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

Study Overview
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Brief Summary
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PELICAN is a randomised phase II trial that aims to evaluate the efficacy and safety of paclitaxel plus pembrolizumab relative to paclitaxel alone, in patients with locally advanced or metastatic ER-positive, HER2-negative, Luminal B breast cancer who have received no prior chemotherapy for advanced or metastatic disease. Patients will be randomised (2:1) to one of the two treatment arms: Pembrolizumab plus Paclitaxel Paclitaxel

Detailed Description
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PELICAN is a randomised phase II trial that aims to evaluate the efficacy and safety of paclitaxel plus pembrolizumab relative to paclitaxel alone, in patients with locally advanced or metastatic ER-positive, HER2-negative, Luminal B breast cancer who have received no prior chemotherapy for advanced or metastatic disease. Luminal B is defined as high Ki67 (≥20%) and /or histological grade 3 and / or Luminal B according to PAM50 assay. This study will include patients irrespective of PD-L1 expression, but patients will be stratified by centrally determined PD-L1 expression. The number of patients with PD-L1 negative tumours (<1% expression) will be capped at 50% of the total study population. Patients will be randomised (2:1) to one of the two treatment arms: Pembrolizumab every 3 weeks (Q3W) plus Paclitaxel on Days 1,8, and 15 every 28 days Paclitaxel on Days 1,8, and 15 every 28 days Paclitaxel alone Randomisation will be stratified by the following two factors: Centrally assessed PD-L1 expression (<1% PD-L1 expression; ≥1%) Presence vs non-presence of visceral metastases Paclitaxel treatment will be continued for at least 6 cycles unless there is evidence of unacceptable toxicity, disease progression, or if the patient requests to stop the treatment. If paclitaxel treatment is discontinued prior to disease progression, patients in the combination arm should continue pembrolizumab single agent therapy until progression or evidence of unacceptable toxicity up to a maximum of 2 years. If disease progression is documented (RECIST 1.1) while the patient is on study medication (in the pembrolizumab plus paclitaxel arm) it would be standard practice for the patient to be taken off study medication. However, in the absence of other discontinuation criteria, patients treated with paclitaxel plus pembrolizumab may be continued on study medication if in the opinion of the treating physician there is clinical benefit. In this case patients must meet all of the following criteria: Evidence of clinical benefit as assessed by the investigator Absence of symptoms and signs (including worsening of laboratory values [e.g., new or worsening hypercalcemia]) indicating clinically significant progression of disease No decline in Eastern Cooperative Oncology Group (ECOG) performance status that can be attributed to disease progression Absence of tumour progression at critical anatomical sites (e.g., leptomeningeal disease) that cannot be managed by protocol-allowed medical interventions (i.e., pain secondary to disease or unmanageable ascites, etc.), as determined by the investigator after an integrated assessment of radiographic data, biopsy results (if available), and clinical status. Pembrolizumab treatment will not exceed 2 years. Patients who were randomized to the paclitaxel alone must discontinue study treatment upon determination of progressive disease. No crossover is allowed. On completion of study treatment in both arms, patients will enter a survival follow-up period during which data on cancer therapy, disease status and survival status will be collected. Endocrine maintenance therapy is not permitted prior to disease progression.

Official Title
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A Phase II, Randomized Study of Paclitaxel Weekly Plus Pembrolizumab Versus Paclitaxel Weekly in ER-positive, Luminal B Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent Ability to comply with the protocol Female ≥ 18 years of age Histologically confirmed metastatic or locally advanced breast cancer that is: ER+ve defined as tumours with ≥1% of tumour cells positive for ER on IHC staining or an IHC score (Allred) of ≥ 3 and HER-2-ve defined as 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH and Luminal B defined as: high Ki67 defined as ≥20% and /or histological grade 3 and / or Luminal B according to PAM50 assay Patients must have: 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 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 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. ECOG performance status 0-1 Adequate haematologic and end-organ function within 28 days prior to the first study treatment defined by the following: ANC ≥ 1500 cells/μL (1.5 x 109/L) (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1) WBC > 2500/μL (2.5 x 109/L) Platelet count ≥ 100,000/μL (100 x 109/L) (without transfusion within 2 weeks prior to Cycle 1, Day 1) Haemoglobin ≥ 9.0 g/dL (90g/L) (patients may be transfused or receive erythropoietic treatment to meet this criterion). Serum albumin ≥ 3g/dL 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). Creatinine ≤ 1.5 x ULN 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. 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: Luminal A breast cancer Prior chemotherapy for advanced or metastatic disease Prior treatment with paclitaxel in the (neo)adjuvant setting within 12 months from the end of paclitaxel treatment and randomisation into this study Patients with neuropathy ≥ Grade 2 Previous systemic treatment for other neoplasms within 5 years prior to randomisation. Patients with prior allogeneic stem cell or solid organ transplantation. 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. 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. 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 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. 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. 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) requiring steroids, or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted). Active infection requiring systemic therapy. 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. Known history of active tuberculosis 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. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol. Concurrent treatment with other experimental drugs or participation in another clinical trial with therapeutic intent within 28 days prior to randomisation. Pregnant and lactating female patients. 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. 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) 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Paclitaxel<br>200 mg Pembrolizumab intravenously (IV) every 3 weeks (Q3W) plus 80 mg/m2 paclitaxel intravenously (IV) on Days 1,8, and 15 of each 28 day cycle. | Drug: Pembrolizumab<br>* 200 mg Pembrolizumab intravenously (IV) every 3 weeks (Q3W).<br>* Other names: lambrolizumab;Drug: Paclitaxel<br>* 80 mg/m2 paclitaxel intravenously (IV) on Days 1,8, and 15 of each 28 day cycle.<br>* Other names: Taxol;|
| Active Comparator: Paclitaxel<br>80 mg/m2 paclitaxel intravenously (IV) on Days 1,8, and 15 of each 28 day cycle. | Drug: Paclitaxel<br>* 80 mg/m2 paclitaxel intravenously (IV) on Days 1,8, and 15 of each 28 day cycle.<br>* Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression (using RECIST 1.1) or death from any cause, whichever occurs first. To be used for both the overall patient population and in patients with PD-L1-positive tumours. | Date of randomisation to date of first tumour progression or death, whichever came first, assessed up to 30 months. | 
| Overall Survival | Overall Survival is defined as the time from date of randomisation to the date of death due to any cause in all patients. To be used for both the overall patient population and in patients with PD-L1-positive tumours. | Date of randomisation to date of death, assessed up to 30 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates | Objective Response Rate is defined as the proportion of the patients in the analysis population who have a CR or PR (using RECIST 1.1). To be used for both the overall patient population and in patients with PD-L1-positive tumours. | Date of first documentation of CR or PR or to the date of first documented tumour progression (using RECIST 1.1) or death from any cause, whichever occurs first, assessed up to 30 months. | 
| Duration of Response | Duration of Response is defined as the time from first documentation of CR or PR to the date of first documented tumour progression (using RECIST 1.1) or death from any cause, whichever occurs first. To be used for both the overall patient population and in patients with PD-L1-positive tumours. | Date of first documentation of CR or PR to the date of first documented tumour progression (using RECIST 1.1) or death from any cause, whichever occurs first, assessed up to 30 months. | 
| Clinical Benefit Rates | Clinical Benefit Rate is defined as the percentage of patients who have achieved at least one CR or PR or met the SD criteria at least once after randomisation for a minimum interval of 24 weeks (using RECIST 1.1). To be used for both the overall patient population and in patients with PD-L1-positive tumours. | Date of randomisation to date of first tumour progression or death, whichever occurs first, assessed over a minimum of 24 weeks and up to 30 months. | 
| Duration of Clinical Benefit | Duration of Clinical Benefit is calculated as time (in months) from randomisation to progression or death from any cause in patients with a clinical benefit. To be used for both the overall patient population and in patients with PD-L1-positive tumours. | Date of randomisation to date of first tumour progression or death, whichever occurs first, assessed up to 30 months. | 
| Safety and tolerability of paclitaxel plus pembrolizumab versus paclitaxel through review of all AEs and SAEs assessed by CTCAE v4.03 | Incidence, nature and severity of adverse events with severity determined according to CTCAE v4.03 | Date of randomisation to date of all adverse event resolution following discontinuation for any reason or death, assessed up to 30 months. | 
| Changes in quality of life (QoL) as assessed by time to deterioration (TTD) in patient reported outcomes (PROs) in patients treated with paclitaxel plus pembrolizumab versus paclitaxel | Measured by the time to deterioration (TTD) in Items 29 and 30 of the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and the percentages of patients with a decrease or increase of ≥ 10 points on the global health status/HRQoL scale of the EORTC QLQ-C30, respectively | Date of randomisation to date of safety visit (125 days after date of discontinuation for any reason) | 
| Changes in quality of life (QoL) as assessed by the global health status/HRQoL scale of the EORTC QLQ-C30 on patient reported outcomes (PROs) in patients treated with paclitaxel plus pembrolizumab versus paclitaxel | Measured by the percentages of patients with a decrease or increase of ≥ 10 points on the global health status/HRQoL scale of the EORTC QLQ-C30 | Date of randomisation to date of safety visit (125 days after date of discontinuation for any reason) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ER-positive, Metastatic, Locally Advanced, Ki67, PAM50, Pembrolizumab, Paclitaxel, HER2-negative