Clinical Trials /

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

NCT04770272

Description:

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

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study to Compare a Mono Atezolizumab Window Followed by a Atezolizumab - CTX Therapy With Atezolizumab - CTX Therapy
  • Official Title: An Adaptive Randomized Neoadjuvant Two Arm Trial in Triple-negative Breast Cancer Comparing a Mono Atezolizumab Window Followed by a Atezolizumab - CTX Therapy With Atezolizumab - CTX Therapy (neoMono)

Clinical Trial IDs

  • ORG STUDY ID: Phaon1
  • NCT ID: NCT04770272

Conditions

  • Triple-negative Breast Cancer

Interventions

DrugSynonymsArms
Atezolizumab 840 MG in 14 ML InjectionTecentriqArm A
Atezolizumab 1200 MG in 20 ML InjectionTecentriqArm A
CarboplatinArm A
PaclitaxelArm A
EpirubicinArm A
CyclophosphamideArm A

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimental2 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.
  • Atezolizumab 840 MG in 14 ML Injection
  • Atezolizumab 1200 MG in 20 ML Injection
  • Carboplatin
  • Paclitaxel
  • Epirubicin
  • Cyclophosphamide
Arm BActive Comparator12-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.
  • Atezolizumab 1200 MG in 20 ML Injection
  • Carboplatin
  • Paclitaxel
  • Epirubicin
  • Cyclophosphamide

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response (ypT0/is, ypN0)
Time Frame:after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
Safety Issue:
Description: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 Measures

Measure:Safety Measures
Time Frame:from date of randomization up to 59 months
Safety Issue:
Description: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)
Measure: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
Safety Issue:
Description: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%.
Measure:Pathological Complete Response (ypT0, ypN0)
Time Frame:after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
Safety Issue:
Description: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)
Measure:Near Pathological Complete Response (Near pCR)
Time Frame:after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
Safety Issue:
Description:Near pCR defined as residual tumor <5 mm in the breast irrespective of in situ and lymph nodes status
Measure:Pathological Complete Response (no invasive tumor)
Time Frame:after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
Safety Issue:
Description:Pathological Complete Response defined as no invasive tumor in the breast, irrespective of lymph node status
Measure:Decrease of Ki-67 as continuous predictor
Time Frame:after 14/28 days (+/- 2 days) of treatment
Safety Issue:
Description:Decrease of Ki-67 versus baseline after 14/28 days (+/- 2 days) of treatment as continuous predictor
Measure:Tumor-infiltrating lymphocytes (TILs)
Time Frame:after 14/28 days (+/- 2 days) of treatment
Safety Issue:
Description:TILs after 14/28 days (+/- 2 days) of treatment as continuous predictor
Measure:Complete Cell Cycle Arrest (CCCA)
Time Frame:after 14/28 days (+/- 2 days) of treatment
Safety Issue:
Description:CCCA: Ki-67 ≤ 2.7%
Measure:Low cellularity
Time Frame:after 14/28 days (+/- 2 days) of treatment
Safety Issue:
Description:Low cellularity: < 500 tumor cells
Measure:Decrease of Ki-67
Time Frame:after 14/28 days (+/- 2 days) of treatment
Safety Issue:
Description:Decrease of Ki-67 versus baseline by 30% or more
Measure:Tumor-infiltrating lymphocytes (TILs) ≥ 60%
Time Frame:after 14/28 days (+/- 2 days) of treatment
Safety Issue:
Description:TILs ≥ 60% after 14/28 days (+/- 2 days) of treatment
Measure:Combined early response
Time Frame:after 14/28 days (+/- 2 days) of treatment
Safety Issue:
Description: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%
Measure: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
Safety Issue:
Description: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
Measure:Overall survival (OS)
Time Frame:from randomization up to 59 months until date of death from any cause
Safety Issue:
Description:Overall survival (OS) defined as length of time from randomization to death from any cause
Measure: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
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Palleos Healthcare GmbH

Trial Keywords

  • TNBC
  • Immunotherapy

Last Updated

March 3, 2021