Paclitaxel Plus Pembrolizumab vs. Paclitaxel Weekly in ER+ Luminal B Metastatic Breast Cancer (PELICAN)

This is an interventional treatment trial for Breast Cancer focused on measuring ER-positive, Metastatic, Locally Advanced, Ki67, PAM50, Pembrolizumab, Paclitaxel, HER2-negative Read More

Inclusion Criteria:

1. Willing and able to provide written informed consent
2. Ability to comply with the protocol
3. Female ≥ 18 years of age

4. Histologically confirmed metastatic or locally advanced breast cancer that is:

   1. ER+ve defined as tumours with ≥1% of tumour cells positive for ER on IHC staining or an IHC score (Allred) of ≥ 3 and
   2. HER-2-ve defined as 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH and
   3. Luminal B defined as: high Ki67 defined as ≥20% and /or histological grade 3 and / or Luminal B according to PAM50 assay

5. Patients must have:

   1. at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or
   2. lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible
6. Representative formalin-fixed paraffin embedded (FFPE) breast tumour samples with an associated pathology report from the primary or recurrent cancer that are determined to be available and sufficient for central testing OR tumour accessible for biopsy.
7. ECOG performance status 0-1

8. Adequate haematologic and end-organ function within 28 days prior to the first study treatment defined by the following:

   1. ANC ≥ 1500 cells/μL (1.5 x 109/L) (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
   2. WBC > 2500/μL (2.5 x 109/L)
   3. Platelet count ≥ 100,000/μL (100 x 109/L) (without transfusion within 2 weeks prior to Cycle 1, Day 1)
   4. Haemoglobin ≥ 9.0 g/dL (90g/L) (patients may be transfused or receive erythropoietic treatment to meet this criterion).
   5. Serum albumin ≥ 3g/dL
   6. AST or ALT and ALP ≤ 2.5 times the institutional upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN (patients with liver metastases who have AST or ALT ≤ 5 x the institutional ULN may be enrolled, and patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled).
   7. Creatinine ≤ 1.5 x ULN
   8. INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
9. Patients of childbearing potential are eligible provided they have a negative serum or urine pregnancy test on Day 1 Cycle 1 (within 72 hours) 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, (see section 6.13) beginning 14 days before the first dose of study drug and for 3 months after the last dose of study drug.

Exclusion Criteria:

1. Luminal A breast cancer
2. Prior chemotherapy for advanced or metastatic disease
3. Prior treatment with paclitaxel in the (neo)adjuvant setting within 12 months from the end of paclitaxel treatment and randomisation into this study
4. Patients with neuropathy ≥ Grade 2
5. Previous systemic treatment for other neoplasms within 5 years prior to randomisation.
6. Patients with prior allogeneic stem cell or solid organ transplantation.
7. Prior treatment with CD137 agonists, AKT inhibitors, anti-CTLA-4, anti-OX-40, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
8. Patients must not have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent), or had oral or IV steroids for 7 days prior to the first dose of study drug; the use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e. for adrenal insufficiency) and mineralocorticoids (e.g. fludrocortisone) is allowed.
9. 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).
10. Administration of a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
11. 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 randomisation.
12. 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.
13. History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung disease), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia) requiring steroids, or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
14. Active infection requiring systemic therapy.
15. History of HIV infection
16. 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.
17. Known history of active tuberculosis
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 randomisation in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.