Pre-operative Immunotherapy Combination Strategies in Breast Cancer

NCT03395899 | Completed Phase 2 DMC

• 2 other identifiers: 011604QM2016-004424-38
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Breast Cancer; Estrogen Receptor-positive Breast Cancer

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 2-fold Increase in GzmB+ CD8+ T cell levels

  Baseline and at 3weeks

Secondary Outcomes (4)

• Status and changes of CD8 in pre- and end-of treatment tumour and/or blood samples

  Baseline and at 3weeks

• Status and changes of PD-L1 in pre- and end-of treatment tumour and/or blood samples

  Baseline and at 3weeks

• Percentage change in Ki67 expression between pre- and end of study-treatment tumour biopsies

  Baseline and at 3weeks

• Percentage change in caspase3 expression

  Baseline and at 3weeks

Study Arms (4)

Atezolizumab alone

ACTIVE COMPARATOR

1200mg of Atezolizumab D1 C1

Drug: Atezolizumab

Atezolizumab + Cobimetinib

EXPERIMENTAL

Atezolizumab (1200mg IV D1 C1) + Cobimetinib (60mg PO D1 - 21 of C1)

Drug: Atezolizumab; Drug: Cobimetinib

Atezolizumab + Ipatasertib

EXPERIMENTAL

Atezolizumab (1200mg IV D1 C1)+ Ipatasertib (400mg OD D1 - 21 of C1)

Drug: Atezolizumab; Drug: Ipatasertib

Atezolizumab + Ipatasertib + Bevacizumab

EXPERIMENTAL

Atezolizumab (1200mg IV D1 C1)+ Cobimetinib (60mg PO D1 - 21 of C1) + Bevacizumab (10mg/kg IV D1 C1)

Drug: Atezolizumab; Drug: Ipatasertib; Drug: Bevacizumab

Interventions

Atezolizumab DRUG

PD-L1 antibody

Atezolizumab + Cobimetinib; Atezolizumab + Ipatasertib; Atezolizumab + Ipatasertib + Bevacizumab; Atezolizumab alone

Cobimetinib DRUG

Highly selective small-molecule inhibitor of MEK1 and MEK2

Atezolizumab + Cobimetinib

Ipatasertib DRUG

Selective, ATP-competitive small molecule inhibitor of all three isoforms of the serine/threonine kinase Akt

Atezolizumab + Ipatasertib; Atezolizumab + Ipatasertib + Bevacizumab

Bevacizumab DRUG

Highly specific humanized monoclonal antibody that targets VEGF

Atezolizumab + Ipatasertib + Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent prior to study entry
• Female ≥ 18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 21
• Histologically confirmed operable primary breast cancer
• Palpable breast tumour of any size, or tumour with an ultrasound / MRI size of ≥ 1 cm or mammogram
• ER+ tumours defined as tumours with ≥1% of tumour cells positive for ER on IHC staining or an IHC score (Allred) of ≥ 3
• HER2-negative tumours defined as 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH.
• 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
• Adequate haematologic and end-organ function within 28 days prior to the first study treatment
• 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 .
• Ability to comply with the protocol
• 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.

You may not qualify if:

• Inflammatory breast cancer
• Concurrent use of HRT (HRT users must stop HRT a minimum of 28 days before the baseline diagnostic biopsy is taken).
• 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.
• Previous systemic treatment for other neoplasms within 1 year prior to randomisation..
• Patients with prior allogeneic stem cell or solid organ transplantation.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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).
• History of HIV infection
• 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.
• Active tuberculosis

Sponsors & Collaborators

• Queen Mary University of London: lead
• Kliniken Essen-Mitte: collaborator
• MedSIR: collaborator
• Asan Medical Center: collaborator
• Hoffmann-La Roche: collaborator

Study Sites (1)

Barts Health NHS Trust

London, EC1M 6BQ, United Kingdom

Location

Related Publications (1)

• Schmid P, Kockx M, Kim S-B et al Dynamic changes of PD-L1 and T-cell activation in ECLIPSE: A phase II study investigating preoperative immune combination strategies in untreated, operable ER+ primary breast cancer. Cancer Res February 15 2021 (81) (4 Supplement) PD14-06.

  RESULT

MeSH Terms

Conditions

Breast Neoplasms

Interventions

atezolizumab; cobimetinib; ipatasertib; Bevacizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Peter Schmid

  Queen Mary University of London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: No masking - open label
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2017
• First Posted: January 10, 2018
• Study Start: December 21, 2017
• Primary Completion: August 18, 2023
• Study Completion: August 18, 2023
• Last Updated: June 18, 2024

Record last verified: 2024-06

Locations

GB (1)