Clinical Trials /

Pre-operative Immunotherapy Combination Strategies in Breast Cancer

NCT03395899

Description:

International, open label, window of opportunity phase II trial that aims to evaluate the effects of immunotherapy based treatment combinations in women with untreated, histologically confirmed, operable, ER+, HER2-negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pre-operative Immunotherapy Combination Strategies in Breast Cancer
  • Official Title: A Phase II Study Investigating Preoperative Combination Strategies for Immunotherapy in Patients With Untreated, Operable ER+, HER2-negative Primary Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 011604QM
  • SECONDARY ID: 2016-004424-38
  • NCT ID: NCT03395899

Conditions

  • Breast Cancer
  • Estrogen Receptor-positive Breast Cancer

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab alone
CobimetinibAtezolizumab + Cobimetinib
IpatasertibAtezolizumab + Ipatasertib
BevacizumabAtezolizumab + Ipatasertib + Bevacizumab

Purpose

International, open label, window of opportunity phase II trial that aims to evaluate the effects of immunotherapy based treatment combinations in women with untreated, histologically confirmed, operable, ER+, HER2-negative breast cancer.

Detailed Description

      ECLIPSE is an international, open label, window of opportunity phase II trial that aims to
      evaluate the effects of immunotherapy based treatment combinations in women with untreated,
      histologically confirmed, operable, ER+, HER2-negative breast cancer. The study is designed
      with the flexibility to open new treatment arms as new treatments become available, or modify
      the patient population e.g. with regards to biomarker status. Only combinations with adequate
      safety data will be tested. The trial will include Luminal B and non-Luminal B patients
      irrespective of PD-L1 status, but the number of patients with non-Luminal B tumours will be
      capped at 50% of the total study population. Luminal B tumours will be defined as high Ki67
      (≥20%) and/or histological grade 3 or alternatively defined via PAM50 assay. All other types
      will be defined as non-Luminal B.

      Eligible patients will be randomised with an approximately equal ratio (1:1:1:1) to one of
      four treatment arms (three experimental arms: (1) Atezolizumab + Cobimetinib, (2)
      Atezolizumab + Ipatasertib, (3) Atezolizumab + Cobimetinib + Bevacizumab and a control arm:
      Atezolizumab alone. Additional patients may be enrolled to ensure balance among treatment
      arms with respect to demographic and baseline characteristics, including potential predictive
      biomarkers, to enable further subgroup analysis. Thereafter, the randomisation ratio will
      depend on the number of experimental arms that are open for enrolment (e.g. if an arm is
      added or enrolment in an arm is suspended pending analysis of results. Randomisation will
      take into account arm-specific exclusion criteria and patients will be ineligible for a
      specific arm if they meet any of the exclusion criteria outlined for that arm.

      Patients will receive treatment for 3 weeks prior to surgery or neoadjuvant therapy.
      Thereafter, patients will either be considered for definitive surgery or primary medical
      treatment (e.g. neoadjuvant chemotherapy) at the discretion of the treating physician.
      Surgery or neoadjuvant chemotherapy should be started within 3 weeks (±3 days) from the start
      of the study treatment. Patients will not be allowed to receive endocrine therapy prior to
      surgery.
    

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab aloneActive Comparator1200mg of Atezolizumab D1 C1
  • Atezolizumab
Atezolizumab + CobimetinibExperimentalAtezolizumab (1200mg IV D1 C1) + Cobimetinib (60mg PO D1 - 21 of C1)
  • Atezolizumab
  • Cobimetinib
Atezolizumab + IpatasertibExperimentalAtezolizumab (1200mg IV D1 C1)+ Ipatasertib (400mg OD D1 - 21 of C1)
  • Atezolizumab
  • Ipatasertib
Atezolizumab + Ipatasertib + BevacizumabExperimentalAtezolizumab (1200mg IV D1 C1)+ Cobimetinib (60mg PO D1 - 21 of C1) + Bevacizumab (10mg/kg IV D1 C1)
  • Atezolizumab
  • Ipatasertib
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Willing and able to provide written informed consent prior to study entry

          2. Female ≥ 18 years of age

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 21

          4. Histologically confirmed operable primary breast cancer

          5. Palpable breast tumour of any size, or tumour with an ultrasound / MRI size of ≥ 1 cm
             or mammogram

          6. ER+ tumours defined as tumours with ≥1% of tumour cells positive for ER on IHC
             staining or an IHC score (Allred) of ≥ 3

          7. HER2-negative tumours defined as 0, 1+ or 2+ intensity on IHC and no evidence of
             amplification of the HER2 gene on ISH.

          8. Patients with either: (a) Luminal B breast cancer defined as: high Ki67 defined as
             ≥20% and /or histological grade 3 and / or Luminal B according to PAM50 assay or (b)
             Non-Luminal B breast cancer

          9. Adequate haematologic and end-organ function within 28 days prior to the first study
             treatment

         10. Patients of childbearing potential are eligible provided they have a negative serum or
             urine pregnancy test within 14 days of Day 1 Cycle 1 of study treatment, preferably as
             close to the first dose as possible. Patients must agree to use adequate
             contraception, defined as those methods with a failure rate of < 1 % per year, (IUD,
             oral contraceptive, sub dermal implant and double barrier (condom with a contraceptive
             sponge or contraceptive pessary) beginning 14 days before the first dose of study drug
             and for 5 months after the last dose of investigational product .

         11. Ability to comply with the protocol

         12. Representative formalin-fixed paraffin embedded (FFPE) breast tumour samples with an
             associated pathology report that are determined to be available and sufficient for
             central testing OR tumour accessible for biopsy.

        Exclusion Criteria:

          1. Inflammatory breast cancer

          2. Concurrent use of HRT (HRT users must stop HRT a minimum of 28 days before the
             baseline diagnostic biopsy is taken).

          3. Previous systemic or local treatment for the new primary breast cancer currently under
             investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments);
             prior treatment for previous breast cancer or other neoplasms is allowed as long as it
             was completed ≥1 year prior to Day 1 Cycle 1.

          4. Previous systemic treatment for other neoplasms within 1 year prior to randomisation..

          5. Patients with prior allogeneic stem cell or solid organ transplantation.

          6. Prior treatment with CD137 agonists, AKT inhibitors, anti-CTLA-4, anti−programmed
             death−1 (PD-1), or anti−PD-L1 therapeutic antibody or pathway-targeting agents.

          7. Patients must not have had oral or IV steroids for 14 days prior to study entry; the
             use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e.
             for adrenal insufficiency) and mineralocorticoids (e.g. fludrocortisone) is allowed.

          8. Received therapeutic oral or intravenous antibiotics within 14 days prior to
             randomisation (Patients receiving prophylactic antibiotics (e.g., for prevention of a
             urinary tract infection or chronic obstructive pulmonary disease) are eligible).

          9. Administration of a live, attenuated vaccine (e.g., FluMist®) within 28 days prior to
             randomisation, treatment, or within 5 months following the last dose of atezolizumab.

         10. Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or interleukin [IL] −2) within 28days or five half-lives of the drug,
             whichever is shorter, prior to enrolment.

         11. History of autoimmune disease including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis. Patients with
             autoimmune-related hypothyroidism on a stable dose of thyroid replacement therapy may
             be eligible for the study following discussion with the medical monitor.

         12. History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung
             disease), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis
             obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on
             screening chest CT scan (History of radiation pneumonitis in the radiation field
             (fibrosis) is permitted).

         13. History of HIV infection

         14. Known active hepatitis infection (defined as having a positive hepatitis B surface
             antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B
             virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg
             test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are
             eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
             polymerase chain reaction (PCR) is negative for HCV RNA.

         15. Active tuberculosis

         16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

         17. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the atezolizumab formulation.

         18. 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 an investigational drug, may
             affect the interpretation of the results, render the patient at high risk from
             treatment complications or interferes with obtaining informed consent.

         19. Psychological, familial, sociological or geographical conditions that do not permit
             compliance with the study protocol.

         20. Concurrent treatment with other experimental drugs or participation in another
             clinical trial with therapeutic intent within 28 days prior to randomisation.

         21. Pregnant and lactating female patients.

         22. Major surgical procedure within 4 weeks prior to randomisation or anticipation of need
             for a major surgical procedure during the course of the study other than for
             diagnosis.

         23. Malignancies other than breast cancer within 5 years prior to Cycle 1, Day 1, with the
             exception of those with a negligible risk of metastasis or death and treated with
             expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
             basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically
             with curative intent)

         24. Severe infections within 28 days prior to enrolment in the study including but not
             limited to hospitalization for complications of infection, bacteraemia, or severe
             pneumonia.

         25. Significant cardiovascular disease, such as history of symptomatic congestive heart
             failure New York Heart Association cardiac disease (Class II or greater with a LVEF
             <50% by either ECHO or MUGA), myocardial infarction within 3 months prior to
             enrolment, severe cardiac arrhythmia requiring medication or severe conduction
             abnormalities, unstable arrhythmias, acute coronary syndromes (including unstable
             angina), or history of coronary angioplasty/stenting/bypass grafting within past 6
             months.

         26. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes
             controlled on a stable insulin regimen are eligible .

         27. Evidence of bleeding diathesis or coagulopathy.

        Exclusion criteria for Atezolizumab + Cobimetinib arm

          1. Inability to swallow medication or malabsorption condition that would alter the
             absorption of orally administered medications.

          2. History of or symptoms of neurosensory retinal detachment, central serous
             chorioretinopathy, retinal vein occlusion or neovascular macular degeneration.

          3. Patients will be excluded from the study if they are currently known to have any of
             the following risk factors for ocular toxicity: (a) History of or ongoing serous
             retinopathy; (b) History of retinal vein occlusion (RVO)

        Exclusion criteria for Atezolizumab + Ipatasertib arm

          1. Inability to swallow medication or malabsorption condition that would alter the
             absorption of orally administered medications.

          2. Clinically significant abnormalities of glucose metabolism

          3. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative
             colitis) or active bowel inflammation (e.g., diverticulitis).

          4. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5
             drug-elimination half-lives, whichever is longer, prior to initiation of study drug.

        Exclusion criteria for Atezolizumab + Cobimetinib + Bevacizumab arm

          1. Inability to swallow medication or malabsorption condition that would alter the
             absorption of orally administered medications.

          2. Known history or symptoms of neurosensory retinal detachment, central serous
             chorioretinopathy, retinal vein occlusion or neovascular macular degeneration.

          3. Patients will be excluded from the study if they are known to have any of the
             following risk factors for ocular toxicity: (a) History of or ongoing serous
             retinopathy; (b) History of retinal vein occlusion (RVO)

          4. Uncontrolled hypertension defined by systolic pressure > 150 mmHg and/or diastolic
             pressure > 110 mmHg, with or without anti-hypertensive medication Patients with
             initial blood pressure elevations are eligible if initiation or adjustment of
             anti-hypertensive medication lowers blood pressure to meet entry criteria.

          5. History of stroke or transient ischemic attack within 6 months prior to randomisation

          6. Clinically significant peripheral vascular disease (e.g., aortic aneurysm requiring
             surgical repair or recent peripheral arterial thrombosis) within 6 months prior to
             randomisation

          7. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months prior to randomisation.

          8. History of haemoptysis (≥ 1/2 teaspoon of bright red blood per episode) or other
             serious haemorrhage or at risk of bleeding (gastrointestinal history of bleeds,
             gastrointestinal ulcers etc.) within 1 month prior to randomisation .

          9. Patients who have had major surgery (or where surgical wounds have not healed) within
             28 days prior to C1 D1.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:2-fold Increase in GzmB+ CD8+ T cell levels
Time Frame:Baseline and at 3weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Status and changes of the biomarkers listed below in pre- and end-of treatment tumour and/or blood samples: Immunephenotyping, CD8, PD-L1, MHC-I
Time Frame:Baseline and at 3weeks
Safety Issue:
Description:
Measure:Percentage change in Ki67 expression between pre- and end of study-treatment tumour biopsies
Time Frame:Baseline and at 3weeks
Safety Issue:
Description:
Measure:Percentage change in caspase3 expression
Time Frame:Baseline and at 3weeks
Safety Issue:
Description:
Measure:Incidence, nature and severity of adverse events with severity determined according to CTCAE v4.03.
Time Frame:Consent to 135 days after last dose of atezolizumab
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Queen Mary University of London

Trial Keywords

  • Atezolizumab
  • Bevacizumab
  • Cobimetinib
  • Ipatasertib
  • pre-operative
  • Window of opportunity

Last Updated

January 4, 2018