JOURNAL ONKOLOGIE – STUDIE

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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

Studienbeginn:
Juni 2023

Letztes Update:
06.07.2023

Wirkstoff:
Atezolizumab 1200 MG in 20 ML Injection, Inavolisib, Ipatasertib, Olaparib, Sacituzumab govitecan, Trastuzumab/pertuzumab

Indikation (Clinical Trials):
Breast Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
German Cancer Research Center

Collaborator:
-

Studienleiter

Andreas Schneeweiss, Prof. Dr.
Principal Investigator
National Center for Tumor Diseases (NCT)

Kontakt

Andreas Schneeweiss, Prof. Dr.
Kontakt:
Phone: +49(0)622156
Phone (ext.): 36051
E-Mail: andreas.schneeweiss@med.uni-heidelberg.de» Kontaktdaten anzeigen

Richard Schlenk, Prof. Dr.
Kontakt:
E-Mail: richard.schlenk@nct-heidelberg.de» Kontaktdaten anzeigen

Studienlocations
(3 von 5)

National Center for Tumor Diseases
69120 Heidelberg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Andreas Schneeweiss, Prof. Dr.
E-Mail: andreas.schneeweiss@med.uni-heidelberg.de» Ansprechpartner anzeigen

Hautkrebszentrum Universitätsklinikum Erlangen
Ulmenweg 18
91054 Erlangen
(Bayern)
DeutschlandNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Peter Fasching, Prof. Dr.
Phone: +49 (0)9131 85
Phone (ext.): 33553
E-Mail: peter.fasching@uk-erlangen.de» Ansprechpartner anzeigen

Leberkrebszentrum Universitätsklinikum Ulm
Albert-Einstein-Allee 23
89081 Ulm
DeutschlandNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Wolfgang Janni, Prof. Dr.
Phone: +49 (0)731 500
Phone (ext.): 58501
E-Mail: Janni_Studien.UKF@uniklinik-ulm.de» Ansprechpartner anzeigen

Universitätsklinikum Carl-Gustav-Carus
01397 Dresden
(Sachsen)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Pauline Wimberger, Prof. Dr.
Phone: +49 (0)351 458
Phone (ext.): 6728
E-Mail: Pauline.Wimberger@uniklinikum-dresden.de» Ansprechpartner anzeigen

Charité - Universitätsmedizin Berlin
Berlin
(Berlin)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Jens Blohmer, Prof. Dr.
Phone: +49 (0)30 450 564
Phone (ext.): 172
E-Mail: jens.blohmer@charite.de» Ansprechpartner anzeigen

Alle anzeigen

Studien-Informationen

Detailed Description:

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.

To date, prospective whole genomic and transcriptomic sequencing in the framework of

precision oncology concepts is predominantly conducted in advanced-stage cancer, limiting the

overall benefit mainly to prolongation of progression-free survival rather than cure.

In contrast, the implementation of precision oncology in an early disease stage may empower

targeted intervention based on high throughput sequencing at a time point with low tumor

burden and limited clonal complexity, harbouring the prospect to substantially improve cure

rates by prohibition of incurable metastasis.

Whole-genome (WGS), whole exome (WES), gene panel and transcriptome sequencing in the

molecular diagnostic registry platform COGNITION (neoadjuvant-treated eBC patients) revealed

relevant diagnostic information on molecular-druggable alterations in a substantial

proportion of patients in different molecular pathways (e.g. phosphatidylinositol 3-kinase

(PI3K)/ serine/threonine kinase (AKT), Mitogen-activated protein kinase (MAPK), apoptosis,

DNA-repair, immune escape etc.).

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.

Eligible patients are identified considering pCR-status and clinical stage estrogen receptor

status grade (CPS-EG)-score following surgery after neoadjuvant therapy.

Allocation to the therapy-arms is conducted by in depth molecular characterization of tumors

within the COGNITION registry program.

Recruitment of adequate patient numbers in well-defined molecular subgroups is achieved in a

multicenter approach.

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

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:

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

Studien-Arme

Experimental: Arm 1 Atezolizumab (Immune Evasion)
Atezolizumab Dosage: 1200 mg, intravenous, on d1, q21d
Experimental: Arm 2 Inavolisib (PI3K)
Inavolisib Dosage: 9 mg, oral, on d1-d28, q28d
Experimental: Arm 3 Ipatasertib (AKT)
Ipatasertib Dosage: 400 mg, oral, on d1-d21, q28d
Experimental: Arm 4 Olaparib (PARP, DNA-Repair)
Olaparib Dosage: 300 mg, oral, bid d1-d28, q28d
Experimental: Arm 5 Sacituzumab Govitecan (TROP-2)
Sacituzumab Govitecan Dosage: 10 mg/kg BW, intravenous, on d1 and d8, q21d
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
No Intervention: Arm 7 Observation
Observation

Geprüfte Regime

Atezolizumab 1200 mg in 20 ML Injection (Tecentriq):
Arm 1
Inavolisib:
Arm 2
Ipatasertib:
Arm 3
Olaparib (Lynparza):
Arm 4
Sacituzumab govitecan (Trodelvy):
Arm 5
Trastuzumab/pertuzumab (Phesgo):
Arm 6

Quelle: ClinicalTrials.gov

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