E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive Metastatic Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
This study is modular in design allowing assessment of safety, tolerability and anti-tumour activity of T-DXd in combination with other anti-cancer agents. Combination-treatment modules will have 2 parts: a dose-finding phase (Part 1), and a dose expansion phase (Part 2); the recommended Phase 2 dose (RP2D) determined in Part 1 will be used for the dose-expansion in Part 2.
The target population of interest in this study is patients with HER2-positive (as per ASCO/CAP 2018 guidelines) advanced/MBC. Part 1 of each module will enroll patients with locally assessed HER2-positive advanced/MBC in second-line or later patients. Part 2 of each module will enroll patients with locally assessed HER2-positive breast cancer who have not received prior treatment for advanced/metastatic disease.
Part 1: To assess the safety and tolerability, and determine RP2D for the T-DXd combinations
Part 2: To assess the safety and tolerability of T-DXd monotherapy and T-DXd combinations |
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E.2.2 | Secondary objectives of the trial |
Part 2: To assess anti-tumour activity of T-DXd combinations at the RP2D, and T-DXd monotherapy
Part 1 and Part 2: To assess the PK of T-DXd and durvalumab, and investigate the immunogenicity of T-DXd, durvalumab, and pertuzumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria: -Patients must be at least 18 years of age - Pathologically documented breast cancer that: a) Is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic b) HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local assessment c) Is documented as hormone receptor-positive (estrogen or progesterone receptor) or negative in the metastatic setting -Patient must have adequate tumor sample for biomarker assessment -ECOG Performance Status of 0 or 1 -Part 1 a) Disease progression on or after the last systemic therapy prior to starting study treatment b) At least 1 prior treatment line in metastatic setting required. -Part 2 a) No prior lines of therapy for advanced/MBC allowed |
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E.4 | Principal exclusion criteria |
Key Exclusion Criteria: -Uncontrolled or significant cardiovascular disease -Active or prior documented (non-infectious) ILD/pneumonitis that required steroids, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening -Lung-specific intercurrent clinically significant illnesses -Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals -Spinal cord compression or a history of leptomeningeal carcinomatosis -Prior treatment with immune checkpoint inhibitors -Prior treatment with an ADC containing a topoisomerase I inhibitor |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: AEs, SAEs, DLTs, laboratory findings
Part 2: AEs, SAEs, laboratory findings |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety will be assessed up to the follow-up period, approximately 40 months |
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E.5.2 | Secondary end point(s) |
1. Part 2: ORR is defined as the proportion of patients who have a CR or PR, as determined by the Investigator at local site per RECIST 1.1.
2. Part 2: PFS is defined as time from the date of randomisation until the date of progression as assessed by the Investigator at local site per RECIST 1.1, or death due to any cause.
3. Part 2: PFS2 is defined as time from the date of randomisation until the date of progression on next line treatment (the earliest of the progression event subsequent to first subsequent anticancer therapy) or death; second progression will be defined according to local standard clinical practice.
4. Part 2: DoR is defined as time from the date of first documented response until the date of documented progression or death in the absence of disease progression.
5. Part 2: OS is defined as time from the date of randomisation until the date of death due to any cause.
6. Serum concentration of T-DXd, total anti-HER2 antibody, MAAA-1181a, and durvalumab
7. Immunogenicity for T-DXd, durvalumab, and pertuzumab |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Until progression, assessed up to approximately 40 months
2. Until progression, assessed up to approximately 40 months
3. Assessed up to approximately 40 months
4. Until progression, assessed up to approximately 40 months
5. Until death, assessed up to approximately 40 months
6. While on study drug up to study completion, approximately 40 months
7. Up to follow-up period, approximately 40 months |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Dose-finding (Part 1) and dose-expansion (Part 2) for T-DXd combinations |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.2.3.1 | Comparator description |
Durvalumab, Pertuzumab, Paclitaxel |
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E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Australia |
Brazil |
Canada |
India |
Korea, Republic of |
Russian Federation |
Taiwan |
Turkey |
United States |
France |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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
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Completing the last expected visit/contact of the last patient undergoing the study (LSLV) |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |