This clinical study is aiming to determine the safest doses and schedule for the combination of two drugs named palbociclib and avelumab.
The study will also be investigating how effective the combination is for a subgroup of breast cancer patients whose cancer expresses the androgen receptor (AR) but not the oestrogen (hormone) or HER2 receptors. Palbociclib is a drug used in routine care for hormone-receptor (HR) positive and HER2 negative advanced breast cancer, the most common subtype of breast cancer.
It is possible that the combination of palbociclib and avelumab will be a more effective cancer treatment than each drug separately, but this is unknown and this study is needed to establish the best dosage and schedule of each drug as well as how effective the combination is.
Patients with recurrent inoperable locally advanced or metastatic breast cancer.
Previously treated with at least one prior line of chemotherapy for advanced disease, but no more than two prior lines of chemotherapy for advanced disease. Patients with ER+ breast cancer must have received at least one prior line of hormone therapy for advanced disease. Patients with HER2+ breast cancer must have received at least one prior line of HER2 directed therapy.
Measurable disease (RECIST 1.1)
Haematological and biochemical indices within the ranges stated in the study protocol. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
Oral chemotherapy within two weeks, weekly iv chemotherapy within three weeks or any other systemic chemotherapy or investigational medicinal products during the previous four weeks.
Hormonal therapy within 7 days except luteinizing hormone-releasing hormone (LHRH) analogues for ovarian suppression. Bisphosphonates or RANK ligand antagonists are permitted for the management of bone metastases.
Previous exposure to immune checkpoint inhibitors or immune co-stimulatory drugs in the advanced setting. (Note: Patients who have received neoadjuvant and/or adjuvant pembrolizumab are eligible if treatment was completed at 6 months prior to metastatic relapse.)
Previous treatment with palbociclib or any agents which inhibit CDK4/6. (Note: Patients who have received adjuvant abemaciclib or ribociclib for early breast cancer are eligible if treatment was completed at least 12 months prior to metastatic relapse.)
Single group
Palbociclib
DrugHighly selective oral inhibitor of CDK4 and CDK6.
Avelumab
DrugFully human IgG1 monoclonal antibody (mAb) binds to the PD-L1 cell surface ligand and blocks its interaction with the PD-1 cell surface receptor.
Part A: Determine maximum tolerated dose (MTD) of palbociclib plus avelumab in advanced breast cancer
Define MTD of palbociclib delivered in combination with avelumab
Part B: Determine the confirmed objective response rate of AR+ TNBC patients treated with palbociclib plus avelumab
Response rate assessed by RECIST 1.1 by local radiology review
Determine the clinical benefit rate (CR/PR/SD for a minimum of 24 weeks) in AR+ TNBC patients treated with palbociclib plus avelumab
Clinical benefit rate (response or stable disease lasting at least 24 weeks), assessed by RECIST 1.1 by local radiology review.
Determine the median PFS in AR+ TNBC patients treated with palbociclib plus avelumab
Progression-free survival, calculated from day 1 of study treatment to the date of radiological disease progression or death from any cause.
Assess the safety and tolerability of palbociclib plus avelumab by recording adverse events until 30 days after the last dose of either study treatment
Overall safety and tolerability of palbociclib with avelumab. Toxicity will be assessed by CTCAE (version 5) every 4 weeks during study treatment. Adverse events, including serious adverse events, will be recorded until 30 days after the last dose of study treatment with palbociclib or avelumab.
Assess overall survival in both parts A & B
Overall survival, calculated from day 1 of study treatment to the date of death from any cause.
RR in patients with PAM50 luminal archival primary tumours compared to PAM50 non luminal as a potential alternative companion diagnostic
Objective response rate in PAM50 luminal tumours compared to PAM50 non-luminal tumours
Determine the RR in patients with PD-L1 positive compared to PDL-1 negative tumours
Objective response rate in PDL-1 positive compared to PDL-1 negative tumours
Determine the RR in patients with high versus low mutational load
Objective response rate in high mutational load tumours compared to low mutational load tumours
Determine the RR in patients with high tumour infiltrating lymphocytes (TILs) in the baseline and on-treatment biopsy compared to low TILs.
Objective response rate in high TILs tumours compared to low TILs tumours at baseline and at D15
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