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JOURNAL ONKOLOGIE – STUDIE
neoMono

Study to Compare a Mono Atezolizumab Window Followed by a Atezolizumab - CTX Therapy With Atezolizumab - CTX Therapy

Rekrutierend

NCT-Nummer:
NCT04770272

Studienbeginn:
März 2021

Letztes Update:
03.03.2021

Wirkstoff:
Atezolizumab 840 MG in 14 ML Injection, Atezolizumab 1200 MG in 20 ML Injection, Carboplatin, Paclitaxel, Epirubicin, Cyclophosphamide

Indikation (Clinical Trials):
Breast Neoplasms, Triple Negative Breast Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Palleos Healthcare GmbH

Collaborator:
Roche Pharma AG, Phaon Scientific GmbH, University Hospital, Essen, University Hospital Erlangen,

Studienleiter

Iris Reiser, Dr.
Study Director
Palleos Healthcare GmbH
Hans-Christian Kolberg, PD Dr.
Principal Investigator
Marienhospital Bottrop gGmbH; Klinik für Frauenheilkunde und Geburtshilfe; 46236 Bottrop

Kontakt

Studienlocations
(1 von 1)

Marienhospital Bottrop gGmbH; Klinik für Frauenheilkunde und Geburtshilfe;
46236 Bottrop
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps

Studien-Informationen

Brief Summary:

This is a randomized, open-label, adaptive, two arm, multicentre, Phase II trial comparing a

neoadjuvant chemotherapy with PDL1-inhibition (Atezolizumab) and Atezolizumab two-week window

to chemotherapy with PDL1-inhibition (Atezolizumab) and identify biomarkers predicting

(early) response to or resistance against Atezolizumab (alone and with CTX) allowing patients

stratification in future clinical trials

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Female and male patients, age at diagnosis 18 years and above

- Written informed consent prior to admission to this study

- Histologically confirmed unilateral primary invasive carcinoma of the breast

- Clinical T1c - T4d

- Stage N0-N3 until 21 patients (5%) with stage N3 are randomized, thereafter N0-N2

- Triple negative breast cancer defined by and confirmed by central pathology:

- ER negative (<10% positive cells in IHC) and PR negative (<10% positive cells on

IHC)

- HER2 negative breast cancer:

- Either defined by IHC: ICH scores of 0-1 or an ICH score of 2 in combination

with a negative in-situ-hybridization (ISH)

- Or defined by ISH: negative ISH

- Identifiable PD-L1 IC-status by central pathology (positive or negative) by means of

VENTANA PD-L1 (SP142) Assay; positive status is defined by PD-L1 expression on IC on ≥

1% of the tumor area, negative status is defined by PD-L1 expression on IC on < 1% of

the tumor area

- No clinical evidence for distant metastasis (cM0)

- Tumor block available for translational research

- Performance Status ECOG ≤ 1 or KI ≥ 80 %

- Negative pregnancy test (urine or serum) within 7 days prior to screening in

premenopausal patients

- Women of childbearing potential and male patients with partners of childbearing

potential must accept to implement a highly effective (less than 1% failure rate

according to Pearl index) including at least one non-hormonal contraceptive measures

during the study treatment and for 5 months following the last dose of study treatment

such as:

- Intrauterine device (IUD)

- bilateral tubal occlusion

- vasectomised partner

- sexual abstinence

- The patient must be accessible for treatment and follow-up

- Normal cardiac function:

- Normal ECG (within 6 weeks prior to screening)

- Normal LVEF on Echocardiorgaphy

- Normal thyroid function

o Normal TSH and FT4

- Blood counts within 14 days prior screening:

- ANC must be ≥ 1500/mm3

- Platelet count must be ≥ 100,000 / mm3

- Hemoglobin must be ≥ 10g/dl

- Hepatic functions:

- Total bilirubin must be ≤ ULN for the lab unless the patient has a bilirubin

elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome

involving slow conjugation of bilirubin

- Alkaline phosphatase must be ≤2,5 X ULN for the lab

- AST and ALT must be ≤1, 5 ULN for the lab.

- Patients with AST and ALT or alkaline phosphatase > ULN are eligible for

inclusion if liver Imaging (CT, MRI, PET-CT, or PET scan) performed within 3

months prior to screening (and part of standard of care) does not demonstrate

metastatic disease and the requirements in criterion (just above) are met

- Patients with alkaline phosphatase that is > ULN but less than or equal to 2, 5 X

ULN or with unexplained bone pain are eligible if bone imaging does not

demonstrate metastatic disease.

- Creatinine clearance ≥ 40 ml/min performed 28 days prior to screening

Exclusion Criteria:

- Previous history of malign diseases, non-melanoma skin cancer and carcinoma of the

cervix are allowed if treated with curative intent

- Any other disease, metabolic dysfunction, physical examination finding, or clinical

laboratory finding that, in the investigator's opinion, gives reasonable suspicion of

a disease or condition that contraindicates the use of paclitaxel, carboplatin,

epirubicin, cyclophosphamide or Atezolizumab

- Psychological, familial, sociological or geographical conditions that do not permit

compliance with the study protocol

- Concurrent treatment with other drugs that are contraindicating the use of the study

drugs

- Existing pregnancy

- Breastfeeding

- Sequential breast cancer

- Concurrent treatment with other experimental drugs and participation in another

clinical trial or clinical research project within 30 days prior to study entry

- Severe and relevant co-morbidity that would interact with the application of cytotoxic

agents or the participation in the study including but not confined to:

- Uncompensated chronic heart failure or systolic dysfunction (LVEF < 55%, CHF NYHA

classes II-IV),

- unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart

rate ≥ 100/min at rest, significant ventricular arrhythmia (ventricular

tachycardia) or highergrade AV-block,

- Angina pectoris within the last 6 months requiring anti-anginal medication,

- Clinically significant valvular heart disease,

- Evidence of myocardial infarction on electrocardiogram (ECG),

- Poorly controlled hypertension (e.g., systolic > 180 mm Hg or diastolic > 100 mm

Hg).

- Inadequate organ function including but not confined to:

- hepatic impairment as defined by bilirubin > ULN x 1,5

- pulmonary disease (severe dyspnea at rest requiring oxygen therapy)

- Abnormal blood values:

- Platelet count below 100,000/mm3

- AST/ALT > 1, 5 ULN

- Hypokalaemia > CTCAE grade 1

- Neutropenia > CTCAE grade 1

- Anaemia > CTCAE grade 1

- Administration of a live, attenuated vaccine within 4 weeks before cycle 1 day 1 or

anticipation that such a vaccine will be required during the study

- Treatment with systemic immunosuppressive medications (including but not limited to

interferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is longer,

prior to randomization.

- Treatment with systemic immunosuppressive medications (including but not limited to

prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor

necrosis [anti-TNF] factor agents) within 14 days prior to screening or anticipation

of need for systemic immunosuppressive medications during the study

- Patients with prior allogeneic stem cell or solid organ transplantation

- Active or history of autoimmune disease or immune deficiency, including but not

limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus

erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid

syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or

multiple sclerosis with the following exceptions:

- Patients with a history of autoimmune-related hypothyroidism on a stable dose of

thyroid replacement hormone may be eligible for this study.

- Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin

regimen may be eligible for this study.

- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with

dermatologic manifestations only (e.g., patients with psoriatic arthritis are

excluded) are permitted provided all of following conditions are met: Rash must

cover < 10% of body surface area; Disease is well controlled at baseline and

requires only low-potency topical corticosteroids; No occurrence of acute

exacerbations of the underlying condition requiring psoralen plus ultraviolet A

radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,

or high-potency or oral corticosteroids within the previous 12 months.

- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis

obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active

pneumonitis on screening chest CT scan.

- History of HIV infection, hepatitis B or hepatitis C infection.

- Patients with significant cardiovascular disease

- Patients with inadequate hematological and end-organ function

- Patients receiving therapeutic anti-coagulants

- Stage N3, as soon as 21 patients with stage N3 are randomized

Studien-Rationale

Primary outcome:

1. Pathological complete response (ypT0/is, ypN0) (Time Frame - after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.):
Pathological Complete Response defined as residual invasive tumor cells not only in the breast but also in the Lymph Nodes (ypT0/is, ypN0)



Secondary outcome:

1. Safety Measures (Time Frame - from date of randomization up to 59 months):
Safety (incidence, relationship, seriousness, and severity of all AEs, SAEs, AESIs coded by MedDRA, summarized by Preferred Term and System Organ Class and graded according to CTCAE v5.0)

2. Pathological Complete Response (ypT0/is, ypN0) (ER/PR expression of <1%) (Time Frame - after 29-30 weeks in Arm A and after 27-28 weeks in Arm B):
Pathological complete response defined as residual invasive tumor cells not only in the breast but also in the Lymph Nodes (ypT0/is, ypN0) in patients with an ER/PR expression of <1% and an ER/PR expression of 1% to 10%.

3. Pathological Complete Response (ypT0, ypN0) (Time Frame - after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.):
Pathological complete response defined as no invasive and no non-invasive tumor cells not only in the breast but also in the lymph nodes (ypN0, ypT0)

4. Near Pathological Complete Response (Near pCR) (Time Frame - after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.):
Near pCR defined as residual tumor <5 mm in the breast irrespective of in situ and lymph nodes status

5. Pathological Complete Response (no invasive tumor) (Time Frame - after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.):
Pathological Complete Response defined as no invasive tumor in the breast, irrespective of lymph node status

6. Decrease of Ki-67 as continuous predictor (Time Frame - after 14/28 days (+/- 2 days) of treatment):
Decrease of Ki-67 versus baseline after 14/28 days (+/- 2 days) of treatment as continuous predictor

7. Tumor-infiltrating lymphocytes (TILs) (Time Frame - after 14/28 days (+/- 2 days) of treatment):
TILs after 14/28 days (+/- 2 days) of treatment as continuous predictor

8. Complete Cell Cycle Arrest (CCCA) (Time Frame - after 14/28 days (+/- 2 days) of treatment):
CCCA: Ki-67 ≤ 2.7%

9. Low cellularity (Time Frame - after 14/28 days (+/- 2 days) of treatment):
Low cellularity: < 500 tumor cells

10. Decrease of Ki-67 (Time Frame - after 14/28 days (+/- 2 days) of treatment):
Decrease of Ki-67 versus baseline by 30% or more

11. Tumor-infiltrating lymphocytes (TILs) ≥ 60% (Time Frame - after 14/28 days (+/- 2 days) of treatment):
TILs ≥ 60% after 14/28 days (+/- 2 days) of treatment

12. Combined early response (Time Frame - after 14/28 days (+/- 2 days) of treatment):
Combined early response defined by CCCA (Ki-67< 2.7%) or low cellularity or decrease of Ki-67 (versus baseline) by 30% or more or TILs ≥ 60%

13. Disease free survival (DFS) (Time Frame - from randomization up to 59 months until date of occurrence of no disease to the first occurrence of disease recurrence or death from any cause):
Disease free survival (DFS) defined as time from the first date of no disease [i.e. date of surgery] to the first occurrence of disease recurrence or death from any cause

14. Overall survival (OS) (Time Frame - from randomization up to 59 months until date of death from any cause):
Overall survival (OS) defined as length of time from randomization to death from any cause

15. Event free survival (EFS) (Time Frame - from randomization up to 59 months until date of death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy):
Event free survival (EFS) defined as length of time after randomization till death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy

Studien-Arme

  • Experimental: Arm A
    2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
  • Active Comparator: Arm B
    12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.

Geprüfte Regime

  • Atezolizumab 840 MG in 14 ML Injection (Tecentriq):
    840 mg Day 1 for two weeks
  • Atezolizumab 1200 MG in 20 ML Injection (Tecentriq):
    1200 mg Day 1 every 3 weeks for 8 cycles
  • Carboplatin:
    Dosing according to Area Under the Curve of 2 Intravenous weekly x 12 cycles
  • Paclitaxel:
    Paclitaxel 80 mg/m² IV weekly x 12 cycles
  • Epirubicin:
    90 mg/m2, day 1 for 4 cycles (12 weeks)
  • Cyclophosphamide:
    600 mg/m2, day 1 for 4 cycles (12 weeks)
  • Biopsy Arm A:
    1st Biopsy two weeks after Baseline visit. 2nd Biopsy after two weeks of Carboplatin + Paclitaxel + Atezolizumab therapy. 3rd Biopsy with tumor size greater 10 mm in diameter.
  • Biopsy Arm B:
    1st Biopsy after two weeks of Carboplatin + Paclitaxel + Atezolizumab therapy. 2nd Biopsy with tumor size greater 10mm in diameter.
  • Surgery:
    After completion of 27-28 weeks (Arm B) or 29-30 weeks (Arm A) of neoadjuvant treatment, surgery is planned for all patients.

Quelle: ClinicalTrials.gov


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