COGNITON-GUIDE
Overview
- Study title: COGNITION-GUIDE Genomics guided targeted post-neoadjuvant therapy in patients with early breast cancer - Module Therapy
- Study design: 7-arm, multicentre, open phase II umbrella study
- Study participants: Patients with early-stage breast cancer and a high risk of recurrence after neoadjuvant chemotherapy and surgery following the COGNITION study
- Study objective: Testing the efficacy of targeted drugs in early breast cancer to reduce the risk of recurrence
- Clinical.trials.gov-Identifier / NCT-ID: NCT05332561
Study status: currently recruiting
COGNITION-GUIDE (Genomics guided targeted post-neoadjuvant therapy in patients with early breast cancer - Module Therapy) is a prospective, multicentre, phase II umbrella study. It includes high-risk patients with early, non-metastatic breast cancer (eBC) whose tumours have shown no response or only a partial response to neoadjuvant systemic therapy (NACT).
Following surgery, patients are assessed for risk status during the postoperative tumour board meeting. High-risk is defined as: Pathologically confirmed residual tumour (i.e., no pathological complete remission; non-pCR) in patients with HER2+ and triple-negative BC (TNBC), and in HR+/HER2- BC with non-pCR and a CPS-EG score ≥ 3 or ≥ 2 in the presence of lymph node involvement (ypN+).
As part of the COGNITION registry study, identified high-risk patients undergo molecular genetic diagnosis of the residual tumour. Based on the individual biomarker profile, patients are assigned to one of 7 treatment arms within COGNITION GUIDE trail. The therapy is applied for a total duration of one year following the standardised post-neoadjuvant therapy.
Important to know:
The molecular profiling of the residual tumour and the resulting stratification are not part of the interventional COGNITION-GUIDE study. These diagnostic procedures are conducted within the framework of the COGNITION registry study or through the GBG registry programme MOMENTUM.
Objectives of COGNITION-GUIDE
Each tumour exhibits a unique molecular profile that influences its biological behaviour and response to therapy. While personalised, molecularly guided treatment strategies have become more established in advanced-stage cancer — where curative potential is often limited — they remain largely unavailable for patients with earlier-stage disease.
The COGNITION / COGNITION-GUIDE programme seeks to close this gap by offering comprehensive molecular diagnostics and personalised, targeted therapy approaches to patients with early-stage breast cancer who are at high risk of recurrence. The aim is to complement standard treatment with molecularly tailored interventions in order to further reduce the risk of relapse in a population with curative intent.
Cancer patients may participate in the COGNITION-GUIDE study via the participating Comprehensive Cancer Centres or clinics at the NCT sites. Registration is carried out either by the treating oncologist or by the patient herself.
The participating NCT study centres and their contact details can be found on the NCT Heidelberg study website.
COGNITION-GUIDE is a multicentre, seven-arm phase II umbrella study designed to treat patients with early breast cancer (eBC). The study was developed at the NCT Heidelberg. As part of the trial, doctors/clincians use data from comprehensive molecular analyses to derive individually tailored treatment options.
In COGNITION-GUIDE, patients are assigned to one of the seven treatment arms based on a detailed molecular characterisation of the tumour following neoadjuvant chemotherapy.
- Atezolizumab (Roche)
- Inavolisib (Roche)
- Ipatasertib (Roche)
- Olaparib (AstraZeneca)
- Sacituzumab-Govitecan (Gilead)
- Trastuzumab/Pertuzumab (Roche)
- Observation arm: (patients for whom either no molecular profile could be created or for whom no relevant biomarkers were detected)
A total of 240 patients can be included in the study.
Objectives of COGNITION-GUIDE
- To reduce the risk of recurrence and/or metastasis in high-risk patients with early breast cancer who have residual tumour following neoadjuvant therapy,
- through biomarker-guided intensified post-neoadjuvant treatment in addition to standard therapy.
- Testing the safety and tolerability of biomarker-based post-neoadjuvant therapy with targeted agents
Inclusion criteria
- Female and male patients aged 18 years or older with non-metastatic eBC
- Patients with either TNBC or HER2+ eBC and
- non-pCR, defined as other than ypT0/is ypN0
- Patients with original HR+ and HER2- eBC and non-pCR and CPS-EG score
- ≥ 3 and ypN0, or
- ≥ 2 and ypN+
- ≥ 3 and ypN0, or
- Eastern Cooperative Oncology Group Performance status ≤ 1
- Completed neoadjuvant therapy, surgery and standard post-neoadjuvant treatment +/- radiotherapy (standard according to German guidelines except for a CDK4/6 inhibitor and olaparib)
- Resolution of acute effects from prior therapy to baseline severity or National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade ≤ 1, except for adverse effects that are not considered by the investigator to pose a safety risk
Exclusion criteria
- Other malignancies within the last 5 years with the exception of: adequately treated non-melanoma skin cancer, curatively treated in situ carcinoma of the cervix, ductal carcinoma in situ (DCIS), stage 1 grade 1 endometrial carcinoma or other solid tumours including lymphomas (without bone marrow involvement) that have been curatively treated with no evidence of disease for the least five years.
- Co-existing severe, uncontrolled systemic diseases that would expose the patient to an unreasonable risk or interfere with the planned treatment
- Concurrent or prior treatment within 30 days in another interventional clinical trial with an investigational anticancer drug
- Persistent toxicity (≥ grade 2 according to NCI CTCAE v5.0, caused by previous cancer therapy, excluding alopecia)
- Clinical signs of active infection (> grade 2 according to NCI CTCAE v5.0)
- Known or newly diagnosed infection with the human immunodeficiency virus and immunocompromised patients
- Active hepatitis A, B and/or C virus infection
- Pregnancy and breastfeeding
- Inability to take oral medication and gastrointestinal disorders that may affect absorption of the study medication
- Major surgical procedures within the past 4 weeks
- Heart failure classified as NYHA II/III/IV
1. Contacting and introducing the patient
The attending physician registers the patient for the study. Patients may also register themselves.
The following documents should be sent to one of the participating study centres near the patient`s place of residence: a current doctor's letter, histology reports, CT/MRI findings, surgical report, tumour board recommendation, patient contact details including telephone number and a referral form.
At an appointment, the patient is informed by the study physician - the decision on participation and the written declaration of consent are then obtained.
2. Patient selection
Patients are selected within the framework of COGNITION: Patients with early breast cancer (all subtypes), following neoadjuvant therapy, surgery and standard post-neoadjuvant therapy according to the current German guidelines with the exception of abemaciclib and olaparib (see inclusion criteria for further details).
3. Assignment to therapy groups
Treatment stratification occurs across six experimental arms with targeted therapies and one observation arm. Patients with relevant predictive biomarker profiles are assigned to one of the following experimental arms:
Arm 1 (atezolizumab, immune evasion):
- PD-L1 positivity (≥4 % on immune cells in tumour tissue, measured by immunohistochemistry [IHC])
- MSI high status (microsatellite instability, validated by polymerase chain reaction [PCR])
- High tumour mutation burden (TMB-H, ≥10 mutations per megabase)
- CD274 amplification
Arm 2 (Inavolisib, PI3K):
- Detection of a (probably) oncogenic/activating PIK3CA mutation
Arm 3 (Ipatasertib, AKT):
- Aberrations indicating increased activity of the PI3K-AKT signalling pathway. If a (probably) oncogenic/activating PIK3CA mutation is detected, patients are preferentially enrolled in the inavolisib arm,
- HR-positive tumour histology
Arm 4 (olaparib, PARP, DNA repair):
- Inactivating oncogenic somatic or germline mutations in BRCA1/2, including homozygous deletions
- Inactivating oncogenic germline mutations in PALB2
Arm 5 (sacituzumab govitecan, TROP-2):
- TROP-2 overexpression (detected by IHC)
- Exclusion for known homozygous polymorphisms in the UGT1A1*28 gene
Arm 6 (trastuzumab / pertuzumab, ERBB2):
- Activating HER2 mutations
Patients for whom either no molecular profile could be established for whom no relevant biomarkers were detected will be assigned to the observation arm of the study.
4. Treatment phase
Patients will be included in COGNITION -GUIDE no earlier than one month and no later than three months after completion of standard therapy (neoadjuvant chemotherapy, surgery, post-neoadjuvant standard therapy including radiotherapy, if indicated). In the case of HR+ eBC, the study medication is administered alongside post-neoadjuvant endocrine therapy according to guidelines.
Adverse events (AEs) are documented continuously during the treatment phase and 28 days or up to 10 weeks, following treatment completion.
Patient-reported-outcomes (PROs) are collected at baseline, after 3, 6 and 12 months and then every 6 months until the end of the 4th year.
5. Follow-up phase
Follow-up is conducted according to standardAGO guidelines with examinations every 3 months for 3 years, then every 6 months for years 4-5. Medical history, physical findings, clinical data and concomitant medication are collected.
Blood samples are taken at the start of the study, after 3 and 12 months and then every 6 months until the end of the 4th year.
Breast cancer status is assessed per standard S3 and AGO guidelines (clinical breast examination, sonography, mammography, and additional examinations as needed).
6. Data analysis / study report / publication
- Primary endpoint: invasive disease-free survival (iDFS) after 4 years in the entire study population
- Secondary endpoints: iDFS in each study arm, metastasis-free survival, distant disease-free survival (dDFS) overall and by each study arm, including overall survival (OS), treatment safety assessed by adverse event recording overall and by study arm; subgroup analyses and patient-reported outcomes (PROs)
- Monitoring treatment success via comprehensive longitudinal liquid biopsies.
The attending physician or the patient herself sends a current doctor's letter, histology, CT/MRI findings, surgical report, tumour board recommendation, contact details of the patient with telephone number and a referral form by post to the address below:
NCT Heidelberg
Patient centre 2
Im Neuenheimer Feld 460
69120 Heidelberg
Phone: 06221 56-5959
Fax: 06221 56-5320
E-Mail: Patientenzentrum2.NCT-at-med.uni-heidelberg.de
Contact details for other NCT study centres can be found on the study website.
The study is supported by patient experts from MammaMia, Brustkrebs Deutschland e.V. and the PATH Biobank.
Coordinating Director of Studies:
Prof Andreas Schneeweiss, MD
Head of the Gynaecological Oncology Section
Heidelberg University Hospital
Phone: 06221 567985
E-Mail: cognition.nct-at-med.uni-heidelberg.de