Impact of eHealth-support on Quality of Life in Metastatic Breast Cancer Patients Treated With Palbociclib and Endocrine Therapy

PRECYCLE: Multicenter, Randomized Phase IV Intergroup Trial to Evaluate the Impact of eHealth-based Patient Reported Outcome (PRO) Assessment on Quality of Life in Patients With Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer Treated With Palbociclib and an Aromatase Inhibitor- or Palbociclib and Fulvestrant

In this study the investigators assess the impact of the eHealth-supported therapy management system CANKADO on Quality of Life in patients with HR+, HER2-locally advanced or metastatic breast cancer treated with the cyclin dependent kinase 4/6 (CDK4/6) Inhibitor Palbociclib in combination with an aromatase inhibitor or fulvestrant. Furthermore this approach will be combined with biomarker screening to identify predictive markers for and to learn more about adherence, symptoms, response, and resistance.

This is a multicenter (80 sites) , randomized, parallel-group, Phase IV clinical trial with the primary objective of testing the hypothesis of superiority for time to deterioration (TTD) in patients using the ePRO system CANKADO active over CANKADO inform version.

Eligible patients will have histologically or cytologically proven diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)- negative locally advanced or metastatic breast cancer and will be either candidates to receive palbociclib in combination with aromatase inhibitor or candidates to receive palbociclib in combination with fulvestrant for their locally advanced or metastatic disease. Patients who are candidates for palbociclib in combination with aromatase inhibitor (AI) or fulvestrant will not be candidates for curative therapies. For Patients who are candidates for palbociclib in combination with aromatase inhibitor or fulvestrant one prior line of chemotherapy for locally advanced or metastatic breast cancer is allowed in addition to a maximum of two lines of endocrine therapy. Patients will be stratified according their eligibility of receiving palbociclib with endocrine therapy (AI or fulvestrant) as first or later lines.

Patients allocated to the combination of palbociclib with aromatase inhibitor will receive:

• Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment and
• Aromatase inhibitor, orally once-daily (continuously).
• Pre- or peri-menopausal patients should additionally receive a Gonadotropin-Releasing-Hormon (GnRH)-agonist

Patients allocated to the combination of palbociclib with fulvestrant will receive:

• Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment and
• Fulvestrant , 500 mg, intramuscularly on Days 1 and 14 of Cycle 1, every 28 days (± 7 days) thereafter starting.
• Pre- or peri-menopausal patients should additionally receive a Gonadotropin-Releasing-Hormon (GnRH)-agonist

Patients of each treatment group (palbociclib / aromatase inhibitor and palbociclib/fulvestrant) will randomized 2:1 in the Intervention Arm A CANKADO active is the fully functional CANKADO-based eHealth treatment support service, including a high density observation of patient reported outcome (HDOB-PRO).

And in the Control Arm B CANKADO inform stands for a CANKADO-based eHealth service with a personal login. On-site surveys without feedback functions for the patient will be available. CANKADO inform will be used for the initial ePRO and further on-site ePROs. Patients can login from at home and can document their drug intake. Further features will not be available.

Patients will continue to receive study treatment together with the assigned ePRO assessment until investigator assessed disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. In addition, should palbociclib related toxicity mandate discontinuation; patients can continue to receive fulvestrant alone.

Patients discontinuing the active treatment phase will enter a follow-up period phase during survival further progression and new anti-cancer therapy information will be collected once a year up to 48 month after randomization.

In addition biomarkers will be assessed as a scientific program within this study. Tumor material (tumor tissue and Blood samples (plasma and serum)) will be collected. Tumor tissue from available primary tumor and available biopsies from recurrent disease will be collected. Blood samples will be collected at four time points (cycle 1 (C1D1), after 2 weeks (C1D14), after 12 weeks (C4D1), and upon progression (End of treatment).

Inclusion Criteria:

1. Post- or pre/peri-menopausal female patients, age ≥18 years
2. Patients with metastatic or locally advanced (non-operable) breast cancer disease
3. Patients who are appropriate candidates for aromatase inhibitor + palbociclib combination therapy OR Patients having already received endocrine therapy who are appropriate candidates for fulvestrant+ palbociclib combination therapy
4. Patient has not received treatment for locally advanced or metastatic disease OR Patient has received one prior line of chemotherapy and/or a maximum of two endocrine therapy lines for locally advanced or metastatic disease
5. Peri-/pre-menopausal patients should additionally receive a GnRH-agonist..
6. The tumor must be hormone-receptor positive
7. The tumor must be HER2-negative defined as either HER2 immunohistochemistry Score 0 or 1+ or as HER2-negative by in situ hybridization..
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
9. Adequate organ and marrow function before palbociclib treatment starts on C1D.
10. In case of patients of child bearing potential: negative pregnancy test (urine or serum) at baseline. Patients must agree to use highly effective non-hormonal contraception
11. Resolution of all acute toxic effects of prior therapy, including radiotherapy grade <1 (except toxicities not considered a safety risk for the patient) and recovery from surgical procedures
12. Signed Written Informed Consent
13. Willingness and capability to use CANKADO
14. Availability of hardware: Computer and/or tablet and/or smartphone with internet access

Exclusion Criteria:

1. Known hypersensitivity to aromatase inhibitor, fulvestrant, palbociclib or any of its excipients
2. Contraindication for aromatase inhibitor, fulvestrant or palbociclib; or GnRH-agonists (if pre-menopausal)
3. Prior treatment with any inhibitor of cyclin dependent kinase (CDK).
4. Patients with locally advanced or metastatic, symptomatic, visceral spread, who are at risk of life threatening complications in the short term
5. Known active uncontrolled or symptomatic central nervous system metastases
6. Current use of food or drugs known to be potent inhibitors or inducers of Cytochrome P450 3A4 (CYP3A4)
7. High cardiovascular risk, including, but not limited to recent myocardial infarction, severe/unstable angina, or severe cardiac dysrhythmias in the past 6 months of enrollment
8. Diagnosis of any second malignancy within the last 5 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix
9. Participation in other clinical trials involving investigational drug(s) (Phases 1-4) within 2 weeks before the current study begins and/or during study participation
10. Lactating women
11. Life expectancy < 3 months
12. Known infection with HIV, hepatitis B virus, or hepatitis C virus
13. Concurrent severe, uncontrolled systemic disease, social or psychiatric condition that might interfere with the planned treatment and with the patient's adherence to the protocol
14. Legal incapacity or limited legal capacity.