| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple 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 |
1. 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.
2. 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. |
|
| E.2.2 | Secondary objectives of the trial |
| 1) To demonstrate superiority of Dato-DXd relative to ICC by assessment of 1) ORR, 2) DoR, 3) PFS by investigator assessment, 4) DCR. To assess in participants treated with Dato-DXd compared to ICC TTD in 5) Pain, 6) Physical functioning, 7) Breast and arm symptoms, and 8) GHS/QoL. To demonstrate superiority of Dato-DXd relative to ICC by assessment of 9) TFST, 10) TSST, 11) PFS2. 12) To assess the pharmacokinetics of Dato-DXd. 13) To investigate the immunogenicity of Dato-DXd. 14) To assess the safety and tolerability of Dato-DXd compared with ICC in the safety analysis set. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1Participant must be ≥ 18 years at the time of screening.
2Histologically or cytologically documented locally recurrent inoperable TNBC, which cannot be treated with curative intent, or metastatic TNBC.
3No prior chemotherapy or other systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer.
4Not a candidate for PD 1/PD L1 inhibitor therapy.
5At 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.
6ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
7Eligible 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.
8Has had an adequate treatment washout period before Cycle 1 Day 1
9Written 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.
10Participants 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
11Adequate organ and bone marrow function within 7 days before randomisation
12Minimum life expectancy of 12 weeks.
13Male or female.
14Negative pregnancy test (serum) for women of childbearing potential.
15Female 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.
16Male 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.
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. |
|
| E.4 | Principal exclusion criteria |
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).
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.
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).
15. Prior exposure to any treatment (including ADC) containing a
chemotherapeutic agent targeting topoisomerase I, or to TROP2-
targeted therapy
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).
24. Known history of severe hypersensitivity reactions to other
monoclonal antibodies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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 HR of PFS.
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 HR 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 (anticipated to be up to 26 months).
For OS, from randomisation until the date of death due to any cause (approximately 42 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 is defined as a best overall
response of CR or PR or having SD, (without subsequent cancer
therapy), per RECIST 1.1, as assessed by BICR/per investigator
assessment and maintained for ≥ 11 weeks from randomization (to
allow for an early assessment within the assessment window). Disease
control rate at 12 weeks (DCR-12) is defined as the percentage of
subjects who have disease control.
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. 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 based on radiological or clinical progression.
8. Clinical Outcome Assessments:The secondary PRO endpoints include:TTD in pain as measured by the pain scale from EORTC IL146, TTD in physical functioning as measured by the physical functioning scale from EORTC IL146, TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC IL146, TTD in breast symptoms as measured by breast symptoms scale from EORTC IL116, TTD in arm symptoms as measured by arm symptoms scale from EORTC IL116
9. Pharmacokinetics
10. Immunogenicity
11. Safety & tolerability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 Randomization to event (response, PD, last evaluable assessment), up to 26m
2 Randomization to event (up to 26m); from date of 1st response until progression or death, up to 26m
3 Randomization to progression (inv. assessment) or death, up to 26m
4 At least 11wk after randomization, up to 26m
5 Randomization to start of 1st subsequent anti-cancer therapy post-discontinuation of randomized treatment, up to 26m
6 Randomization to start of 2nd subsequent anti-cancer therapy post-discontinuation of 1st subsequent therapy, up to 26m
7 Randomization to 2nd progression or death, up to 26m
8 Randomization to 18wks post-progression
9 D1 of C1, C2, C4, & C8
10 D1 of C1, C2, C4, C8, C12 & then every 4 cycles until EoT & 28 days after last dose
11 Randomization to Safety follow-up visit, up to 26m |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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 |
| Argentina |
| Singapore |
| Taiwan |
| Belgium |
| Brazil |
| Canada |
| China |
| France |
| Germany |
| Hungary |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Poland |
| South Africa |
| Spain |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
A participant is considered to have completed the study if they have completed all phases of the study, including the last visit and undergone determination of OS.
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at undue risk because of clinically significant findings.
The end of the study is defined as the date of the last visit of the last participant in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
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