Clinical Trials /

HR+/HER2- Advanced Breast Cancer and Endocrine Resistance

NCT03322215

Description:

This is a randomized, 2-arm, open-label, multicenter, international phase II trial. A total of 196 patients will be included. The study will include patients with metastatic Hormone Receptor positive / Human Epidermal Growth Factor Receptor (HER2) negative breast cancer with progressive disease after endocrine treatment. Patients will be randomized (1:1) between two treatment arms: A. palbociclib + fulvestrant and b. capecitabine.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: HR+/HER2- Advanced Breast Cancer and Endocrine Resistance
  • Official Title: A Phase 2, International, Multicenter, Open-labeled, Randomized Trial of PAlbociclib and Fulvestrant vs. Standard Oral Capecitabine In Patients With Hormone Receptor (HR)+ / HER2- Advanced Breast Cancer and Documented Endocrine Resistance

Clinical Trial IDs

  • ORG STUDY ID: 2016-002893-11
  • NCT ID: NCT03322215

Conditions

  • Breast Cancer Metastatic

Interventions

DrugSynonymsArms
PalbociclibIbrancePalbociclib and fulvestrant
FulvestrantFaslodexPalbociclib and fulvestrant
CapecitabineXelodaCapecitabine

Purpose

This is a randomized, 2-arm, open-label, multicenter, international phase II trial. A total of 196 patients will be included. The study will include patients with metastatic Hormone Receptor positive / Human Epidermal Growth Factor Receptor (HER2) negative breast cancer with progressive disease after endocrine treatment. Patients will be randomized (1:1) between two treatment arms: A. palbociclib + fulvestrant and b. capecitabine.

Trial Arms

NameTypeDescriptionInterventions
Palbociclib and fulvestrantExperimentalCombination of palbociclib and fulvestrant Palbociclib: 125 mg capsule administered orally once daily for 21 consecutive days followed by 7 days off treatment. Dose modification is recommended based on individual safety and tolerability. Fulvestrant: 500 mg administered intramuscularly on days 1 and 15 of cycle 1, and then on day 1 of each subsequent 28-day cycle.
  • Palbociclib
  • Fulvestrant
CapecitabineActive Comparator1,000 mg/m2 tablet administered orally twice daily for 2 weeks followed by one week of rest. Depending on adverse reactions, both dose escalation and dose reductions will be performed.
  • Capecitabine

Eligibility Criteria

        Inclusion Criteria:

          1. Women 18 years or older.

          2. Postmenopausal, defined by at least one of the following criteria:

               1. Prior bilateral oophorectomy

               2. Age ≥60

               3. Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
                  tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the
                  postmenopausal range according to the local laboratory reference. Note: For women
                  with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are
                  needed to ensure postmenopausal status. OR Pre/perimenopausal if treated with
                  goserelin that was initiated at least 4 weeks prior to randomization.

          3. Locally advanced or metastatic breast cancer deemed not amenable to curative surgery
             or curative radiation therapy.

          4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

          5. Known estrogen-receptor positive and/or progesterone receptor positive breast cancer
             reported by local laboratory.

          6. Known HER2-negative breast cancer defined as a negative in situ hybridization test or
             an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH,
             CISH, or SISH) test is required by local laboratory testing.

          7. Documented resistance to endocrine therapy (tamoxifen or aromatase inhibitors) defined
             as:

               1. Recurrence while on or within 12 months after the end of adjuvant endocrine
                  treatment OR

               2. Progression while on or within 1 month after the end of endocrine treatment for
                  advanced disease

          8. Previous chemotherapy for breast cancer including an anthracycline and a taxane (only
             one line for metastatic disease) is permitted.

          9. Radiological or other objective evidence (eg. new skin lesions or new lymph node
             lesions) of recurrence during or after the most recent systemic therapy for recurrent
             / metastatic disease prior to randomization.

         10. At least one tumor lesion accessible for biopsy that is a non-bone lesion or a
             predominantly lytic bone lesion, and that measures at least 10 mm in largest diameter.
             This lesion must not have been treated previously with irradiation (although the area
             may have been irradiated before the occurrence of the lesion).

         11. Patient is interested to participate in the trial, including the obligatory biopsies
             at a metastatic site/site before the start of study treatment.

         12. Clinically and/or radiographically documented measurable disease according to RECIST
             v1.1 criteria or bone-only disease with at least one predominantly lytic or mixed bone
             lesion. For measurable disease, at least one site of disease must have largest tumor
             diameter of at least:

               1. 10 mm if measured by CT-scan, ultrasound, or physical exam

               2. 20 mm if measured by Chest X-ray

               3. 15 mm if suspiciously enlarged lymph node (short axis) see Eisenhauer et al. for
                  more details All radiology studies must be performed within 28 days prior to
                  registration (35 days if negative).

         13. Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7
             days prior to enrollment:

               1. Hematology: Absolute granulocytes > 1.5 x 109/L, Platelets > 100 x 109/L

               2. Biochemistry: Bilirubin ≤ 1.5 x upper limit of normal (ULN), Serum creatinine ≤
                  1.5 x ULN.

         14. 14. APTT and INR ≤ 1.5 x ULN or institution accepted values for biopsy within 7 days
             prior to enrollment.

         15. Signed written informed consent provided by the patient.

        Exclusion Criteria:

          1. Previous treatment with a CDK4/6 inhibitor, mTOR or PI3K inhibitor, fulvestrant or
             capecitabine. Short-term (<28 days) exposure to mTOR or PI3K inhibitor in the
             (neo)adjuvant setting is allowed.

          2. More than one prior chemotherapy lines for metastatic breast cancer. Previous
             (neo)adjuvant chemotherapy or for radically treated local or regional relapse is
             allowed in addition to one prior chemotherapy line for metastatic breast cancer Note:
             A chemotherapy line in advanced disease is an anticancer regimen that contains at
             least one chemotherapy agent and is given for 21 days or longer. If a cytotoxic
             chemotherapy regimen was discontinued for a reason other than disease progression and
             the decision for its discontinuation was taken within 21 days after starting it, then
             this regimen does not count as a "prior line of chemotherapy". Chemotherapy regimens
             composed of more than one drug are considered as one line of therapy.

          3. No measurable lesions amenable to biopsy (e.g. pleural effusion, ascites, skin rash,
             sclerotic bone etc).

          4. CNS metastases unless asymptomatic and adequately controlled with surgery or
             radiotherapy. Stable CNS disease is defined as CNS metastases or cord compression that
             have been definitively treated and the patient is clinically stable off
             anticonvulsants and steroids for at least 4 weeks before randomization.

          5. Leptomeningeal carcinomatosis

          6. Advanced, symptomatic visceral spread (visceral crisis) with risk of life-threatening
             complications in the short term.

          7. Concurrent malignancy of any site, except adequately controlled limited basal cell
             carcinoma or squamous-cell carcinoma of the skin, in situ melanoma or carcinoma in
             situ of the cervix.

          8. Active cardiac disease or a history of cardiac dysfunction including any of the
             following:

               1. History of angina pectoris, symptomatic pericarditis, or myocardial infarction
                  within 12 months prior to study entry

               2. History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV)

               3. Documented cardiomyopathy

               4. QTc > 480 msec as measured by Bazett's formula, family or personal history of
                  long or short QT syndrome, Brugada syndrome or known history of QTc prolongation
                  or Torsade de Pointes.

               5. Uncontrolled hypertension.

          9. Patients being treated with drugs recognized as strong inhibitors or inducers of the
             isoenzyme CYP3A (including, but not limited, to - see table 6 - Rifabutin, Rifampicin,
             Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin)
             continuously for at least 7 days during any time period in the last 2 weeks prior to
             randomization.

         10. Subjects with known dihydropyrimidine dehydrogenase (DHPD) deficiency or previous
             severe reactions to a fluoropyrimidine.

         11. Known abnormalities in coagulation such as bleeding diathesis or ongoing treatment
             with anticoagulants that preclude intramuscular administration of drugs.

         12. Ongoing pregnancy or lactation.

         13. Any psychological, familial, sociological or geographical condition potentially
             hampering compliance with the study protocol and follow-up schedule; those conditions
             should be discussed with the patient before registration in the trial.

         14. A previous metastatic tumor biopsy reported to be negative for both estrogen receptor
             and progesterone receptor (i.e. <1% for both), or positive for HER2 status (amplified
             ERBB2).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS), as assessed locally by the investigator.
Time Frame:Time from the date of randomization to the date of progression, assessed up to 5 years.
Safety Issue:
Description:Time to progression will be measured according to the RECIST criteria (version 1.1). Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression.

Secondary Outcome Measures

Measure:Health related quality of life score EuroQol (EQ-5D)
Time Frame:Baseline to progression up to 2 years
Safety Issue:
Description:Change from baseline to Health related quality of life score EuroQol (EQ-5D)
Measure:Health related quality of life score EORTC QLQ-C30
Time Frame:Baseline to progression up to 2 years
Safety Issue:
Description:European Organisation for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ-C30).
Measure:Health related quality of life score EORTC QLQ-BR23
Time Frame:Baseline to progression up to 2 years
Safety Issue:
Description:European Organisation for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23).
Measure:Correlation of efficacy measures with tumor Biomarkers
Time Frame:Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years..
Safety Issue:
Description:PgR IHC status (10% cut-off), will be correlated with PFS
Measure:Correlation of efficacy measures with tumor Biomarkers
Time Frame:Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years.
Safety Issue:
Description:Ki67 IHC status, will be correlated with PFS
Measure:Correlation of efficacy measures with tumor Biomarkers
Time Frame:Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years.
Safety Issue:
Description:ESR1 DNA somatic mutation status, will be correlated with PFS
Measure:Correlation of efficacy measures with tumor Biomarkers
Time Frame:Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years.
Safety Issue:
Description:Somatic mutations in cancer genes identified by sequencing, will be correlated with PFS
Measure:Correlation of efficacy measures with tumor Biomarkers
Time Frame:Correlative analyses will be performed after the end of the trial. PFS is defined as time from the date of randomization to the date of progression assessed up to 5 years.
Safety Issue:
Description:SET index, will be correlated with PFS
Measure:Overall survival (OS)
Time Frame:Time from randomization to death from any cause, assessed up to 5 years.
Safety Issue:
Description:Overall survival from time of randomization to death from any cause.
Measure:1-year survival
Time Frame:Time from randomization to death from any cause, assessed up to 5 years.
Safety Issue:
Description:1-year survival rate from time of randomization to death from any cause.
Measure:2-year survival
Time Frame:Time from randomization to death from any cause, assessed up to 5 years.
Safety Issue:
Description:2-year survival rate from time of randomization to death from any cause.
Measure:Objective response
Time Frame:From randomization until end of treatment, assessed up to 5 years.
Safety Issue:
Description:Objective tumor response will be measured according to the RECIST criteria (version 1.1). Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression.
Measure:Duration of response
Time Frame:From randomization until end of treatment, up to 5 years.
Safety Issue:
Description:Response duration will be measured from the time measurement criteria for complete response (CR)/ partial response (PR) (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented.
Measure:Clinical Benefit Rate
Time Frame:From randomization until end of treatment, up to 5 years.
Safety Issue:
Description:Clinical Benefit Rate is defined as CR+PR+stable disease (SD) for > 24 weeks
Measure:Frequency of adverse events (AE)
Time Frame:From randomization until 28 days after the last dose of study medication, assessed up to 5 years.
Safety Issue:
Description:Adverse events will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Theodoros Foukakis

Trial Keywords

  • palbociclib
  • fulvestrant
  • capecitabine

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