| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Adult patients with advanced breast cancer after at least a first line of chemotherapy in metastatic setting:
-if HER2 IHC3+ or IHC2+/ISH+ resistant to trastuzumab and TDM-1
-if HER2 IHC0+ or IHC1+ or IHC2+/ISH- HR+ resistant to endocrine therapy.
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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 | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
The main objective is to evaluate the anti-tumor activity of DS-8201a in three cohorts of advanced breast cancer patients:
• a cohort of HER2 over-expressing (HER2 IHC3+ or HER2 IHC2+/ISH+)
• a cohort HER2 low-expressing (IHC1+ or IHC2+/ISH-)
• a cohort HER2 non-expressing (IHC0+)
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy in each cohort, in term of:
Best objective response as assessed by central review
Progression Free Survival (PFS)
Duration of response (DOR)
Clinical benefit rate (CBR)
Overall survival (OS)
• To evaluate the safety of DS-8201a overall and per cohort by NCI-CTCAE v5.0
TRANSLATIONAL OBJECTIVE:
• Exploration of bystander effect of DS-8201a in human samples
• Description of immune effects of DS-8201a
• Develop predictors of primary resistance or outcome
• Identify mechanisms of secondary resistance
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Deciphering mechanisms of action of DS8201
Objectives:
1. Exploration of bystander effect of DS-8201 in human samples.
2. Description of immune effects of DS-8201.
3. Develop predictors of primary resistance or outcome.
4. Identify mechanisms of secondary resistance
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| E.3 | Principal inclusion criteria |
1. Patient must have signed a written informed consent form prior to any study specific procedures. When the patient is physically unable to give his/her written consent, a trusted person of his/her choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent.
2. Female or male subjects aged ≥18 years.
3. Patient with histologically-confirmed diagnosis of invasive breast cancer. Tumors can be either HER2 IHC3+/ISH positive or IHC2+/ISH positive or IHC2+/ISH negative or IHC1+ or IHC0+, of most recent tumor tissue sample available.
4. Patient with a documented radiologic metastatic progression.
5. Patient considered by the investigator as not amenable to any other validated therapeutic option, after at least 1 line of chemotherapy in metastatic setting. Patient must have been previously treated with anthracyclines and taxanes (in (neo-)adjuvant and/or metastatic setting). Additionally:
• Patient with HER2 over-expressing (IHC3+ and IHC2+/ISH+) tumor must have been treated and have progressed on trastuzumab and on TDM-1. Prior treatment with pertuzumab is not required.
• Patient with HER2 negative (IHC0, 1+, and 2+/ISH-) and hormone receptor positive (ER+ and/or PR+) tumor must be resistant to endocrine therapy and CDK4/6 inhibitors, and must have been treated with capecitabine.
6. Non-bone metastatic site easily accessible to biopsy.
7. Presence of at least one measurable lesion according to RECIST v1.1.
8. Patient with WHO performance status ≤1.
9. Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and hemoglobin ≥9 g/dL (transfusion is not allowed within 1 week prior to baseline assessment).
10. Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN) range if no liver metastases or <3 x ULN in the presence of documented Gilbert’s Syndrome or liver metastases. AST and ALT levels ≤3 × ULN (AST and ALT≤ 5 ULN when documented liver metastasis).
11. Adequate blood clotting function: International Normalized Ratio (INR)/Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) ≤1.5 x ULN.
12. Adequate renal function: estimated creatinine clearance ≥30 mL/min according to the Cockcroft-Gault formula or serum creatinine ≤1.5 x ULN.
13. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before inclusion.
14. Male and female subjects of reproductive/childbearing potential must agree to use of a highly effective contraception for subjects throughout the study and for at least 4.5 months after last study treatment administration if the risk of conception exists.
15. Women of childbearing potential must have a negative serum pregnancy test within 14 days of enrolment or urine pregnancy test 72 hours prior to enrolment.
16. Patient is willing to comply with 2 sequential tumor biopsies (baseline and at first progression), and with a series of blood samples throughout the study.
17. Patients must be affiliated to a Social Security System.
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| E.4 | Principal exclusion criteria |
1. Patient with a breast cancer amenable for resection or radiation therapy with curative intent.
2. Patient has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and 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.
3. Patient with bone metastatic disease only.
4. Patient with multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated, or contralateral breast cancer.
5. Persistent unresolved toxicities with grade ≥2 (except alopecia and renal function). Subject with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).
6. Patient receiving treatments such as chemotherapy ) within 3 weeks before inclusion , immunotherapy within 4 weeks before inclusion, radiotherapy within 4 weeks or major surgery within 4 weeks. Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation.
7. Patient using drugs that could have pharmacokinetics interaction with investigational drugs. Concomitant use of strong CYP3A4 inhibitors or OATP 1B inhibitors should be avoided...reaction.
8. Patients with a 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.) Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study.
9. Patient with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
10. Patient with clinically significant corneal disease in the opinion of the Investigator.
11. Known prior severe hypersensitivity to investigational product or any component in its formulation, including known severe hypersensitivity reactions to study drug (NCI CTCAE v5.0 Grade ≥3).
12. Patient has a history of severe hypersensitivity reactions to other monoclonal antibodies.
13. Patients previously treated with topoisomerase 1 inhibitor.
14. Patient has substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation of the subject or evaluation of the clinical study in the opinion of the Investigator.
15. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
16. Known active hepatitis B virus or hepatitis C virus infection at screening.
17. Active infection requiring systemic therapy (as IV antibiotics, antivirals, antifungals,…).
18. Other severe acute or chronic medical conditions or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
19. Patient with a history of symptomatic congestive heart failure (New York Heart Association Class II to IV), serious cardiac arrhythmia requiring treatment, history of myocardial infarction or troponin levels consistent with myocardial infarction 28 days prior to inclusion, or unstable angina within 6 months prior to inclusion, or current dyspnea at rest due to advanced malignancy.
20. Patient with a corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) based on average of the screening triplicate12-lead ECG.
21. Pregnant women, women who are likely to become pregnant or are breastfeeding or women who want donate, or retrieve for their own use, ova from the time of screening and throughout the study and for at least 4.5 months after last study treatment administration.
22. Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
23. Patient unwilling to participate to the biological investigations.
24. Individual deprived of liberty or placed under the authority of a tutor.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is anti-tumor activity of DS-8201a carried out by the determination of the confirmed best objective response (BOR) rate in each cohort. The BOR is defined as the presence of a confirmed partial or complete response observed on treatment and assessed by investigators. The investigator will evaluate the objective response using RECIST v1.1 every 6 weeks.
For the cohort 3 (IHC0+), a short term primary endpoint is used for the interim analysis. The short term primary endpoint is the rate of patient without progression at 3 months. The investigator will evaluate the progression using RECIST v1.1 every 6 weeks
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The efficacy endpoint will be evaluated with:
PFS is defined as the time from inclusion until progression or death from any cause, whichever occurs first. At the time of analysis, the patient alive and without progression will be censored at the date of the last tumor assessment
DOR is applicable to subject with BOR, either complete response (CR) or partial response (PR), and is defined as the time from the first documented CR or PR until the date of disease progression, or until the date of death
CBR is defined as the presence of at least a PR or CR, or a stable disease (SD) >6 months under treatment
OS is defined as the time from inclusion until death. Patients alive at last follow-up will be censored at this date
Safety will be evaluated continuously using NCI-CTCAE v5.0
TRANSLATIONAL ENDPOINT(S):
•Concentration of trastuzumab and deruxtecan in HER2 expressing and HER2 non expressing tumor cells at 24h after treatment initiation
•Percentage of stained cells and intensity of staining for immune response markers detected by IHC on tumor samples at baseline and 21 days after treatment initiation
•Percentage of stained cells and intensity of staining for biomarkers detected by IF and IHC on tumor samples at baseline
•Identification of genomic alterations of interest through whole exome sequencing and RNA sequencing on tumor and ctDNA samples collected after resistance to DS-8201a
•Describe the variation of CTC levels and evaluate its predictive value on the objective response, the clinical benefit, and survival
•Explore changes over time in tumor CTC phenotype induced by ADC
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
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| 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
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