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Genomics Guided Targeted Post-neoadjuvant Therapy in Patients With Early Breast Cancer (COGNITION-GUIDE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT05332561
Recruitment Status : Recruiting
First Posted : April 18, 2022
Last Update Posted : July 6, 2023
Information provided by (Responsible Party):
German Cancer Research Center

Brief Summary:

In early breast cancer (eBC), pathological complete response (pCR) after neoadjuvant therapy acts as surrogate marker for metastasis and overall survival. Therapy intensification by adding an adjuvant therapy line (post-neoadjuvant treatment) substantially lowers the risk of relapse in high-risk breast cancer patients with residual disease after neoadjuvant treatment (non-pCR). While this approach was exemplified in two phase III trials without biomarker-stratification (CREATE-X, KATHERINE), even higher efficiency might be achieved by individualized genomic-guided post-neoadjuvant therapies.

Within the seven-arm umbrella phase-II clinical trial COGNITION-GUIDE, we aim to deliver molecularly-tailored cancer care by implementing an additional response- and genomics-guided post-neoadjuvant therapy after finishing the guideline-compliant post-neoadjuvant treatment in high-risk breast cancer patients with residual cancer burden after neoadjuvant therapy to reduce the substantial risk of local and distant relapse.

The trial evaluates not a single drug but rather a general strategy of precision oncology in the curative setting and provides the basis for future confirmatory biomarker-driven trials.

Allocation to the therapy-arms is conducted by in depth molecular characterization of tumors within the COGNITION registry program.

The study aims to show an overall benefit of the precision medicine approach in high-risk eBC patients and to allow for secondary exploratory evaluation of each study-arm.

The primary endpoint of the study is invasive Disease-Free Survival (IDFS) after 4 years measured from surgery to local or distant relapse or death. The sample size of the entire trial is 240 eligible patients.

Condition or disease Intervention/treatment Phase
Early-stage Breast Cancer Drug: Atezolizumab 1200 mg in 20 ML Injection Drug: Inavolisib Drug: Ipatasertib Drug: Olaparib Drug: Sacituzumab govitecan Drug: Trastuzumab/pertuzumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Umbrella
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Genomics Guided Targeted Post-neoadjuvant Therapy in Patients With Early Breast Cancer - a Multicenter, Open-label, Umbrella Phase-II Study - COGNITION-GUIDE
Actual Study Start Date : June 29, 2023
Estimated Primary Completion Date : March 2030
Estimated Study Completion Date : December 2030

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Arm 1 Atezolizumab (Immune Evasion)
Atezolizumab Dosage: 1200 mg, intravenous, on d1, q21d
Drug: Atezolizumab 1200 mg in 20 ML Injection
Arm 1
Other Name: Tecentriq

Experimental: Arm 2 Inavolisib (PI3K)
Inavolisib Dosage: 9 mg, oral, on d1-d28, q28d
Drug: Inavolisib
Arm 2

Experimental: Arm 3 Ipatasertib (AKT)
Ipatasertib Dosage: 400 mg, oral, on d1-d21, q28d
Drug: Ipatasertib
Arm 3

Experimental: Arm 4 Olaparib (PARP, DNA-Repair)
Olaparib Dosage: 300 mg, oral, bid d1-d28, q28d
Drug: Olaparib
Arm 4
Other Name: Lynparza

Experimental: Arm 5 Sacituzumab Govitecan (TROP-2)
Sacituzumab Govitecan Dosage: 10 mg/kg BW, intravenous, on d1 and d8, q21d
Drug: Sacituzumab govitecan
Arm 5
Other Name: Trodelvy

Experimental: Arm 6 Trastuzumab/Pertuzumab (ERBBB)
Trastuzumab/Pertuzumab Administration: subcutaneous; Initial dose: Trastuzumab 600 mg, Pertuzumab 1200 mg, 30 000 units hyaluronidase; Maintainance dose: Trastuzumab 600 mg, Pertuzumab 600 mg, 20 000 units hyaluronidase; Frequency: on d1, q21d
Drug: Trastuzumab/pertuzumab
Arm 6
Other Name: Phesgo

No Intervention: Arm 7 Observation

Primary Outcome Measures :
  1. Invasive Disease-free Survival (IDFS) as defined by Hudis et al in the entire study population four years after surgery [ Time Frame: Four years after surgery ]
    Primary objective is to improve clinical outcome in early high-risk breast cancer by biomarker-guided post-neoadjuvant therapy (systemic treatment in the adjuvant setting following neoadjuvant therapy, surgery and post-neoadjuvant standard therapy)

Secondary Outcome Measures :
  1. Invasive Disease-free Survival (IDFS) as defined by Hudis et al [ Time Frame: Four years after surgery ]
    in each study arm separately

  2. Distant Disease-free Survival (DDFS) as defined by Hudis et al [ Time Frame: Four years after surgery ]
    in each study arm separately and overall

  3. Overall Survival [ Time Frame: When the last patient has completed four years after surgery ]
    in each study arm separately and overall

  4. Incidence of Treatment-Emergent Adverse Events (safety and tolerability) [ Time Frame: Through treatment period of the study, an average of 1 year ]
    in each study arm separately and overall

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Provision of written informed consent
  2. Female and male patients with non-metastatic early (stage I-III) breast cancer aged ≥ 18 years
  3. Conducted neoadjuvant chemotherapy and surgery as well as conducted standard post-neoadjuvant treatment +/- radiotherapy (standard according to German guidelines except Abemaciclib and Olaparib)
  4. For patients with initially triple negative (TNBC) or HER2-positive breast cancer:

    • Non-pCR defined as other than ypT0/is ypN0

  5. For patients with initially hormone receptor positive and HER2-negative breast cancer: Non-pCR and CPS-EG score

    • ≥ 3 and ypN0, or
    • ≥ 2 and ypN+
  6. ECOG Performance Status ≤ 1
  7. Acute effects of any prior therapy resolved 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 not constituting a safety risk by investigator judgement
  8. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential negative urine pregnancy test at post-operative screening and baseline as well as highly effective forms of contraception have to be in place thereafter

    • Evidence of childbearing potential is defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile
    • Postmenopausal or evidence of non-childbearing status is defined as:

      • Amenorrhea for 1 year or more without an alternative medical cause following cessation of exogenous hormonal treatments plus follicle stimulating hormone (FSH) levels in the postmenopausal range in women not using hormonal contraception or hormonal replacement therapy
      • Chemotherapy-induced menopause
      • Surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, total hysterectomy or tubal ligation at least 6 weeks before IMP treatment)
      • Female patients with age ≥ 60 years
    • A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy
  9. Female patients of childbearing potential and male patients with partners of childbearing potential who are sexually active must agree to the use of two forms of contraception in combination (male condom and one highly effective method). These should be started immediately after signing the informed consent form and continued throughout the period of study treatment plus a substance-depending time period (see respective sub-protocol) for female patients and a substance-depending time period for male patients. Details on contraception and pregnancy testing for male and female patients (and if indicated their partners) under IMP treatment are described within the respective sub-protocol
  10. Ability of patient to understand and comply with the protocol for the duration of the study, including treatment and scheduled visits and examinations
  11. Adequate bone marrow, renal, and hepatic function defined by laboratory tests*

The biomarker-guided eligibility for the respective study arm is evaluated and determined exclusively by the NCT molecular tumor board on the basis of results of the COGNITION molecular diagnostic registry platform. Biomarkers that allow inclusion in the respective arm are:

  • Arm 1 (Atezolizumab, Immune Evasion ): PD-L1 positivity measure by IHC (≥1% on immune cells within the tumor), MSI-high status (validated by PCR), TMB-H (≥10mut/MB), CD274 amplification
  • Arm 2 (Inavolisib, PI3K): Known/reported oncogenic mutation in PIK3Ca
  • Arm 3 (Ipatasertib, AKT): Aberrations predicting increased PI3K-AKT pathway activity except PI3K-mutations, HR positive histology
  • Arm 4 (Olaparib, PARP, DNA-Repair): Inactivating somatic or germline BRCA1/2 mutation including homozygous deletions, Inactivating germline PALB2 mutations
  • Arm 5 (Sacituzumab Govitecan, TROP-2): Trop-2-overexpression (with IHC and except known/reported homozygous polymorphism in UGT1A1*28)
  • Arm 6 (Trastuzumab / Pertuzumab, ERBBB): HER2 exon-20 insertion, Activating HER2-mutation

Exclusion Criteria:

  1. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥ 5 year
  2. Concurrent severe, uncontrolled systemic disease that would place patient at undue risk or interfere with planned treatment
  3. Concurrent participation or previous treatment within 30 days in another interventional clinical trial
  4. Persistent toxicity (≥ Grade 2 according to NCI CTCAE v5.0 caused by previous cancer therapy, excluding alopecia
  5. Clinical signs of active infection (> Grade 2 according NCI CTCAE v5.0)
  6. History of or newly diagnosed human immunodeficiency virus (HIV) infection and immunocompromised patients
  7. Active Hepatitis A virus infection
  8. Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV DNA viral load per local guidelines
  9. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA
  10. Dementia or significant impairment of cognitive state
  11. Epilepsy requiring pharmacologic treatment
  12. Pregnancy and breast feeding
  13. Inability to take oral medication and gastrointestinal disorders likely to interfere with absorption of study medication
  14. Major surgery (any invasive operative procedure in which a more extensive resection is performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered) within four weeks before screening and baseline excluding breast-tumor resection after neoadjuvant chemotherapy. Patients must have recovered from any effects of any major surgery
  15. Systemic chemotherapy or radiotherapy within four weeks or a longer period depending on the characteristics of the agents used
  16. Heart failure classified as New York Heart Association (NYHA) II/III/IV
  17. Severe obstructive or restrictive ventilation disorder
  18. Patients with clinically active tuberculosis
  19. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug
  20. Is taking or requiring the continued use of any of the prohibited concomitant medications listed in the respective subprotocols at baseline
  21. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression or, superior vena cava syndrome.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT05332561

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Contact: Andreas Schneeweiss, Prof. Dr. +49(0)622156 ext 36051
Contact: Richard Schlenk, Prof. Dr.

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National Center for Tumor Diseases Recruiting
Heidelberg, Baden-Wuerttemberg, Germany, 69120
Contact: Andreas Schneeweiss, Prof. Dr.   
Universitätsklinikum Erlangen Not yet recruiting
Erlangen, Bayern, Germany, 91054
Contact: Peter Fasching, Prof. Dr.    +49 (0)9131 85 ext 33553   
Universitätsklinikum Ulm Not yet recruiting
Ulm, Bayern, Germany, 89075
Contact: Wolfgang Janni, Prof. Dr.    +49 (0)731 500 ext 58501   
Universitätsklinikum Carl-Gustav-Carus Not yet recruiting
Dresden, Sachsen, Germany, 01397
Contact: Pauline Wimberger, Prof. Dr.    +49 (0)351 458 ext 6728   
Charité - Universitätsmedizin Berlin Not yet recruiting
Berlin, Germany
Contact: Jens Blohmer, Prof. Dr.    +49 (0)30 450 564 ext 172   
Sponsors and Collaborators
German Cancer Research Center
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Principal Investigator: Andreas Schneeweiss, Prof. Dr. National Center for Tumor Diseases (NCT)
  Study Documents (Full-Text)

Documents provided by German Cancer Research Center:
Study Protocol  [PDF] April 12, 2023

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Responsible Party: German Cancer Research Center Identifier: NCT05332561    
Other Study ID Numbers: DKFZ-2019-008
2020-002606-22 ( EudraCT Number )
01EK2202A ( Other Grant/Funding Number: Federal Ministry of Education and Research (BMBF) )
First Posted: April 18, 2022    Key Record Dates
Last Update Posted: July 6, 2023
Last Verified: July 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by German Cancer Research Center:
Breast Cancer
Post-neoadjuvant therapy
molecular diagnostic
targeted therapy
high risk
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Sacituzumab govitecan
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Phosphoinositide-3 Kinase Inhibitors