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

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ClinicalTrials.gov Identifier: NCT03425838
Recruitment Status : Recruiting
First Posted : February 8, 2018
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
Borstkanker Onderzoek Groep

Tracking Information
First Submitted Date  ICMJE June 15, 2017
First Posted Date  ICMJE February 8, 2018
Last Update Posted Date January 18, 2020
Actual Study Start Date  ICMJE November 9, 2017
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 1, 2018)
PFS2 [ Time Frame: 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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 21, 2018)
  • OS [ Time Frame: Date of randomization until date of death due to any cause, assessed up to 60 months ]
    Overall survival
  • FACT-B questionnaire [ Time Frame: Questionnaires will be administered at baseline and thereafter every three months, up to 60 months ]
    Quality of Life questionnaire
  • EQ-5D questionnaire [ Time Frame: Questionnaires will be administered at baseline and thereafter every three months, up to 60 months ]
    Quality of Life questionnaire
  • iMTA RUQ-B questionnaire [ Time Frame: Questionnaires will be administered at baseline and thereafter every six months, up to 60 months ]
    Quality of Life questionnaire
  • Number of participants with grade 3 or 4 treatment-related neutropenia as assessed by CTCAE v4.0 [ Time Frame: 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)
  • Number of participants with grade 3 or 4 treatment-related thrombocytopenia as assessed by CTCAE v4.0 [ Time Frame: 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)
  • Number of participants with grade 3 or 4 treatment-related anemia as assessed by CTCAE v4.0 [ Time Frame: Through study completion, assessed up to 60 months ]
    Safety assessment will consist of monitoring of all grade 3 and grade 4 anemia (mmol/L)
  • Number of participants with grade 3 or 4 treatment-related elevated liver enzymes (ALAT/ASAT/AF/GGT/bilirubin) as assessed by CTCAE v4.0 [ Time Frame: 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)
  • Number of participants with grade 3 or 4 treatment-related other toxicities as defined in CTCAE v4.0 [ Time Frame: 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
  • Cost-effectiveness by means of a decision model (a multistate Markov model or a Discrete Event Simulation model) [ Time Frame: 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.
  • ORR [ Time Frame: Through study completion, assessed up to 60 months ]
    Objective response rate
  • Plasma through levels [ Time Frame: 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.
  • Pharmacogenomics [ Time Frame: 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.
  • Liquid biopsies [ Time Frame: 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.
  • Tissue microarray [ Time Frame: At baseline ]
    Tissue microarray on archived FFPE tissue blocks of the tumor
Original Secondary Outcome Measures  ICMJE
 (submitted: February 1, 2018)
  • OS [ Time Frame: Date of randomization to date of death due to any cause, assessed up to 60 months ]
    Overall survival
  • FACT-B questionnaire [ Time Frame: Questionnaires will be administered at baseline and thereafter every three months, up to 60 months ]
    Quality of Life questionnaire
  • EQ-5D questionnaire [ Time Frame: Questionnaires will be administered at baseline and thereafter every three months, up to 60 months ]
    Quality of Life questionnaire
  • iMTA RUQ-B questionnaire [ Time Frame: Questionnaires will be administered at baseline and thereafter every six months, up to 60 months ]
    Quality of Life questionnaire
  • Number of participants with grade 3 or 4 treatment-related neutropenia as assessed by CTCAE v4.0 [ Time Frame: 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)
  • Number of participants with grade 3 or 4 treatment-related thrombocytopenia as assessed by CTCAE v4.0 [ Time Frame: 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)
  • Number of participants with grade 3 or 4 treatment-related anemia as assessed by CTCAE v4.0 [ Time Frame: Through study completion, assessed up to 60 months ]
    Safety assessment will consist of monitoring of all grade 3 and grade 4 anemia (mmol/L)
  • Number of participants with grade 3 or 4 treatment-related elevated liver enzymes (ALAT/ASAT/AF/GGT/bilirubin) as assessed by CTCAE v4.0 [ Time Frame: 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)
  • Number of participants with grade 3 or 4 treatment-related other toxicities as defined in CTCAE v4.0 [ Time Frame: 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
  • Cost-effectiveness by means of a decision model (a multistate Markov model or a Discrete Event Simulation model) [ Time Frame: 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.
  • ORR [ Time Frame: Through study completion, assessed up to 60 months ]
    Objective response rate
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone (SONIA) Receptor Positive Advanced Breast Cancer
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Neoplasm Female
Intervention  ICMJE
  • 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 Name: 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 Name: 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 Name: SERD, Faslodex®
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: CDK 4/6 inhibitor
    • Drug: Non-Steroidal Aromatase Inhibitor
    • Drug: Fulvestrant
  • 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).
    Interventions:
    • Drug: CDK 4/6 inhibitor
    • Drug: Non-Steroidal Aromatase Inhibitor
    • Drug: Fulvestrant
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 1, 2018)
1050
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2022
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: A. Jager, MD, PhD +31-10-7041733 a.jager@erasmusmc.nl
Contact: A E van Leeuwen-Stok, PhD +31882346730 e.vanleeuwen@boogstudycenter.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03425838
Other Study ID Numbers  ICMJE BOOG 2017-03
2017-002334-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Individual participant data will not be shared with other researchers.
Responsible Party Borstkanker Onderzoek Groep
Study Sponsor  ICMJE Borstkanker Onderzoek Groep
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: A. Jager, MD, PhD Borstkanker Onderzoek Groep
Study Director: A E van Leeuwen-Stok, PhD BOOG Study Center
PRS Account Borstkanker Onderzoek Groep
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP