| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced and or metastatic breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced and or metastatic breast cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate superiority w.r.t. time to deterioration (TTD) of quality of life for patients with eHealth-based high density observation using CANKADO (CANKADO active) versus eHealth-based static observation on site (CANKADO inform). |
|
| E.2.2 | Secondary objectives of the trial |
i. Sensitivity Analysis: To compare TTD DQoL between the two treatment arms in terms of DQoL as minimally important difference (5-point drop on FACT-G).
ii. To demonstrate that an eHealth-based high density observation using CANKADO does not have a negative impact on clinical outcome (PFS, OS).
iii. To analyze the effect of patient reported outcome (PRO; data of daily drug intake behavior, global health status, quality of life) w.r.t. clinical outcome (PFS, OS) and DQoL
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Women 18 years of age or older, who are either:
• Post-menopausal, as defined by at least one of the following criteria:
- Age ≥ 60 years;
- Age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; or serum
estradiol and FSH level within the laboratory’s reference range for post-menopausal females;
- Documented bilateral oophorectomy;
- Medically confirmed ovarian failure.
OR
- Pre/peri-menopausal, i.e., not meeting the criteria for being postmenopausal.
- Pre/peri-meopausal women can be enrolled if amenable to be treated with a
LHRH-agonist. Patients should be treated with a LHRH-agonist.
2. Patients have to have metastatic disease or locally advanced (non-operable) breast cancer disease.
3. Patients who are appropriate candidates for aromatase inhibitor + palbociclib combination
OR
Patients having already received endocrine therapy who are appropriate candidates for fulvestrant + palbociclib combination therapy
4. Patient has not received prior treatment of 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 LHRH-agonist
6. The tumor has to be hormone-receptor positive (ER-positive and/or PR-positive tumor (≥ 1% positive stained cells).
7. The tumor has to be HER2-negative defined as either HER2 immunohistochemistry Score 0 or 1+ or as HER2-negative by ISH.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
9. Adequate organ and bone marrow function confirmed before palbociclib treatment start on C1D1, evidenced by the following laboratory results below:
- absolute neutrophil count ≥ 1500 cells/μL,
platelet count ≥ 100000 cells/μL,
- hemoglobin ≥ 9 g/dL
- ALT (SGPT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
- AST (SGOT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
- bilirubin ≤ 1.5 × ULN (with the exception of Gilbert’s syndrome)
- creatinine ≤ 2.0 mg/dl or 177μmol/L
10. In case of patients of child bearing potential:
Negative pregnancy test (urine or serum) at baseline (within 7 days prior to randomization). Patient must agree to use highly effective non-hormonal contraceptive methods that result in a failure rate of < 1% per year, (intrauterine device (IUD), bilateral tubal occlusion, vasectomised partner1, sexual abstinence2 ) beginning 2 weeks before the first dose of investigational medicinal product (IMP) and for 2 years after the last dose of study treatment.
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. Patients who are able and willing to sign the informed consent form
13. Willingness and capability to use CANKADO
14. Availability of hardware: Computer and/or tablet and/or smartphone with internet access |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Known hypersensitivity to aromatase inhibitor, fulvestrant, Palbociclib or any of its excipients
1 Provided that the partner is the sole sexual partner of the patient and that the vasectomised partner has
received medical assessment of the surgical success.
2 Sexual abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
2. Contraindication for aromatase inhibitor, fulvestrant or palbociclib; or LHRH-agonists if pre-menopausal
3. Prior treatment with any CDK inhibitor.
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 CNS metastases
6. Current use of food or drugs known to be potent inhibitors or inducers of 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 prior to enrollment.
8. Diagnosis of any second malignancy within the last 3 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 studies 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• TTD (time to deterioration) with respect to DQoL (deterioration of quality of life as a 10-point drop on FACT-G)
Time to deterioration (TTD) with respect to DQoL is defined as the difference between time of treatment allocation (randomization) and time of DQoL. Patients not meeting deterioration criteria are to be censored at death or a maximum of 48 months of follow-up after treatment allocation.
The event “deterioration of quality of life” (DQoL) is defined as any decrease of 10 or more points from baseline in QoL as assessed using the FACT-G scale, unless a recovery is achieved in the subsequent assessment. A recovery is defined as a QoL score no worse than 9 points below baseline. If data of the subsequent visit is missing, a decrease of 10 or more points will be considered as event.
The definition of DQoL as a 10-point decrease on the FACT-G scale is based on Cella et al. (2002) and corresponds to a mean change from baseline in a subgroup of various cancer patients who classified the change as “minimally worse” according to a global rating of change (GRC) scale administered immediately after the FACT-G.
Note that Eton et al. (2004) also suggested a 5-6 points change on FACT-G as minimally important difference (MID) in metastatic breast cancer patients. It is expected that the conservative choice of a 10-point decrease will be more robust against less meaningful fluctuations of the QoL measurement time series in the context of the precycle trial.
A definition of DQoL in terms of MID (5-point decrease on FACT-G) will be used for sensitivity analyses in a dedicated secondary objective. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients in Arm A have to complete the EQ-VAS scale and document their drug intake daily. Additionally a FACT-B questionnaire can be triggered if the reported health status on the EQ-VAS scale changes by 10 or more score points in comparison to the mean value of the last three days or over a period of seven days compared to the mean value of seven days before.
Patients in Arm B will be provided with FACT-B questionnaire on-site and can document the daily drug intake.
For both study arms patients have to fill in the FACT-B questionnaire on-site on day 1 of every planned study visit during active treatment phase. In the event of dose interruptions when patients must come on-site more often than for the scheduled visits they may also be requested to complete the FACT-B questionnaire. |
|
| E.5.2 | Secondary end point(s) |
Secondary Objectives:
i. Sensitivity Analysis: To compare TTD DQoL between the two treatment arms in terms of DQoL as minimally important difference (5-point drop on FACT-G).
ii. To demonstrate that an eHealth-based high density observation using CANKADO does not have a negative impact on clinical outcome (PFS, OS).
iii. To analyze the effect of patient reported outcome (PRO; data of daily drug intake behavior, global health status, quality of life) w.r.t. clinical outcome (PFS, OS) and DQoL.
Endpoints:
• PFS (progression-free survival)
• OS (overall survival)
• DQoL (deterioration of quality of life)
Progression-free survival (PFS) is considered to be the main clinical outcome and is defined as the time between treatment allocation and either first documentation of objective progression of disease (PD, as assessed by Investigator) or death due to any cause in absence of PD.
Overall survival is defined as the time between treatment allocation and death due to any cause.
The event “deterioration of quality of life” (DQoL) is defined as any decrease of 10 or more points from baseline in QoL as assessed using the FACT-G scale, unless a recovery is achieved in the subsequent assessment. A recovery is defined as a QoL score no worse than 9 points below baseline. If data of the subsequent visit is missing, a decrease of 10 or more points will be considered as event.
The definition of DQoL as a 10-point decrease on the FACT-G scale is based on Cella et al. (2002) and corresponds to a mean change from baseline in a subgroup of various cancer patients who classified the change as “minimally worse” according to a global rating of change (GRC) scale administered immediately after the FACT-G.
Note that Eton et al. (2004) also suggested a 5-6 points change on FACT-G as minimally important difference (MID) in metastatic breast cancer patients. It is expected that the conservative choice of a 10-point decrease will be more robust against less meaningful fluctuations of the QoL measurement time series in the context of the precycle trial.
A definition of DQoL in terms of MID (5-point decrease on FACT-G) will be used for sensitivity analyses in a dedicated secondary objective.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Outcome Measure(s) and Timepoint(s):
- PFS (progression-free survival): every 3 months as long as under study treatment
- OS (overall survival): every 12 months under study treatment and during follow up phase
- DQoL (deterioration of quality of life): every 28 days as long sa under study treatment
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| To assess the impact of an eHealth-supported therapy management on Quality of Life in patients treated with Palbociclib in combination with endocrine therapy with HR+, HER2-advanced/metastatic breast cancer |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| CANKADO active versus CANKADO inform |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 80 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
A participant is considered to have completed the study if she has completed the active treatment phase until objective investigator assessed disease progression and survival follow-up until end of study visit scheduled at the end of month 48 calculated from randomization or patient’s death whatever occurs first.
The end of the study is defined as the date of the end of treatment visit of the last participant in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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