Chemotherapy Monitoring by ctDNA in HER2- Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is a one-arm, single site, open-label phase II study. Patients will be enrolled in the screening step at the start of the second line of chemotherapy, and will undergo blood draws for ctDNA detection. Patients for whom ctDNA was successfully detected and found informative by the study executive board could then be included in the interventional step when starting a new line of therapy. ctDNA will be quantified using the customized test, at baseline and day 15 (+/- 3 working day) of cycle #1, and results will be made available before the cycle 2 Day 1, together with a treatment management recommendation by the Study Executive Board (continuation or discontinuation of the corresponding chemotherapy)

Detailed Description
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Patients will be enrolled in the screening step at the start of the second line of chemotherapy, and will undergo blood draws for ctDNA detection: That second line of treatment will be managed by clinical and radiological evaluations (RECIST); ctDNA will not be released to clinician and patient in real time. While the included patient is being treated by second line therapy, a customized ctDNA detection based on tumor mutations (droplet-digital PCR) will be developed. Once set up, the two blood above-mentioned samples will be subjected to ctDNA detection. The SEB will then retrospectively assess whether ctDNA levels changes during the second line of treatment were indicative of the efficacy of the second line therapy. Patients for whom ctDNA was successfully detected and found informative by the SEB (Steering Executive Board) could then be included in the interventional step when starting a new line of therapy. The third blood draw for ctDNA detection will be used to compare results to the tumor evaluation performed by imaging. In the interventional step, ctDNA analyses and interpretation will be performed in real time; results made available before the cycle 2. Quantitative results will be interpreted by the laboratory committee, with two possible recommendations: ctDNA changes at day 15 display a major drop (Mutant Allelic Frequency (MAF) or copies/ml) reduced by 40% or more compared to baseline: continuing the same chemotherapy will be recommended; ctDNA changes at day 15 display no major drop (MAF or copies/ml) either increased, stable or reduced by less than 40% compared to baseline: changing chemotherapy will be recommended; In light of ctDNA levels changes observed during the second line for each included patient, the above-mentioned thresholds might be modified, on a case-by-case basis, by the SEB (to keep into account individual characteristics). The test will be repeated for any new line of therapy that may be initiated during the first 6 months following the accrual of each patient in the interventional step. If this strategy is considered efficient (on an individual basis), further ctDNA tests will be made available on request for the next six months. Consequently, the patients who will change chemotherapy line after the recommendation following result from C1D15 ctDNA results will have a new ctDNA test at C1D1 and C1D15 of the new chemotherapy line.

Official Title
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Chemotherapy Monitoring by Circulating Tumor DNA (ctDNA) in HER2 (Human Epidermal Growth Factor Receptor-2)- Metastatic Breast Cancer (MONDRIAN): a Phase 2 Study

Conditions
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HER2-negative Metastatic Breast Cancer

Intervention / Treatment
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* Biological: Chemotherapy monitoring by circulating tumor DNA analysis


Participation Criteria
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Eligibility Criteria
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Written informed consent Woman ≥ 18 years old Performance status 0-2 Advanced HER2-negative metastatic breast cancer on the last tumor tissue assessed (ASCO-CAP (College of American Pathologists) guidelines) Eligible to a second line of chemotherapy for MBC (Metastatic Breast Cancer) Evaluable disease (per RECIST v1.1) Organ functions compatible with the use of chemotherapies (as decided by the investigator) No isolated CNS progression or leptomeningeal carcinomatosis No concurrent stage IV malignancy No concurrent severe and/or uncontrolled medical or psychological condition that would contraindicate participation in this study Additional criteria for the screening step : Presence of a known somatic mutation deemed trackable in circulating cell-free DNA. If the tumoral genetic landscape is unknown at inclusion, its characterization should be requested (or ongoing) at inclusion Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm phase 2 study, Chemotherapy monitoring based on ctDNA early changes
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>Patients with HER2-negative metastatic breast cancer, starting a second line of chemotherapy | Biological: Chemotherapy monitoring by circulating tumor DNA analysis<br>* During the screening step (2nd chemotherapy line, cycle 1) : at each time point (L2C1D1 & L2C1D15), 30 ml of blood will be drawn on special tubes with conservative suited for ctDNA analyses (e.g. STRECK® tubes).Then cell-free circulating DNA (cfcDNA) will be extracted from plasma following the manufacturer recommendations. cfcDNA will be quantified, and minimum 500-1000 copies will be analyzed by droplet digital PCR (ddPCR). Analyses will define if ctDNA could be detected during L2. For the interventional step, from L3 (3rd chemotherapy line) : 20 ml of blood will be drawn at L3C1D1 and L3C1D15. If ctDNA at D15 shows a major drop (> 40%) from D1, treatment will be continued. If ctDNA at D15 shows no major drop from D1, chemotherapy will be changed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| L3C1 : ctDNA quantification | ctDNA quantification (Mutant Allelic Frequency (MAF) %) during 3rd chemotherapy Line, 1st cycle (L3C1) | At the Day 1 of Cycle 1 (each cycle is 21 days) | 
| L3C1 : ctDNA quantification | ctDNA quantification (Mutant Allelic Frequency (MAF) %) during 3rd chemotherapy Line, 1st cycle (L3C1) | At the Day 15 of Cycle 1 (each cycle is 21 days) | 
| L3C1 : chemotherapy efficacy | ctDNA change : if major drop from D1 to D15 (MAF>40%), no change on treatment. If no major drop from D1 to D15, change of chemotherapy | ctDNA difference between Day 15 and Day 1 | 
| LxC1 : ctDNA quantification | ctDNA quantification (MAF %) during 4th chemotherapy line and following : Line x, 1st cycle (LxC1) | At the Day 1 of the Cycle 1 (each cycle is 21 days) | 
| LxC1 : ctDNA quantification | ctDNA quantification (MAF %) during 4th chemotherapy line and following : Line x, 1st cycle (LxC1) | At the Day 15 of the Cycle 1 (each cycle is 21 days) | 
| LxC1 : chemotherapy efficacy | ctDNA change : if major drop from D1 to D15 (MAF>40%), no change on treatment recommanded If no major drop from D1 to D15, change of chemotherapy recommanded | ctDNA difference between Day 15 and Day 1 | 
| Progression Free Survival (PFS) | Tumor assessment (MRI and/or CT) by RECIST 1.1 | From date of inclusion until the date of first documented progression or date of death from any cause, whichever came first, assessed every 8-weeks up to 18 months |