Clinical Trials /

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

NCT03425838

Description:

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.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone 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

Clinical Trial IDs

  • ORG STUDY ID: BOOG 2017-03
  • SECONDARY ID: 2017-002334-23
  • NCT ID: NCT03425838

Conditions

  • Breast Neoplasm Female

Interventions

DrugSynonymsArms
CDK 4/6 inhibitorpalbociclib,Ibrance,ribociclib,Kisqali,abemaciclib,VerzenioStrategy A CDK4/6 inhibitor in 1st line
Non-Steroidal Aromatase InhibitorNSAI, letrozole, Femara®, anastrozole, Arimidex®Strategy A CDK4/6 inhibitor in 1st line
FulvestrantSERD, Faslodex®Strategy A CDK4/6 inhibitor in 1st line

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Strategy A CDK4/6 inhibitor in 1st lineActive ComparatorNon-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.
  • CDK 4/6 inhibitor
  • Non-Steroidal Aromatase Inhibitor
  • Fulvestrant
Strategy B CDK4/6 inhibitor in 2nd lineActive ComparatorNon-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).
  • CDK 4/6 inhibitor
  • Non-Steroidal Aromatase Inhibitor
  • Fulvestrant

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 21 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/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.

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Progression-free survival after two lines of treatment (PFS2)

Secondary Outcome Measures

Measure:OS
Time Frame:Date of randomization until date of death due to any cause, assessed up to 60 months
Safety Issue:
Description:Overall survival
Measure:FACT-B questionnaire
Time Frame:Questionnaires will be administered at baseline and thereafter every three months, up to 60 months
Safety Issue:
Description:Quality of Life questionnaire
Measure:EQ-5D questionnaire
Time Frame:Questionnaires will be administered at baseline and thereafter every three months, up to 60 months
Safety Issue:
Description:Quality of Life questionnaire
Measure:iMTA RUQ-B questionnaire
Time Frame:Questionnaires will be administered at baseline and thereafter every six months, up to 60 months
Safety Issue:
Description:Quality of Life questionnaire
Measure: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 Issue:
Description:Safety assessment will consist of monitoring of all grade 3 and grade 4 neutropenia (absolute neutrophil count/L)
Measure: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 Issue:
Description:Safety assessment will consist of monitoring of all grade 3 and grade 4 thrombocytopenia (platelet count/L)
Measure: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 Issue:
Description:Safety assessment will consist of monitoring of all grade 3 and grade 4 anemia (mmol/L)
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
Time Frame:Through study completion, assessed up to 60 months
Safety Issue:
Description:Safety assessment will consist of monitoring of all grade 3 and grade 4 elevated liver enzymes (elevation compared to upper limit of normal)
Measure: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 Issue:
Description:Safety assessment will consist of monitoring of all grade 3 and grade 4 other toxicities as defined in CTCAE v4.0
Measure: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
Safety Issue:
Description: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.
Measure:ORR
Time Frame:Through study completion, assessed up to 60 months
Safety Issue:
Description:Objective response rate
Measure:Plasma through levels
Time Frame:Through study completement
Safety Issue:
Description: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.
Measure:Pharmacogenomics
Time Frame:On day 15 of cycle 1 (a cycle is 28 days)
Safety Issue:
Description:DNA sequencing in a blood sample obtained at cycle 1, day 15 (of 28 days in one cycle) of treatment with CDK4/6 inhibitor.
Measure: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
Safety Issue:
Description: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.
Measure:Tissue microarray
Time Frame:At baseline
Safety Issue:
Description:Tissue microarray on archived FFPE tissue blocks of the tumor

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Borstkanker Onderzoek Groep

Trial Keywords

  • CDK 4/6 inhibitor

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