Clinical trial NCT03425838: Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone (SONIA) Receptor Positive Advanced Breast Cancer
Official title: BOOG 2017-03: Endocrine Therapy Plus CDK 4/6 Inhibition in First- or Second-line for Hormone Receptor Positive Advanced Breast Cancer - the SONIA Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Neoplasm Female
Keywords: CDK 4/6 inhibitor
Lead sponsor: Borstkanker Onderzoek Groep
Sponsor class: NETWORK
First posted: 2018-02-08
Enrollment: 1050
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Given the uncertain benefit in efficacy of adding CDK 4/6 to first rather than second line endocrine treatment, the aim of this project is to evaluate whether the sequence of an aromatase inhibitor plus CDK 4/6 in first line followed by fulvestrant in second line is superior to the sequence of an aromatase inhibitor in first line followed by fulvestrant plus CDK4/6 in second line.

Detailed description: Combining cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors with endocrine therapies in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer has shown to result in substantial improvements in progression-free survival. There is however no evidence that this combination strategy leads to an improved overall survival. Furthermore, no specific subgroups that will or will not benefit from the combination of drugs have been identified yet. This means the optimal strategy for deploying CDK 4/6 inhibitors in clinical practice is not yet known. Since CDK 4/6 inhibitors are costly and can have toxic effects, it is important to determine the optimal treatment strategy to avoid both over- and undertreatment.

The SONIA-trial is an investigator-initiated, multicenter, randomized phase III study. The primary objective of this study is to evaluate if treatment with a non-steroidal aromatase inhibitor combined with CDK 4/6 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). The primary end point is progression-free survival after two lines (PFS2), secondary end points include overall survival, quality of life, safety and biomarker analyses.

Eligibility criteria: Inclusion Criteria:

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.
3. Previously untreated with any systemic anti-cancer therapy for loco-regional recurrent or metastatic HR+ disease, with the exception of recently started (within 28 days of randomization) endocrine therapy.
4. Women who are not post-menopausal must use LHRH agonist. Postmenopausal status is defined as:

   1. prior bilateral surgical oophorectomy, or
   2. spontaneous cessation of regular menses for at least 12 consecutive months without OAC
   3. in case of doubt serum estradiol \<20 umol/l and follicle stimulating hormone (FSH) levels \>15 IU/L at screening
5. Measurable or evaluable 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:

   1. ANC ≥1,000/mm3 (1.0 x 10e9 /L);
   2. Platelets ≥50,000/mm3 (50 x 10e9 /L);
   3. Estimated creatinine clearance ≥ 30 mL/min as calculated using the method standard for the institution;
   4. Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert's disease);
   5. AST and 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.

Exclusion Criteria:

1. Patients with advanced, symptomatic, visceral spread, who are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% liver involvement).
2. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable without the use of steroids for at least 4 weeks before randomization
3. Prior neoadjuvant or adjuvant treatment with an aromatase inhibitor (i.e., anastrozole, letrozole or exemestane) with disease recurrence while on or within 12 months of treatment.
4. Prior treatment with any CDK4/6 inhibitor.
5. Patients treated within the last 7 days prior to randomization with:

   1. Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice);
   2. Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort).
6. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before randomization. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible independent of when it was received.
7. Diagnosis of any other malignancy prior to randomization, except those that are not believed to influence the patient's prognosis and do not require any further treatment. This includes, but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix.
8. QTc \>480 msec at baseline
9. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
10. Known hypersensitivity to letrozole or anastrozole, or any of its excipients, or to any palbociclib excipients.
11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
12. Recent or active suicidal ideation or behavior.

Primary outcomes:
measure: PFS2
timeFrame: Until objective disease progression, symptomatic deterioration, or unacceptable toxicity on second line treatment, death, strategy violation, or withdrawal of consent, whichever occurs first, assessed up to 60 months
Secondary outcomes:
measure: OS
timeFrame: Date of randomization until date of death due to any cause, assessed up to 60 months
measure: FACT-B questionnaire
timeFrame: Questionnaires will be administered at baseline and thereafter every three months, up to 60 months
measure: EQ-5D questionnaire
timeFrame: Questionnaires will be administered at baseline and thereafter every three months, up to 60 months
measure: iMTA RUQ-B questionnaire
timeFrame: Questionnaires will be administered at baseline and thereafter every six months, up to 60 months
measure: Number of participants with grade 3 or 4 treatment-related neutropenia as assessed by CTCAE v4.0
timeFrame: Through study completion, assessed up to 60 months
measure: Number of participants with grade 3 or 4 treatment-related thrombocytopenia as assessed by CTCAE v4.0
timeFrame: Through study completion, assessed up to 60 months
measure: Number of participants with grade 3 or 4 treatment-related anemia as assessed by CTCAE v4.0
timeFrame: Through study completion, assessed up to 60 months
measure: Number of participants with grade 3 or 4 treatment-related elevated liver enzymes (ALAT/ASAT/AF/GGT/bilirubin) as assessed by CTCAE v4.0
timeFrame: Through study completion, assessed up to 60 months
measure: Number of participants with grade 3 or 4 treatment-related other toxicities as defined in CTCAE v4.0
timeFrame: Through study completion, assessed up to 60 months
measure: Cost-effectiveness by means of a decision model (a multistate Markov model or a Discrete Event Simulation model)
timeFrame: At 60 months after entry into the study
measure: ORR
timeFrame: Through study completion, assessed up to 60 months
measure: Plasma through levels
timeFrame: Through study completement
measure: Pharmacogenomics
timeFrame: On day 15 of cycle 1 (a cycle is 28 days)
measure: Liquid biopsies
timeFrame: At baseline of first line, at cycle 1 day 15 (a cycle is 28 days), at cycle 4 day 1, at baseline of second line, at cycle 1 day 15 (a cycle is 28 days), at cycle 4 day 1 and at disease progression
measure: Tissue microarray
timeFrame: At baseline
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: Noordwestziekenhuisgroep
city: Almelo
country: Netherlands
facility: ZGT
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
city: Amstelveen
country: Netherlands
facility: Ziekenhuis Amstelland
city: Amsterdam
country: Netherlands
facility: Nki - Avl
city: Amsterdam
country: Netherlands
facility: VUmc
city: Amsterdam
country: Netherlands
facility: AMC
city: Amsterdam
country: Netherlands
facility: BovenIJ Ziekenhuis
city: Amsterdam
country: Netherlands
facility: OLVG
city: Apeldoorn
country: Netherlands
facility: Gelre ziekenhuizen
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Assen
country: Netherlands
facility: Wilhelmina ziekenhuis
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Bilthoven
country: Netherlands
facility: Alexander Monro Ziekenhuis
city: Boxmeer
country: Netherlands
facility: Maasziekenhuis Pantein
city: Breda
country: Netherlands
facility: Amphia
city: Capelle Aan Den IJssel
country: Netherlands
facility: IJsselland
city: Delft
country: Netherlands
facility: Reinier de Graaf
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Den Haag
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Den Haag
country: Netherlands
facility: HaGaziekenhuis
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Dirksland
country: Netherlands
facility: Van Weel-Bethesda Ziekenhuis
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer ziekenhuis
city: Drachten
country: Netherlands
facility: Nij Smellinghe
city: Ede
country: Netherlands
facility: Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Emmen
country: Netherlands
facility: Treant Zorggroep
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Geldrop
country: Netherlands
facility: St. Anna Ziekenhuis
city: Goes
country: Netherlands
facility: Admiraal de Ruyter
city: Gorinchem
country: Netherlands
facility: Rivas Beatrixziekenhuis
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Hardenberg
country: Netherlands
facility: Ropcke Zweers
city: Harderwijk
country: Netherlands
facility: Sint Jansdal
city: Heerenveen
country: Netherlands
facility: Tjongerschans
city: Helmond
country: Netherlands
facility: Elkerliek ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Hoorn
country: Netherlands
facility: Dijklander Ziekenhuis
city: Leeuwarden
country: Netherlands
facility: MC Leeuwarden
city: Leiden
country: Netherlands
facility: Alrijne Ziekenhuis
city: Leiden
country: Netherlands
facility: LUMC
city: Nieuwegein
country: Netherlands
facility: St. Antonius
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Roermond
country: Netherlands
facility: Laurentius
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis & Vlietland
city: Rotterdam
country: Netherlands
facility: Ikazia
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
city: Sittard
country: Netherlands
facility: Zuyderland
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
city: Spijkenisse
country: Netherlands
facility: Spijkenisse Medisch Centrum
city: Terneuzen
country: Netherlands
facility: ZorgSaam
city: Tiel
country: Netherlands
facility: Ziekenhuis Rivierenland
city: Tilburg
country: Netherlands
facility: Elisabeth Tweesteden
city: Uden
country: Netherlands
facility: Bernhoven
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Venlo
country: Netherlands
facility: VieCuri
city: Weert
country: Netherlands
facility: St. Jans Gasthuis
city: Winterswijk
country: Netherlands
facility: Streekziekenhuis Koningin Beatrix
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
city: Zoetermeer
country: Netherlands
facility: Langeland
city: Zwolle
country: Netherlands
facility: Isala
Study officials:
affiliation: Borstkanker Onderzoek Groep
name: A. Jager, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: BOOG Study Center
name: A E van Leeuwen-Stok, PhD
role: STUDY_DIRECTOR
References:
citation: van Ommen-Nijhof A, Konings IR, van Zeijl CJJ, Uyl-de Groot CA, van der Noort V, Jager A, Sonke GS; SONIA study steering committee. Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer - the SONIA study: study protocol for a randomized controlled trial. BMC Cancer. 2018 Nov 20;18(1):1146. doi: 10.1186/s12885-018-4978-1.