BIG 14-04

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A phase II, multicentre clinical trial of palbociclib in combination with fulvestrant in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer whose disease has progressed after prior endocrine therapy (1st or 2nd line)

PYTHIA will assess whether there are any molecular predictors of response to the combination of a drug called palbociclib, with standard endocrine treatment for a subtype of advanced (metastatic) breast cancer called “luminal”.

Palbociclib is a drug that may stop cancer cells from growing. It blocks the activity of two closely related enzymes (proteins that help chemical reactions occur in the body), called cyclin D kinases 4 and 6 (CDK 4/6). These proteins are part of a pathway, or a sequence of steps, which is known to regulate cell growth. Laboratory testing has suggested that palbociclib may stop the growth of breast cancer cells of the luminal subtype.

The endocrine therapy in this study consists of fulvestrant.

The standard treatment for the luminal subtype of breast cancer is endocrine therapy: this is a therapy that prevents breast cancer cell growth by blocking oestrogen stimulation. Despite its success, some patients still develop recurrence of their disease.

Previous clinical studies have shown that patients with endocrine sensitive breast cancer may have better results when treated with a combination of palbociclib and endocrine therapy rather than endocrine therapy alone.

The aim of PYTHIA is to evaluate the anti-tumour activity (how well the treatment works), safety and tolerability (how severe the side effects are) of the combination of palbociclib and fulvestrant (endocrine treatment) in postmenopausal women with HR+ / HER2- metastatic breast cancer whose disease has progressed after prior endocrine therapy.

The study will focus on investigating the predictive utility of several molecular abnormalities that could influence the sensitivity to the provided treatment combination.

More specifically, since PYTHIA is a downstream trial of the AURORA research programme, an extensive molecular characterisation of tumour tissues will be done for all patients participating in the study.

Coupling of this molecular data with the clinical outcomes of patients receiving the PYTHIA study treatment will allow us to identify specific molecular abnormalities that could possibly predict treatment outcomes.

Results from the pre-planned biomarker analysis performed on the 122 patients enrolled in the PYTHIA trial were presented on December 9 at the San Antonio Breast Cancer Symposium (SABCS) 2020 by Dr Luca Malorni, Principal Investigator of the study and Medical Oncologist at the Prato Hospital, Italy. 

They were published on 14 February 2022 in the European Journal of Cancer

The prospective analysis revealed that serum thymidine kinase activity (TKa) may be an independent prognostic biomarker in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant, helping doctors to identify those patients who will develop primary resistance to the treatment. 

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PYTHIA is a single-arm trial: all patients enrolled in the study receive the palbociclib plus fulvestrant treatment.

They will be treated until disease progression, lack of tolerability, or if the patient declines further protocol treatment: the duration of the therapy may thus be different for each patient.
Biological samples (blood and tissue) from the metastatic tumour will be collected and analysed according to the requirements of the AURORA programme.

The study is open to patients who already take part in the AURORA programme and who are postmenopausal with an endocrine-resistant (ER+ HER2-) metastatic or locally relapsed breast cancer, whose disease has progressed after prior endocrine therapy (1st or 2nd line).

The recruitment was completed on 28 May 2019 with a total of 122 patients from 19 hospitals in Europe were enrolled in this study.

This study is conducted and sponsored by the International Breast Cancer Study Group (IBCSG), in collaboration with the Breast International Group (BIG).

Recruitment opened at the end of August 2016 and completed in May 2019. Results of the biomarker analysis were presented at the San Antonio Breast Cancer Symposium 2020.

19 hospitals in Belgium, Italy and the United Kingdom are participating.

PYTHIA is made possible by research grants and drugs provided by Pfizer (palbociclib) and AstraZeneca (fulvestrant). BIOVICA supplied support for sample handling and thymidine kinase assays.

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