Early Detection of Triple Negative Breast Cancer Relapse (CUPCAKE) (CUPCAKE)

Early Detection of Triple Negative Breast Cancer Relapse: a Clinical Utility Phase II Trial

CUPCAKE is a randomized, non-comparative, multicenter, proof-of-concept phase II trial, using the Trials within Cohorts concept(1) to assess the clinical utility of ctDNA monitoring combined with 68Ga-FAPI-46-PET-CT imaging upon ctDNA detection for the surveillance of patients with a non-metastatic TNBC at high risk of relapse.

The study has two steps. In Step 1, patients who have completed the treatments for a localized TNBC will undergo ctDNA monitoring every ~4 months (± 2 weeks). In Step 2, patients for whom ctDNA will be detected will then be randomized between an observation arm, in which monitoring will continue until the detection of a clinical relapse, and an experimental arm, in which the ctDNA detection will be revealed to both the patient and the clinician: patients will then undergo a 18F-FDG PET-CT and a 68Ga-FAPI-46-PET-CT, in addition to whatever workup the investigator will deem necessary.

Study Overview

• Status: Recruiting
• Conditions: Triple Negative Breast Cancer
• Intervention / Treatment: Diagnostic test: 68Ga-FAPI-46-PET-CT; Diagnostic test: ctDNA monitoring

Detailed Description

The CUPCAKE trial will follow the Trials within Cohorts (TwiCs) approach. Non-metastatic TNBC patients at high risk of relapse will be included, after having signed a written informed consent, in a cohort allowing them to be followed by ctDNA monitoring every 4 months.

For each patient included, a ctDNA detection assay will be performed in blood samples every 4 months for a maximum of 24 months, while extra-plasma will be banked. ctDNA results will be available with a turnaround time of less than 3 weeks. When negative, ctDNA detection results will not be disclosed to patients nor clinicians.

First line therapy will not be started until a metastatic relapse has been found by imagining: no treatment will be started in the sole basis of a positive ctDNA test.

If, at any timepoint, ctDNA is detected (molecular relapse), patients will be randomized in a 1:1 ratio.

• In the experimental arm, patients and their treating physician will be made aware of the molecular relapse (positive ctDNA detection results). To locate metastatic deposits, patients will be offered to undergo a whole-body imaging with 18F-FDG PET-CT and 68Ga-FAPI-46-PET-CT, in addition to any other workup considered as relevant by their treating physician. If/when a clinical/radiological relapse is observed, the patient performance status will be registered (secondary objective) and systemic or local treatments will be decided by physicians. These treatments could be informed by the genetic landscape of the relapse, assessed by ctDNA.
• In the control arm, patients and their treating physician will not be made aware of the molecular relapse and will continue the standard surveillance with repeated ctDNA test every 4 months (blinded) for a maximum of 24 months from enrolement in the study. At the time of the clinical/radiological diagnosis of relapse, similar procedures will be performed (18F-FDG PET-CT, 68Ga-FAPI-46-PET-CT, and tumor genetic landscape assessment by ctDNA analysis).

• Study Type: Interventional
• Enrollment (Estimated): 450
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne-Claire COYNE; Phone Number: 0147111515; Email: drci.promotion@curie.fr

Study Locations

• France
  • Avignon, France, 84918
    • Not yet recruiting
    • Sainte-Catherine Institut du Caner Avignon-Provence
    • Contact: Julien GRENIER
    • Principal Investigator: Julien Grenier
  • Bordeaux, France, 33000
    • Not yet recruiting
    • Institut Bergonie
    • Contact: Monica Arnedos, MD
    • Principal Investigator: Monica ARNEDOS, MD
  • Clermont-Ferrand, France, 63011
    • Not yet recruiting
    • Centre Jean Perrin
    • Principal Investigator: Marie-Ange MOURET-REYNIER, MD
    • Contact: Marie-Ange MOURET-REYNIER
  • Lyon, France, 69008
    • Not yet recruiting
    • Centre Léon Bérard
    • Principal Investigator: Olivier TREDAN
    • Contact: Olivier TREDAN, MD
  • Marseille, France, 13009
    • Not yet recruiting
    • Institut Paoli-Calmettes
    • Principal Investigator: Renaud SABATIER, MD
    • Contact: Renaud SABATIER, MD
  • Montpellier, France, 34298
    • Not yet recruiting
    • Institut du Cancer de Montpellier
    • Principal Investigator: William JACOT, MD
    • Contact: William JACOT, MD
  • Nîmes, France, 30900
    • Not yet recruiting
    • CHU Nimes
    • Contact: Frédéric FITENI, MD
    • Principal Investigator: Frédéric FITENI, MD
  • Paris, France, 75020
    • Not yet recruiting
    • Hopital Tenon
    • Principal Investigator: Joseph Gligorov
    • Contact: Joseph GLIGOROV
  • Paris, France, 75010
    • Not yet recruiting
    • Hopital Saint-Louis
    • Contact: Louis TEXEIRA, MD
    • Principal Investigator: Louis TEXEIRA, MD
  • Rennes, France, 35000
    • Not yet recruiting
    • Centre Eugene Marquis
    • Contact: Thibault DE LA MOTTE ROUGE, MD
    • Principal Investigator: Thibault DE LA MOTTE ROUGE, MD
  • Saint-Cloud, France, 92340
    • Recruiting
    • Institut Curie
    • Principal Investigator: François-Clément BIDARD, MD
    • Contact: François-Clément BIDARD
  • Toulouse, France, 31059
    • Not yet recruiting
    • Oncopole Claudius Regaud
    • Principal Investigator: Florence Dalenc
    • Contact: Florence Dalenc, MD
  • Vandœuvre-lès-Nancy, France, 54519
    • Not yet recruiting
    • Institut de Cancerologie de Lorraine
    • Contact: Vincent Massard, MD
    • Principal Investigator: Vincent MASSARD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must have signed a written informed consent before inclusion
2. Patients must be female ≥ 18 years old
3. Patients diagnosed with a non-metastatic TNBC (ER & PR <10%, HER2- per ASCO/CAP guidelines). Patients must have been previously evaluated by a 18F-FDG PET-CT or a bone scintigraphy combined with a thorax, abdomen and pelvis CT scan with contrast
4. Patients who have undergone surgery with curative intent for their non-metastatic TNBC. Surgery must have been performed between 3 to 9 months before inclusion. Patients must have initiated their adjuvant therapy, whenever indicated, since at least 12 weeks. For patients receiving an experimental adjuvant treatment in a clinical trial, any intervention planned as part of this trial must be completed before inclusion.

5. High-risk primary tumor, defined as:

   1. Lack of pathological complete response after neoadjuvant chemotherapy (RCB I, II or III; RCB I being capped to a maximum of 30% of included patients) OR, in the absence of neoadjuvant chemotherapy,
   2. Stage IIB-III (i.e., T2N1, any T3-T4, any N2-3) OR
   3. Any loco-regional relapse occurring after a prior ipsilateral, curatively treated TNBC
6. No sign of local or distant relapse, as per investigator assessment
7. Performance status < 2
8. Available FFPE tumor block with > 10% cellularity or 11 tumor sections with >10% cellularity
9. Patient able to comply with protocol requirements
10. Patients covered by a health insurance

Exclusion Criteria:

1. Any uncontrolled disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding or any other medical condition that, in the opinion of the investigator, interferes with the trial procedures
2. Male participants
3. Patients with altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
4. Patients who have difficulty undergoing trial procedures for geographic, social or psychological reasons
5. Person deprived of liberty or under guardianship

6. History of another primary malignancy except for the following :

   1. Basal cell carcinoma or any in situ carcinoma treated with curative intent
   2. Any stage I-II malignancy treated with curative intent with no evidence of active disease in the last five years
7. For step #2 (randomization after ctDNA detection): clinical/radiological metastatic relapse before the detection of the molecular relapse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental arm; In the experimental arm, patients and their treating physician will be made aware of the molecular relapse (positive ctDNA detection results) in study steps 1 (ctDNA monitoring). To locate metastatic deposits, patients will be offered to undergo a whole-body imaging with 18F-FDG PET-CT and 68Ga-FAPI-46-PET-CT, in addition to any other workup considered as relevant by their treating physician.	Diagnostic test: 68Ga-FAPI-46-PET-CT; ). To locate metastatic deposits, patients will be offered to undergo a whole-body imaging with 18F-FDG PET-CT and 68Ga-FAPI-46-PET-CT, in addition to any other workup considered as relevant by their treating physician.; Diagnostic test: ctDNA monitoring; For each patient included, a ctDNA detection assay will be performed in blood samples every 4 months, while extra-plasma will be banked. ctDNA results will be available with a turnaround time of less than 3 weeks. When negative, ctDNA detection results will not be disclosed to patients nor clinicians.
Sham Comparator: Control arm; In the control arm, patients and their treating physician will not be made aware of the molecular relapse and will continue the standard surveillance with repeated ctDNA test every 4 months (blinded). ). At the time of the clinical/radiological diagnosis of relapse, similar procedures will be performed (18F-FDG PET-CT, 68Ga-FAPI-46-PET-CT, and tumor genetic landscape assessment by ctDNA analysis).	Diagnostic test: 68Ga-FAPI-46-PET-CT; ). To locate metastatic deposits, patients will be offered to undergo a whole-body imaging with 18F-FDG PET-CT and 68Ga-FAPI-46-PET-CT, in addition to any other workup considered as relevant by their treating physician.; Diagnostic test: ctDNA monitoring; For each patient included, a ctDNA detection assay will be performed in blood samples every 4 months, while extra-plasma will be banked. ctDNA results will be available with a turnaround time of less than 3 weeks. When negative, ctDNA detection results will not be disclosed to patients nor clinicians.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	OS rate for the main analysis (primary endpoint) is defined as the percentage of patients still alive 36 months after the randomization. If the patient is not present at the 36th month visit, survival data may be obtained by other means, such as telephone contact with the patient, his family, his current physician, or consulting local death registries. A non-comparative analysis will be conducted in the experimental arm, and the control arm will serve as reference.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Best ORR is defined as the proportion of patients with a complete response (CR) or partial response (PR) based on local investigator assessment according to RECIST 1.1, until first progression or last tumor assessment in the absence of progression. ORR will be reported with its 95% confidence interval by arm.	12 months
5-level EQ-5D version (EQ-5D-5L)	y. Each state is referred to in terms of a 5 digit code. For example, state 11111 indicates no problems on any of the 5 dimensions, while state 12345 indicates no problems with mobility, slight problems with washing or dressing, moderate problems with doing usual activities, severe pain or discomfort and extreme anxiety or depression. A completely healthy patient would have a score of 11111. This 5-digit number can be converted into a score using a special algorithm that is not publicly available. This point value is called the EQ-5D-5L Index and represents the patient's health status.	Clinical/radiological relapse up to 24 months
Number of metastatic sites at the time of the clinical/radiological relapse.	The number of metastatic sites upon clinical/radiological relapse will be defined post-hoc by the Adjudication Committee as the number of organs or systems in which metastases are detected at the time of the clinical/radiological relapse, among the following propositions: lymph nodes, bones, liver, lungs, central nervous system/meninges, peritoneum, others.	Clinical/radiological relapse up to 36 months
Recurrence-free survival	RFS [recurrence-free survival], defined as the time from randomization to clinical/radiological relapse or death; PFS [progression-free survival], defined as the time from randomization to the first progression or death occurring after clinical/radiological relapse; 1L-PFS [first line PFS], defined as the time from clinical/radiological relapse to first progression or death ; 2L-PFS [second line PFS], defined as the time from first to second progression or death; progression being defined per RECIST criteria.	Clinical/radiological relapse up to 36 months
Overal Survival	Overall Survival is defined as the time between randomization and death.	Up to 36 months
Performance Status Scale	Proportion of patients presenting with an altered general condition (PS ≥2) at first evidence of clinical or radiological relapse. The population of interest consists in randomized patients.	Clinical/radiological relapse up to 36 months
EORTC Core Quality of Life questionnaire (EORTC-QLQ-C30) with the QLQ-BR42 module	The EORTC-QLQ-C30 questionnaire with the QLQ-BR42 is used to report health-related QoL in all included patients. Summary statistics of the scores for all functional/symptom scales will be calculated at each assessment time point, according to the scoring procedure recommended by the EORTC. All of the scales and single item measures range in score from 0 to 100. A high score for the functional scales and functional single items represents a high/healthy level of functioning, whereas a high score for the symptom scales and symptom item represents a high level of symptomatology or problems.	Clinical/radiological relapse up to 36 months
Proportion of patients receiving local treatment for oligometastatic disease	Proportion of patients receiving local treatment for oligometastatic disease	36 months

Collaborators and Investigators

• Sponsor: Institut Curie
• Collaborators: Roche Pharma AG; National Research Agency, France; UNICANCER; Personalis Inc.
• Investigators: Principal Investigator: Francois-Clement BIDARD, Institut Curie

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2026
• Primary Completion (Estimated): August 3, 2031
• Study Completion (Estimated): August 3, 2031

Study Registration Dates

• First Submitted: December 12, 2023
• First Submitted That Met QC Criteria: January 16, 2024
• First Posted (Actual): January 26, 2024

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: ctDNA; Triple negative breast cancer; 68Ga-FAPI-46
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Skin and Connective Tissue Diseases; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; FAPI-46
• Other Study ID Numbers: IC 2022-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Investigators will share de-identified data sets with interested researchers, educators or clinicians. Materials generated under the project will be disseminated in accrodance with Institut Curie policies.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after article publication and will be made accessible for up to 12 months.
• IPD Sharing Access Criteria: Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific reserach, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a data sharing agreement (DSA).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No