Studieoverzicht - 2017-03 SONIA

Primary objective:

• to evaluate if treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition in first line followed at progression by fulvestrant in second line (strategy A) improves progression-free survival compared to treatment with a non-steroidal aromatase inhibitor in first line followed at progression by fulvestrant combined with CDK4/6 inhibition in second line (strategy B) in women with HR+/HER2- metastatic breast cancer who have not received any prior systemic anti-cancer therapy for metastatic disease

Secondary objectives:

• to compare overall survival (OS);
• to compare quality of life;
• to compare safety and tolerability;
• to compare objective response rate (ORR);
• to compare cost-effectiveness;
• to determine alterations in genes, proteins, and (mi)RNAs in tumor tissues in order to select patients primary resistant to single agent first line endocrine therapy;
• to determine circulating tumor DNA (ctDNA) in plasma before and during treatment, to investigate the prognostic and possibly predictive values of these measures;
• to evaluate the predictive value of nuclear imaging for palbociclib benefit;
• to develop a limited sampling model for palbociclib pharmacokinetics (PK), investigate the relationship between palbociclib PK exposure and common side-effects and determine the prevalence of polymorphisms in CYP3A4 and SULT2A1.

Primary endpoint:

• primary endpoint is progression-free survival after two lines of treatment (PFS2) defined as time from randomization until objective disease progression, symptomatic deterioration, or initiation of a new therapeutic agent on second line treatment, death, or progression during a break in therapy and without further therapy within one month, whichever occurs first.

Secondary endpoints

-          overall survival

-          quality of life

-          safety and tolerability

-          objective response rate (ORR)

-          Cost-effectiveness will be determined using a healthcare and societal perspective.

Costs will be computed for the following categories:

i. Direct health care related costs

a. within the hospital (costs of the drug palbociclib, admissions to the  hospital, day-care treatment, additional treatments such as palliative radiotherapy and outpatient visits because of (bone-marrow) toxicity);

b. outside the hospital (health care professionals such as GP, other medical facilities, concomitant medication)

ii. Direct non-health care related costs (travelling expenses and informal care)

iii. Indirect non-healthcare related costs (productivity losses).

-          type and incidence of grade 3 and 4 (serious) adverse events ((S)AE) (as graded by      
           NCI CTCAE v4.0) and its relation to study medications.

-          tumor tissue biomarkers, including genes, proteins and (mi)RNA expression

-          circulating tumor DNA (ctDNA) in plasma

-          nuclear imaging, including FDG-PET and FES-PET

-          Pharmacokinetics, -dynamics and -genomics of palbociclib

Main eligibility criteria:

Patients must meet the following inclusion criteria to be eligible for enrollment:

1.       Adult women (≥ 18 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of loco-regional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.

2.       Documentation of histologically or cytologically confirmed diagnosis of estrogen-receptor (ER) expression >10% and/or progesterone receptor (PR) expression >10% breast cancer based on local laboratory results. In case ER ≤ 10% and PR >10% the ER and PR expression need to be confirmed in a referral center. Tumor must be HER2-negative as defined by ASCO-CAP guidelines [6]. If HER2 status is unavailable then testing must be performed/repeated prior to randomization.

3.       Previously untreated with any systemic anti-cancer therapy for loco-regional recurrent or metastatic HR+ disease.

4.       Women who are not post-menopausal must use LHRH agonist. Postmenopausal status is defined as:

a. prior bilateral surgical oophorectomy, or

b. spontaneous cessation of regular menses for at least 12 consecutive months without OAC

c. in case of doubt serum estradiol <20 umol/l and follicle stimulating hormone (FSH) levels >15 IU/L at screening

5.       Measurable disease as defined per RECIST v.1.1 (see Appendix 3) or bone-only disease. Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented.

6.       Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.

7.       Adequate organ and marrow function defined as follows:

a. ANC ≥1,000/mm3 (1.0 x 10e9 /L);

b. Platelets ≥50,000/mm3 (50 x 10e9 /L);

c. Estimated creatinine clearance ≥ 30 mL/min as calculated using the method standard for the institution;

d. Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease);

e. AST and/or ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);

8      Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade ≤1, except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion.

9.     Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

10.   Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed.

Informatie voor patiënten over deze studie en de deelnemende ziekenhuizen kunt u vinden op:

https://www.kanker.nl/trials/863-boog-2017-03-sonia-studie-borstkanker