PAveMenT: Palbociclib and Avelumab in Metastatic AR+ Triple Negative Breast Cancer
- Conditions
- Triple Negative Breast CancerLocally Advanced Breast CancerRecurrent Breast CancerMetastatic Breast CancerER+ Breast CancerHER2-positive Breast Cancer
- Interventions
- Registration Number
- NCT04360941
- Lead Sponsor
- Royal Marsden NHS Foundation Trust
- Brief Summary
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.
- Detailed Description
This is a phase Ib study designed to confirm the safety and evaluate the efficacy of palbociclib combined with avelumab in AR positive TNBC. It is a multi-centre study design (it will run at several hospitals in the UK).
Palbociclib inhibits two proteins involved in cell growth called cyclin dependent kinase 4 and cyclin dependent kinase 6 (CDK4/6). Inhibiting CDK4/6 stops cells, such as cancer cells, from dividing and multiplying further. Palbociclib is currently approved for the treatment of metastatic HR positive HER2 negative breast cancer, based on good results from large clinical trials. Laboratory studies have shown that palbociclib might be also useful in some patients with triple negative breast cancer, an aggressive subtype of breast cancer that does not express the hormone receptors or HER2 receptor, but only if the cancer is positive for the androgen-receptor (AR).
Avelumab is an immunotherapy drug which does not destroy cancer cells, but tries to stimulate the body's immune system to do this. Avelumab has been tested in a number of different types of tumours including breast cancer, but although approved for use in the USA, it is not currently an approved standard treatment in the UK. The combination of both drugs has never been tested in humans before.
Recruitment to Part A will be conducted only at the Royal Marsden Hospital and Part A of the study will establish the maximum tolerated dose (MTD) and optimal schedule of the combination in any suitable patients with advanced breast cancer. Once this dose schedule has been confirmed, the chosen dose level will be recruited to, aiming to include 27 patients with AR positive TNBC (Part B).Part B will recruit at up to 8 high volume centres. The androgen receptor is not routinely tested for in hospital laboratories, so patients with advanced triple negative breast cancer who are interested in taking part in the study will be asked to provide consent for previously taken cancer samples/biopsies to be sent to the Royal Marsden for testing, to see if the cancer expresses the androgen receptor, which would make participants potentially eligible for part B of the study. Approximately 20% of triple negative breast cancers express AR. This phase of the study will include important translational work using new cancer samples (biopsies) and blood samples to investigate potential "biomarkers" -predictors of efficacy and resistance to the combination.
In Part A of the study, patients with previously treated, advanced breast cancer will have an ECG (heart trace) a CT scan of the body and potentially an MRI scan of the brain and a bone scan (depending upon where the breast cancer is known to have spread to) as well as blood tests to determine if participants are suitable for the study.
During the study participants will receive daily palbociclib tablets and intravenous infusions of avelumab every two weeks. Participants will be monitored with regular blood tests and repeat CT scans every 8 weeks. At whatever time point the treatment stops working, the patient will stop treatment and will be asked to have further blood tests one month later as well as a check up with the study doctor.
In Part B of the study, patients with triple negative histology and positive androgen receptor status tested at the Royal Marsden will be required to have a cancer biopsy before participants start treatment on the study. LIke in Part A, participants will also have an ECG (heart trace)a CT scan of the body and potentially an MRI scan of the brain and a bone scan (depending upon where the breast cancer is known to have spread to) as well as blood tests to determine if participants are suitable for the study. During the study participants will receive daily palbociclib tablets and intravenous infusions of avelumab every two weeks. Participants will be monitored with regular blood tests and check-ups with the study doctor and repeat CT scans every 8 weeks as well as additional blood tests for research. After 3 weeks of treatment, the patient may have a further tumour biopsy, which is optional. At whatever timepoint the treatment stops working, the patient will stop treatment and will be asked to have further blood tests and a further biopsy. Participants will also have a check-up with the study doctor and blood tests one month later.
A maximum of 45 breast cancer patients will be enrolled; up to 18 patients in part A and 27 patients with AR+ triple negative breast cancer in part B.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 45
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Two-part phase 1b trial of induction palbociclib with avelumab Avelumab Recruitment to Part A will be conducted at the Royal Marsden Hospital only. Up to 18 patients will be recruited for dose escalation of palbociclib in combination with fixed dose avelumab. Part B will recruit at up to 8 high volume centres. Up to 27 patients will be recruited to treatment with the maximum tolerated dose and schedule established in part A. In Part B of the study, additional selection by triple negative histology and positive androgen receptor status will define the study population. Two-part phase 1b trial of induction palbociclib with avelumab Palbociclib Recruitment to Part A will be conducted at the Royal Marsden Hospital only. Up to 18 patients will be recruited for dose escalation of palbociclib in combination with fixed dose avelumab. Part B will recruit at up to 8 high volume centres. Up to 27 patients will be recruited to treatment with the maximum tolerated dose and schedule established in part A. In Part B of the study, additional selection by triple negative histology and positive androgen receptor status will define the study population.
- Primary Outcome Measures
Name Time Method Part A: Determine maximum tolerated dose (MTD) of palbociclib plus avelumab in advanced breast cancer 18 month recruitment period 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 Up to 24 month recruitment period Response rate assessed by RECIST 1.1 by local radiology review
- Secondary Outcome Measures
Name Time Method Determine the clinical benefit rate (CR/PR/SD for a minimum of 24 weeks) in AR+ TNBC patients treated with palbociclib plus avelumab Total 42 month recruitment period Clinical benefit rate (response or stable disease lasting at least 24 weeks), assessed by RECIST 1.1 by local radiology review.
Assess overall survival in both parts A & B Total 42 month recruitment period Overall survival, calculated from day 1 of study treatment to the date of death from any cause.
Determine the median PFS in AR+ TNBC patients treated with palbociclib plus avelumab Total 42 month recruitment period 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 Total 42 month recruitment period 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.
Trial Locations
- Locations (8)
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, Greater Manchester, United Kingdom
Addenbrooke's Hospital Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, United Kingdom
Barts Cancer Institute
🇬🇧London, United Kingdom
Royal Marsden NHS Foundation Trust
🇬🇧London, United Kingdom
Nottingham University Hospital
🇬🇧Nottingham, United Kingdom
Weston Park Hospital
🇬🇧Sheffield, United Kingdom