Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone (SONIA) Receptor Positive Advanced Breast Cancer

• Sponsor: Borstkanker Onderzoek Groep (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03425838
• Collaborator: (none)
• Enrollment: 1,050
• Locations: 72
• Arms: 2
• Anticipated Duration (Months): 61.7
• Patients Per Site: 14.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasm Female	Drug: CDK 4/6 inhibitor; Drug: Non-Steroidal Aromatase Inhibitor; Drug: Fulvestrant	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1050 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Nov 9, 2017
• Anticipated Primary Completion Date: Jan 1, 2023
• Anticipated Study Completion Date: Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Strategy A CDK4/6 inhibitor in 1st line Non-steroidal aromatase inhibitor (letrozole or anastrozole, at the discretion of the treating physician) plus CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib, depending on availability and physician's preference) in first line followed by fulvestrant in second line.	Drug: CDK 4/6 inhibitor; Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer; Other Names: palbociclib,Ibrance,ribociclib,Kisqali,abemaciclib,Verzenio ; Drug: Non-Steroidal Aromatase Inhibitor; Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer; Other Names: NSAI, letrozole, Femara®, anastrozole, Arimidex® ; Drug: Fulvestrant; Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer; Other Names: SERD, Faslodex®
Active Comparator: Strategy B CDK4/6 inhibitor in 2nd line Non-steroidal aromatase inhibitor (letrozole or anastrozole, at the discretion of the treating physician) in first line followed by fulvestrant plus CDK4/6 inhibitor in second line (palbociclib, ribociclib or abemaciclib, depending on availability and physician's preference).	Drug: CDK 4/6 inhibitor; Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer; Other Names: palbociclib,Ibrance,ribociclib,Kisqali,abemaciclib,Verzenio ; Drug: Non-Steroidal Aromatase Inhibitor; Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer; Other Names: NSAI, letrozole, Femara®, anastrozole, Arimidex® ; Drug: Fulvestrant; Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer; Other Names: SERD, Faslodex®

Outcome Measures

Primary Outcome Measures

1. PFS2 [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]

   Progression-free survival after two lines of treatment (PFS2)

Secondary Outcome Measures

1. OS [Date of randomization until date of death due to any cause, assessed up to 60 months]

   Overall survival

2. FACT-B questionnaire [Questionnaires will be administered at baseline and thereafter every three months, up to 60 months]

   Quality of Life questionnaire

3. EQ-5D questionnaire [Questionnaires will be administered at baseline and thereafter every three months, up to 60 months]

   Quality of Life questionnaire

4. iMTA RUQ-B questionnaire [Questionnaires will be administered at baseline and thereafter every six months, up to 60 months]

   Quality of Life questionnaire

5. Number of participants with grade 3 or 4 treatment-related neutropenia as assessed by CTCAE v4.0 [Through study completion, assessed up to 60 months]

   Safety assessment will consist of monitoring of all grade 3 and grade 4 neutropenia (absolute neutrophil count/L)

6. Number of participants with grade 3 or 4 treatment-related thrombocytopenia as assessed by CTCAE v4.0 [Through study completion, assessed up to 60 months]

   Safety assessment will consist of monitoring of all grade 3 and grade 4 thrombocytopenia (platelet count/L)

7. Number of participants with grade 3 or 4 treatment-related anemia as assessed by CTCAE v4.0 [Through study completion, assessed up to 60 months]

   Safety assessment will consist of monitoring of all grade 3 and grade 4 anemia (mmol/L)

8. Number of participants with grade 3 or 4 treatment-related elevated liver enzymes (ALAT/ASAT/AF/GGT/bilirubin) as assessed by CTCAE v4.0 [Through study completion, assessed up to 60 months]

   Safety assessment will consist of monitoring of all grade 3 and grade 4 elevated liver enzymes (elevation compared to upper limit of normal)

9. Number of participants with grade 3 or 4 treatment-related other toxicities as defined in CTCAE v4.0 [Through study completion, assessed up to 60 months]

   Safety assessment will consist of monitoring of all grade 3 and grade 4 other toxicities as defined in CTCAE v4.0

10. Cost-effectiveness by means of a decision model (a multistate Markov model or a Discrete Event Simulation model) [At 60 months after entry into the study]

    The cost and outcomes of both arms will be assessed by means of a decision model (a multistate Markov model or a Discrete Event Simulation model). Cost-effectiveness will be determined by comparing costs and effects of both treatment strategies. Quality adjusted life years will be computed by multiplying life-years with the observed utility scores during those life years. The friction cost method will be used for estimating the societal costs of productivity losses. Unit costs for drugs will be derived from www.medicijnkosten.nl or the Z-index. The costs of a hospital day, outpatient visit, and day care treatment, will be based on the Dutch costing manual. Other costs will be collected from NZA tariffs. All costs will be expressed in Euros.

11. ORR [Through study completion, assessed up to 60 months]

    Objective response rate

12. Plasma through levels [Through study completement]

    Plasma through levels of CDK4/6 inhibitor measured in blood samples obtained at cycle 1, day 15 (of 28 days in one cycle) and at cycle 2, day 15 in participants treated with CDK4/6 inhibitors.

13. Pharmacogenomics [On day 15 of cycle 1 (a cycle is 28 days)]

    DNA sequencing in a blood sample obtained at cycle 1, day 15 (of 28 days in one cycle) of treatment with CDK4/6 inhibitor.

14. Liquid biopsies [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]

    Circulating tumor DNA isolated from blood samples collected at 7 timepoints during the study. Mutation level during the study and at disease progression will be compared to base-line mutation level.

15. Tissue microarray [At baseline]

    Tissue microarray on archived FFPE tissue blocks of the tumor

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

1. 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.

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

3. prior bilateral surgical oophorectomy, or

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

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

6. 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.

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

8. Adequate organ and marrow function defined as follows:

9. ANC ≥1,000/mm3 (1.0 x 10e9 /L);

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

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

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

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

14. 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.

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

16. 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:

6. 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);

7. Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort).

8. 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.

9. 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.

10. QTc >480 msec at baseline

11. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.

12. Known hypersensitivity to letrozole or anastrozole, or any of its excipients, or to any palbociclib excipients.

13. 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.

14. Recent or active suicidal ideation or behavior.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Noordwestziekenhuisgroep	Alkmaar		Netherlands
2	ZGT	Almelo		Netherlands
3	Flevoziekenhuis	Almere		Netherlands
4	Meander Medisch Centrum	Amersfoort		Netherlands
5	Ziekenhuis Amstelland	Amstelveen		Netherlands
6	Nki - Avl	Amsterdam		Netherlands	1066 CX
7	VUmc	Amsterdam		Netherlands	1081 HV
8	AMC	Amsterdam		Netherlands
9	BovenIJ Ziekenhuis	Amsterdam		Netherlands
10	OLVG	Amsterdam		Netherlands
11	Gelre ziekenhuizen	Apeldoorn		Netherlands
12	Rijnstate	Arnhem		Netherlands
13	Wilhelmina ziekenhuis	Assen		Netherlands
14	Rode Kruis Ziekenhuis	Beverwijk		Netherlands
15	Alexander Monro Ziekenhuis	Bilthoven		Netherlands
16	Maasziekenhuis Pantein	Boxmeer		Netherlands
17	Amphia	Breda		Netherlands
18	IJsselland	Capelle Aan Den IJssel		Netherlands
19	Reinier de Graaf	Delft		Netherlands
20	Jeroen Bosch Ziekenhuis	Den Bosch		Netherlands
21	Haaglanden Medisch Centrum	Den Haag		Netherlands
22	HaGaziekenhuis	Den Haag		Netherlands
23	Deventer Ziekenhuis	Deventer		Netherlands
24	Van Weel-Bethesda Ziekenhuis	Dirksland		Netherlands
25	Slingeland Ziekenhuis	Doetinchem		Netherlands
26	Albert Schweitzer ziekenhuis	Dordrecht		Netherlands
27	Nij Smellinghe	Drachten		Netherlands
28	Gelderse Vallei	Ede		Netherlands
29	Catharina Ziekenhuis	Eindhoven		Netherlands
30	Maxima Medisch Centrum	Eindhoven		Netherlands
31	Treant Zorggroep	Emmen		Netherlands
32	Medisch Spectrum Twente	Enschede		Netherlands
33	St. Anna Ziekenhuis	Geldrop		Netherlands
34	Admiraal de Ruyter	Goes		Netherlands
35	Rivas Beatrixziekenhuis	Gorinchem		Netherlands
36	Groene Hart Ziekenhuis	Gouda		Netherlands
37	Martini Ziekenhuis	Groningen		Netherlands
38	UMC Groningen	Groningen		Netherlands
39	Ropcke Zweers	Hardenberg		Netherlands
40	Sint Jansdal	Harderwijk		Netherlands
41	Tjongerschans	Heerenveen		Netherlands
42	Elkerliek ziekenhuis	Helmond		Netherlands
43	Tergooi	Hilversum		Netherlands
44	Spaarne Gasthuis	Hoofddorp		Netherlands
45	Dijklander Ziekenhuis	Hoorn		Netherlands
46	MC Leeuwarden	Leeuwarden		Netherlands
47	Alrijne Ziekenhuis	Leiden		Netherlands
48	LUMC	Leiden		Netherlands
49	St. Antonius	Nieuwegein		Netherlands
50	Canisius-Wilhelmina Ziekenhuis	Nijmegen		Netherlands
51	Radboudumc	Nijmegen		Netherlands
52	Laurentius	Roermond		Netherlands
53	Bravis ziekenhuis	Roosendaal		Netherlands
54	Erasmus MC	Rotterdam		Netherlands	3015 CE
55	Franciscus Gasthuis & Vlietland	Rotterdam		Netherlands
56	Ikazia	Rotterdam		Netherlands
57	Maasstad Ziekenhuis	Rotterdam		Netherlands
58	Zuyderland	Sittard		Netherlands
59	Antonius Ziekenhuis	Sneek		Netherlands
60	Spijkenisse Medisch Centrum	Spijkenisse		Netherlands
61	ZorgSaam	Terneuzen		Netherlands
62	Ziekenhuis Rivierenland	Tiel		Netherlands
63	Elisabeth Tweesteden	Tilburg		Netherlands
64	Bernhoven	Uden		Netherlands
65	Diakonessenhuis	Utrecht		Netherlands
66	UMC Utrecht	Utrecht		Netherlands
67	VieCuri	Venlo		Netherlands
68	St. Jans Gasthuis	Weert		Netherlands
69	Streekziekenhuis Koningin Beatrix	Winterswijk		Netherlands
70	Zaans Medisch Centrum	Zaandam		Netherlands
71	Langeland	Zoetermeer		Netherlands
72	Isala	Zwolle		Netherlands

Sponsors and Collaborators

• Borstkanker Onderzoek Groep

Investigators

• Principal Investigator: A. Jager, MD, PhD, Borstkanker Onderzoek Groep
• Study Director: A E van Leeuwen-Stok, PhD, BOOG Study Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Borstkanker Onderzoek Groep
• ClinicalTrials.gov Identifier: NCT03425838
• Other Study ID Numbers: BOOG 2017-03; 2017-002334-23
• First Posted: Feb 8, 2018
• Last Update Posted: Apr 4, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Borstkanker Onderzoek Groep: CDK 4/6 inhibitor
• Additional relevant MeSH terms: Breast Neoplasms; Letrozole; Fulvestrant; Palbociclib; Anastrozole; Aromatase Inhibitors

Study Results

No Results Posted as of Apr 4, 2022