TROP2-targeted therapy
- 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 hormonal therapy for non‑cancer‑related conditions.
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.
19. Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications except for managing adverse events (inhaled steroids or intra articular steroid injections are permitted in this study).
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 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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.
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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For PFS, from randomization until progression as assessed by BICR or death due to any cause (up to 21 months).
For OS, up to 44 months. |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate: 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.
2. Duration of Response: 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.
3. 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).
4. Disease Control Rate: 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.
5. 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.
6. 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.
7. 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.
8. Clinical Outcome Assessments:The secondary PRO endpoints include:TTD in pain as measured by the pain scale from EORTC QLQ-C30, TTD in physical functioning as measured by the physical functioning scale from EORTC QLQ-C30, TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC QLQ-C30
9. Pharmacokinetics
10. Immunogenicity |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Randomization to event (response, progression, last evaluable assessment) up to 21m
2. Randomization to event up to 21m; from date of 1st response until progression or death up to 20m
3. Randomization to progression (inv. assessment) or death (up to 21m)
4. At least 11wks after randomization up to 18m
5. Randomization to start of 1st subsequent anti-cancer therapy post discontinuation of randomized treatment (up to 21m)
6. Randomization to start of 2nd subsequent anti-cancer therapy post discontinuation of 1st subsequent therapy (up to 21m)
7. Randomization to 2nd progression or death (up to 21m)
8. Randomization to 18wks post-progression
9. D1 of C1, C2, C4, C6, C8, C12 then every 4 cycles until EOT
10.D1 of C1, C2, C4, C6, C8, C12 and every 4 cycles until EOT & 28 days after last dose |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Mexico |
| South Africa |
| Argentina |
| Belgium |
| Brazil |
| Canada |
| China |
| Germany |
| Hungary |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
| France |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| It may be necessary for a participant to permanently discontinue study intervention. If study intervention is permanently discontinued, the participant will remain in the study to be evaluated for PFS (if the participant has not progressed according to RECIST 1.1), PFS2, OS, TFST and TSST. A participant that decides to discontinue study intervention will always be asked about the reason and the presence of any AEs. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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